Sharon Worcester

BARCELONA – Nivolumab was associated with improved overall survival and a favorable safety profile, compared with chemotherapy, in patients with previously treated advanced esophageal squamous cell carcinoma (ESCC) in the open-label phase 3 ATTRACTION-3 study.

The overall survival (OS) benefit was observed regardless of tumor programmed death-ligand 1 (PD-L1) expression, Byoung Chul Cho, MD, reported at the European Society for Medical Oncology Congress.

The findings were reported online simultaneously in The Lancet Oncology.

Median OS at a minimum follow-up of 17.6 months was 10.9 vs. 8.4 months in 210 patients randomized to receive treatment with the PD-1 inhibitor nivolumab and 209 who received chemotherapy, respectively (hazard ratio, 0.77), said Dr. Cho of Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.

“Notably, there was a 13% and 10% improvement in overall survival rates at 12 months (47% vs. 34%) and 18 months (31% vs. 21%), respectively,” he said, also noting that the HRs for death favored nivolumab vs. chemotherapy across multiple prespecified subgroups, including those based on tumor PD-L1 expression (HRs, 0.69 and 0.84 for PD-L1 of 1% or greater and less than 1%, respectively).

No meaningful difference was seen in progression-free survival between the nivolumab and chemotherapy groups (12% vs. 7%; HR, 1.08), or in objective response rates (19% vs. 22%), he said.

“However, responses were substantially more durable with nivolumab, compared to chemotherapy; duration of response was 6.9 months with nivolumab vs. 3.9 months in the chemotherapy arm,” he said. “Notably, 21% of patients in the nivolumab arm were still in response, compared to only 6% in the chemotherapy arm.”

Patients enrolled in the open label study had unresectable advanced or recurrent ESCC refractory or intolerant to one prior fluoropyrimidine/platinum-based therapy. They were randomized 1:1 to receive 240 mg of nivolumab every 2 weeks or investigators’ choice of paclitaxel or docetaxel.

Fewer treatment-related adverse events (TRAEs) were reported with nivolumab, Dr. Cho said.

Any grade TRAEs occurred in 66% vs. 95% of patients in the groups, respectively, and grade 3-4 TRAEs occurred in 18% vs. 63%. The majority of select TRAEs – defined as those with potential immunologic etiology, including endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin effects – were grade 1 or 2, and the only difference between the nivolumab and chemotherapy groups with respect to those was in endocrine effects, which affected 11% vs. less than 1% of patients, respectively.

Grade 3/4 select TRAEs occurred in less than 2% of patients, Dr. Cho noted.

An exploratory analysis further showed significant overall improvement in health-related quality of life with nivolumab through week 42 on treatment, he added.

The findings are of note, because metastatic esophageal cancer has a 5-year relative survival rate of less than 8%, and ESCC accounts for about 90% of cases worldwide, he said, adding that current second-line chemotherapy options for ESCC offer poor long-term survival and are associated with toxicity.

Nivolumab, which showed promising antitumor activity and manageable toxicity for advanced ESCC in patients who were refractory to or intolerant of standard chemotherapies in the phase 2 ATTRACTION-1 study, is the first immune checkpoint inhibitor to demonstrate a statistically significant, clinically meaningful improvement in OS vs. chemotherapy in this setting, he said.

The findings of this final analysis of ATTRACTION-3, which shows a 23% reduction in the risk of death, a 2.5-month improvement in median OS, benefit across PD-L1 subgroups, and a favorable safety profile, suggest that nivolumab represents a new standard second-line treatment option for patients with advanced ESCC, he concluded.

ATTRACTION-3 was funded by Ono Pharmaceutical Co., in collaboration with Bristol-Myers Squibb. Dr. Cho reported relationships with Bristol-Myers Squibb, Ono Pharmaceutical, and others. He also reported stock ownership and/or patents with TheraCanVac and Champions Oncology.

SOURCE: Cho B et al. ESMO 2019, Abstract LBA11.

BARCELONA – Nivolumab was associated with improved overall survival and a favorable safety profile, compared with chemotherapy, in patients with previously treated advanced esophageal squamous cell carcinoma (ESCC) in the open-label phase 3 ATTRACTION-3 study.

The overall survival (OS) benefit was observed regardless of tumor programmed death-ligand 1 (PD-L1) expression, Byoung Chul Cho, MD, reported at the European Society for Medical Oncology Congress.

The findings were reported online simultaneously in The Lancet Oncology.

Median OS at a minimum follow-up of 17.6 months was 10.9 vs. 8.4 months in 210 patients randomized to receive treatment with the PD-1 inhibitor nivolumab and 209 who received chemotherapy, respectively (hazard ratio, 0.77), said Dr. Cho of Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.

“Notably, there was a 13% and 10% improvement in overall survival rates at 12 months (47% vs. 34%) and 18 months (31% vs. 21%), respectively,” he said, also noting that the HRs for death favored nivolumab vs. chemotherapy across multiple prespecified subgroups, including those based on tumor PD-L1 expression (HRs, 0.69 and 0.84 for PD-L1 of 1% or greater and less than 1%, respectively).

No meaningful difference was seen in progression-free survival between the nivolumab and chemotherapy groups (12% vs. 7%; HR, 1.08), or in objective response rates (19% vs. 22%), he said.

“However, responses were substantially more durable with nivolumab, compared to chemotherapy; duration of response was 6.9 months with nivolumab vs. 3.9 months in the chemotherapy arm,” he said. “Notably, 21% of patients in the nivolumab arm were still in response, compared to only 6% in the chemotherapy arm.”

Patients enrolled in the open label study had unresectable advanced or recurrent ESCC refractory or intolerant to one prior fluoropyrimidine/platinum-based therapy. They were randomized 1:1 to receive 240 mg of nivolumab every 2 weeks or investigators’ choice of paclitaxel or docetaxel.

Fewer treatment-related adverse events (TRAEs) were reported with nivolumab, Dr. Cho said.

Any grade TRAEs occurred in 66% vs. 95% of patients in the groups, respectively, and grade 3-4 TRAEs occurred in 18% vs. 63%. The majority of select TRAEs – defined as those with potential immunologic etiology, including endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin effects – were grade 1 or 2, and the only difference between the nivolumab and chemotherapy groups with respect to those was in endocrine effects, which affected 11% vs. less than 1% of patients, respectively.

Grade 3/4 select TRAEs occurred in less than 2% of patients, Dr. Cho noted.

An exploratory analysis further showed significant overall improvement in health-related quality of life with nivolumab through week 42 on treatment, he added.

The findings are of note, because metastatic esophageal cancer has a 5-year relative survival rate of less than 8%, and ESCC accounts for about 90% of cases worldwide, he said, adding that current second-line chemotherapy options for ESCC offer poor long-term survival and are associated with toxicity.

Nivolumab, which showed promising antitumor activity and manageable toxicity for advanced ESCC in patients who were refractory to or intolerant of standard chemotherapies in the phase 2 ATTRACTION-1 study, is the first immune checkpoint inhibitor to demonstrate a statistically significant, clinically meaningful improvement in OS vs. chemotherapy in this setting, he said.

The findings of this final analysis of ATTRACTION-3, which shows a 23% reduction in the risk of death, a 2.5-month improvement in median OS, benefit across PD-L1 subgroups, and a favorable safety profile, suggest that nivolumab represents a new standard second-line treatment option for patients with advanced ESCC, he concluded.

ATTRACTION-3 was funded by Ono Pharmaceutical Co., in collaboration with Bristol-Myers Squibb. Dr. Cho reported relationships with Bristol-Myers Squibb, Ono Pharmaceutical, and others. He also reported stock ownership and/or patents with TheraCanVac and Champions Oncology.

SOURCE: Cho B et al. ESMO 2019, Abstract LBA11.

BARCELONA – Nivolumab was associated with improved overall survival and a favorable safety profile, compared with chemotherapy, in patients with previously treated advanced esophageal squamous cell carcinoma (ESCC) in the open-label phase 3 ATTRACTION-3 study.

The overall survival (OS) benefit was observed regardless of tumor programmed death-ligand 1 (PD-L1) expression, Byoung Chul Cho, MD, reported at the European Society for Medical Oncology Congress.

The findings were reported online simultaneously in The Lancet Oncology.

Median OS at a minimum follow-up of 17.6 months was 10.9 vs. 8.4 months in 210 patients randomized to receive treatment with the PD-1 inhibitor nivolumab and 209 who received chemotherapy, respectively (hazard ratio, 0.77), said Dr. Cho of Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.

“Notably, there was a 13% and 10% improvement in overall survival rates at 12 months (47% vs. 34%) and 18 months (31% vs. 21%), respectively,” he said, also noting that the HRs for death favored nivolumab vs. chemotherapy across multiple prespecified subgroups, including those based on tumor PD-L1 expression (HRs, 0.69 and 0.84 for PD-L1 of 1% or greater and less than 1%, respectively).

No meaningful difference was seen in progression-free survival between the nivolumab and chemotherapy groups (12% vs. 7%; HR, 1.08), or in objective response rates (19% vs. 22%), he said.

“However, responses were substantially more durable with nivolumab, compared to chemotherapy; duration of response was 6.9 months with nivolumab vs. 3.9 months in the chemotherapy arm,” he said. “Notably, 21% of patients in the nivolumab arm were still in response, compared to only 6% in the chemotherapy arm.”

Patients enrolled in the open label study had unresectable advanced or recurrent ESCC refractory or intolerant to one prior fluoropyrimidine/platinum-based therapy. They were randomized 1:1 to receive 240 mg of nivolumab every 2 weeks or investigators’ choice of paclitaxel or docetaxel.

Fewer treatment-related adverse events (TRAEs) were reported with nivolumab, Dr. Cho said.

Any grade TRAEs occurred in 66% vs. 95% of patients in the groups, respectively, and grade 3-4 TRAEs occurred in 18% vs. 63%. The majority of select TRAEs – defined as those with potential immunologic etiology, including endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin effects – were grade 1 or 2, and the only difference between the nivolumab and chemotherapy groups with respect to those was in endocrine effects, which affected 11% vs. less than 1% of patients, respectively.

Grade 3/4 select TRAEs occurred in less than 2% of patients, Dr. Cho noted.

An exploratory analysis further showed significant overall improvement in health-related quality of life with nivolumab through week 42 on treatment, he added.

The findings are of note, because metastatic esophageal cancer has a 5-year relative survival rate of less than 8%, and ESCC accounts for about 90% of cases worldwide, he said, adding that current second-line chemotherapy options for ESCC offer poor long-term survival and are associated with toxicity.

Nivolumab, which showed promising antitumor activity and manageable toxicity for advanced ESCC in patients who were refractory to or intolerant of standard chemotherapies in the phase 2 ATTRACTION-1 study, is the first immune checkpoint inhibitor to demonstrate a statistically significant, clinically meaningful improvement in OS vs. chemotherapy in this setting, he said.

The findings of this final analysis of ATTRACTION-3, which shows a 23% reduction in the risk of death, a 2.5-month improvement in median OS, benefit across PD-L1 subgroups, and a favorable safety profile, suggest that nivolumab represents a new standard second-line treatment option for patients with advanced ESCC, he concluded.

ATTRACTION-3 was funded by Ono Pharmaceutical Co., in collaboration with Bristol-Myers Squibb. Dr. Cho reported relationships with Bristol-Myers Squibb, Ono Pharmaceutical, and others. He also reported stock ownership and/or patents with TheraCanVac and Champions Oncology.

SOURCE: Cho B et al. ESMO 2019, Abstract LBA11.

BARCELONA – Nivolumab, compared with docetaxel chemotherapy, led to a fivefold improvement in 5-year overall survival among previously treated patients with non–small cell lung cancer (NSCLC), according to a pooled analysis of data from the phase 3 CheckMate 017 and 057 trials.

Sharon Worcester/MDedge News

The 5-year overall survival (OS) rates from the two randomized registrational trials, which established the programmed death-1 (PD-1) inhibitor nivolumab as the standard salvage therapy for NSCLC, were 13.4% vs. 2.6% (median, 11.1 vs. 8.1 months) with nivolumab and docetaxel, respectively, Scott Gettinger, MD, reported at the World Conference on Lung Cancer.

“These are the first randomized trials to report 5-year outcomes for a PD-1 axis inhibitor in patients with previously treated advanced non–small lung cancer,” said Dr. Gettinger, a professor at the Yale Comprehensive Cancer Center, New Haven, Conn. “This is really unprecedented; we wouldn’t expect many patients to be out 5 years in this scenario.”

Notably, the 5-year OS benefit was seen in both trials, he said, explaining that each compared nivolumab and docetaxel, but CheckMate 017 included patients with only squamous NSCLC, and CheckMate 057 included only non–squamous NSCLC patients.

The trials randomized 272 and 582 patients, respectively, and both demonstrated significantly improved 12-month OS with nivolumab – regardless of programmed death-ligand 1 (PD-L1) expression levels. Common eligibility criteria included stage IIIb/IV disease, good performance status (ECOG performance score of 0-1), and 1 prior platinum-based chemotherapy; CheckMate 057 further allowed prior tyrosine kinase inhibitor treatment for known anaplastic lymphoma kinase (ALK) translocation or epidermal growth factor receptor (EGFR) mutation, and allowed prior maintenance therapy. Doses in both trials were 3 mg/kg of nivolumab every 2 weeks or 75 mg/m² of intravenous docetaxel every 3 weeks until disease progression or unacceptable toxicity.

The pooled data also showed an improvement in progression-free survival (PFS) at 5 years (8% vs. 0%) with nivolumab vs. docetaxel groups.

“Again, we don’t see this in trials – more commonly we see zero patients without progression, and that’s what we saw with the docetaxel arm,” said Dr. Gettinger, who also is the Disease Aligned Research Team Leader, Thoracic Oncology Program, at the cancer center.

The median duration of responses with nivolumab was 19.9 months vs. 5.6 months with docetaxel, and 32.2% of nivolumab responders were still without progression at 5 years, he noted.

A common question in the clinic relates to the prognosis in patients who do well with PD-1 axis inhibitors, which prompted an additional analysis across the two trials, he said, noting that 60%, 78%, and 88% of patients who had not progressed at 2, 3, or 4 years, respectively, also had not progressed at 5 years, and 80%, 93%, and 100%, of patients in those groups were alive at 5 years. In the docetaxel arm, only 4, 1, and 0 patients had PFS at 2, 3, and 4, years, respectively, and none of those patients survived to 5 years, he said.

No new safety signals were seen with long-term follow-up, he added.

“In fact there was only one grade 3 or higher toxicity that was related to treatment in the nivolumab arm, and this was a grade 3 lipase elevation. There was one patient who discontinued nivolumab after 3 years, and this was for a grade 2 rash and eczema that had waxed and waned since starting nivolumab,” he said.

Also of note, 10% of nivolumab-treated patients who were off treatment at 5 years – for variable periods of time – had not progressed and had not received subsequent therapy.

“So we clearly see benefit in our patients long after they finish a course or stop for some reason,” he said.

CheckMate 017 and 057 were funded by Bristol-Myers Squibb. Dr. Gettinger reported advisory board and/or consulting work for, and/or research funding from Bristol-Myers Squibb, Nektar Therapeutics, Genentech/Roche, Iovance, and Takeda/Ariad.

SOURCE: Gettinger S et al. WCLC 2019, Abstract PR04.03.

BARCELONA – Nivolumab, compared with docetaxel chemotherapy, led to a fivefold improvement in 5-year overall survival among previously treated patients with non–small cell lung cancer (NSCLC), according to a pooled analysis of data from the phase 3 CheckMate 017 and 057 trials.

Sharon Worcester/MDedge News

The 5-year overall survival (OS) rates from the two randomized registrational trials, which established the programmed death-1 (PD-1) inhibitor nivolumab as the standard salvage therapy for NSCLC, were 13.4% vs. 2.6% (median, 11.1 vs. 8.1 months) with nivolumab and docetaxel, respectively, Scott Gettinger, MD, reported at the World Conference on Lung Cancer.

“These are the first randomized trials to report 5-year outcomes for a PD-1 axis inhibitor in patients with previously treated advanced non–small lung cancer,” said Dr. Gettinger, a professor at the Yale Comprehensive Cancer Center, New Haven, Conn. “This is really unprecedented; we wouldn’t expect many patients to be out 5 years in this scenario.”

Notably, the 5-year OS benefit was seen in both trials, he said, explaining that each compared nivolumab and docetaxel, but CheckMate 017 included patients with only squamous NSCLC, and CheckMate 057 included only non–squamous NSCLC patients.

The trials randomized 272 and 582 patients, respectively, and both demonstrated significantly improved 12-month OS with nivolumab – regardless of programmed death-ligand 1 (PD-L1) expression levels. Common eligibility criteria included stage IIIb/IV disease, good performance status (ECOG performance score of 0-1), and 1 prior platinum-based chemotherapy; CheckMate 057 further allowed prior tyrosine kinase inhibitor treatment for known anaplastic lymphoma kinase (ALK) translocation or epidermal growth factor receptor (EGFR) mutation, and allowed prior maintenance therapy. Doses in both trials were 3 mg/kg of nivolumab every 2 weeks or 75 mg/m² of intravenous docetaxel every 3 weeks until disease progression or unacceptable toxicity.

The pooled data also showed an improvement in progression-free survival (PFS) at 5 years (8% vs. 0%) with nivolumab vs. docetaxel groups.

“Again, we don’t see this in trials – more commonly we see zero patients without progression, and that’s what we saw with the docetaxel arm,” said Dr. Gettinger, who also is the Disease Aligned Research Team Leader, Thoracic Oncology Program, at the cancer center.

The median duration of responses with nivolumab was 19.9 months vs. 5.6 months with docetaxel, and 32.2% of nivolumab responders were still without progression at 5 years, he noted.

A common question in the clinic relates to the prognosis in patients who do well with PD-1 axis inhibitors, which prompted an additional analysis across the two trials, he said, noting that 60%, 78%, and 88% of patients who had not progressed at 2, 3, or 4 years, respectively, also had not progressed at 5 years, and 80%, 93%, and 100%, of patients in those groups were alive at 5 years. In the docetaxel arm, only 4, 1, and 0 patients had PFS at 2, 3, and 4, years, respectively, and none of those patients survived to 5 years, he said.

No new safety signals were seen with long-term follow-up, he added.

“In fact there was only one grade 3 or higher toxicity that was related to treatment in the nivolumab arm, and this was a grade 3 lipase elevation. There was one patient who discontinued nivolumab after 3 years, and this was for a grade 2 rash and eczema that had waxed and waned since starting nivolumab,” he said.

Also of note, 10% of nivolumab-treated patients who were off treatment at 5 years – for variable periods of time – had not progressed and had not received subsequent therapy.

“So we clearly see benefit in our patients long after they finish a course or stop for some reason,” he said.

CheckMate 017 and 057 were funded by Bristol-Myers Squibb. Dr. Gettinger reported advisory board and/or consulting work for, and/or research funding from Bristol-Myers Squibb, Nektar Therapeutics, Genentech/Roche, Iovance, and Takeda/Ariad.

SOURCE: Gettinger S et al. WCLC 2019, Abstract PR04.03.

BARCELONA – Nivolumab, compared with docetaxel chemotherapy, led to a fivefold improvement in 5-year overall survival among previously treated patients with non–small cell lung cancer (NSCLC), according to a pooled analysis of data from the phase 3 CheckMate 017 and 057 trials.

Sharon Worcester/MDedge News

The 5-year overall survival (OS) rates from the two randomized registrational trials, which established the programmed death-1 (PD-1) inhibitor nivolumab as the standard salvage therapy for NSCLC, were 13.4% vs. 2.6% (median, 11.1 vs. 8.1 months) with nivolumab and docetaxel, respectively, Scott Gettinger, MD, reported at the World Conference on Lung Cancer.

“These are the first randomized trials to report 5-year outcomes for a PD-1 axis inhibitor in patients with previously treated advanced non–small lung cancer,” said Dr. Gettinger, a professor at the Yale Comprehensive Cancer Center, New Haven, Conn. “This is really unprecedented; we wouldn’t expect many patients to be out 5 years in this scenario.”

Notably, the 5-year OS benefit was seen in both trials, he said, explaining that each compared nivolumab and docetaxel, but CheckMate 017 included patients with only squamous NSCLC, and CheckMate 057 included only non–squamous NSCLC patients.

The trials randomized 272 and 582 patients, respectively, and both demonstrated significantly improved 12-month OS with nivolumab – regardless of programmed death-ligand 1 (PD-L1) expression levels. Common eligibility criteria included stage IIIb/IV disease, good performance status (ECOG performance score of 0-1), and 1 prior platinum-based chemotherapy; CheckMate 057 further allowed prior tyrosine kinase inhibitor treatment for known anaplastic lymphoma kinase (ALK) translocation or epidermal growth factor receptor (EGFR) mutation, and allowed prior maintenance therapy. Doses in both trials were 3 mg/kg of nivolumab every 2 weeks or 75 mg/m² of intravenous docetaxel every 3 weeks until disease progression or unacceptable toxicity.

The pooled data also showed an improvement in progression-free survival (PFS) at 5 years (8% vs. 0%) with nivolumab vs. docetaxel groups.

“Again, we don’t see this in trials – more commonly we see zero patients without progression, and that’s what we saw with the docetaxel arm,” said Dr. Gettinger, who also is the Disease Aligned Research Team Leader, Thoracic Oncology Program, at the cancer center.

The median duration of responses with nivolumab was 19.9 months vs. 5.6 months with docetaxel, and 32.2% of nivolumab responders were still without progression at 5 years, he noted.

A common question in the clinic relates to the prognosis in patients who do well with PD-1 axis inhibitors, which prompted an additional analysis across the two trials, he said, noting that 60%, 78%, and 88% of patients who had not progressed at 2, 3, or 4 years, respectively, also had not progressed at 5 years, and 80%, 93%, and 100%, of patients in those groups were alive at 5 years. In the docetaxel arm, only 4, 1, and 0 patients had PFS at 2, 3, and 4, years, respectively, and none of those patients survived to 5 years, he said.

No new safety signals were seen with long-term follow-up, he added.

“In fact there was only one grade 3 or higher toxicity that was related to treatment in the nivolumab arm, and this was a grade 3 lipase elevation. There was one patient who discontinued nivolumab after 3 years, and this was for a grade 2 rash and eczema that had waxed and waned since starting nivolumab,” he said.

Also of note, 10% of nivolumab-treated patients who were off treatment at 5 years – for variable periods of time – had not progressed and had not received subsequent therapy.

“So we clearly see benefit in our patients long after they finish a course or stop for some reason,” he said.

CheckMate 017 and 057 were funded by Bristol-Myers Squibb. Dr. Gettinger reported advisory board and/or consulting work for, and/or research funding from Bristol-Myers Squibb, Nektar Therapeutics, Genentech/Roche, Iovance, and Takeda/Ariad.

SOURCE: Gettinger S et al. WCLC 2019, Abstract PR04.03.

Certain myeloablative conditioning regimens are among several novel risk factors for melanoma after allogeneic hematopoietic stem cell transplantation (HCT), according to findings from a nested case-control study.

The study included 140 cases of melanoma and 557 controls matched by age at HCT, sex, primary disease, and survival time. The results showed a significantly increased melanoma risk in HCT survivors who received total body irradiation–based myeloablative conditioning, reduced-intensity conditioning with melphalan, or reduced-intensity conditioning with fludarabine, compared with those who received busulfan-based myeloablative conditioning (odds ratios, 1.77, 2.60, and 2.72, respectively), Megan M. Herr, PhD, of the division of cancer epidemiology and genetics at the National Cancer Institute, and the Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and colleagues reported in the Journal of the American Academy of Dermatology.

Melanoma risk also was increased in patients who experienced acute graft-versus-host disease (GVHD) with stage 2 or greater skin involvement (OR, 1.92 vs. those with no acute GVHD), chronic GVHD without skin involvement (OR, 1.91 vs. those with no chronic GVHD), or keratinocytic carcinoma (OR, 2.37), and in those who resided in areas with higher ambient ultraviolet radiation (OR for the highest vs. lowest tertile, 1.64).

The UV radiation finding was more pronounced for melanomas occurring 6 or more years after transplant (OR, 3.04 for highest vs. lowest tertile), whereas ambient UV radiation was not associated with melanomas occurring earlier (ORs, 1.37 for less than 3 years and 0.98 at 3-6 years), the investigators noted.

The findings, based on large-scale and detailed clinical data from the Center for International Blood and Marrow Transplant Research for HCT performed during 1985-2012, show that melanoma after HCT has a multifactorial etiology that includes patient-, transplant-, and posttransplant-related factors, they said, noting that the findings also underscore the importance of “prioritization of high-risk survivors for adherence to prevention and screening recommendations.”

Those recommendations call for routine skin examination and photoprotective precautions – particularly in HCT survivors at the highest risk – but studies of screening behaviors suggest that fewer than two-thirds of HCT survivors adhere to these recommendations, they said, concluding that further research on the cost-effectiveness of melanoma screening is warranted, as is investigation into whether current approaches are associated with melanoma risk.

This work was supported by the intramural research program of the National Cancer Institute, the National Institutes of Health, and the Department of Health & Human Services. The authors reported having no conflicts of interest.

[email protected]

SOURCE: Herr MM et al. J Am Acad Dermatol. 2019 Oct 22. doi: 10.1016/j.jaad.2019.10.034.




 

Certain myeloablative conditioning regimens are among several novel risk factors for melanoma after allogeneic hematopoietic stem cell transplantation (HCT), according to findings from a nested case-control study.

The study included 140 cases of melanoma and 557 controls matched by age at HCT, sex, primary disease, and survival time. The results showed a significantly increased melanoma risk in HCT survivors who received total body irradiation–based myeloablative conditioning, reduced-intensity conditioning with melphalan, or reduced-intensity conditioning with fludarabine, compared with those who received busulfan-based myeloablative conditioning (odds ratios, 1.77, 2.60, and 2.72, respectively), Megan M. Herr, PhD, of the division of cancer epidemiology and genetics at the National Cancer Institute, and the Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and colleagues reported in the Journal of the American Academy of Dermatology.

Melanoma risk also was increased in patients who experienced acute graft-versus-host disease (GVHD) with stage 2 or greater skin involvement (OR, 1.92 vs. those with no acute GVHD), chronic GVHD without skin involvement (OR, 1.91 vs. those with no chronic GVHD), or keratinocytic carcinoma (OR, 2.37), and in those who resided in areas with higher ambient ultraviolet radiation (OR for the highest vs. lowest tertile, 1.64).

The UV radiation finding was more pronounced for melanomas occurring 6 or more years after transplant (OR, 3.04 for highest vs. lowest tertile), whereas ambient UV radiation was not associated with melanomas occurring earlier (ORs, 1.37 for less than 3 years and 0.98 at 3-6 years), the investigators noted.

The findings, based on large-scale and detailed clinical data from the Center for International Blood and Marrow Transplant Research for HCT performed during 1985-2012, show that melanoma after HCT has a multifactorial etiology that includes patient-, transplant-, and posttransplant-related factors, they said, noting that the findings also underscore the importance of “prioritization of high-risk survivors for adherence to prevention and screening recommendations.”

Those recommendations call for routine skin examination and photoprotective precautions – particularly in HCT survivors at the highest risk – but studies of screening behaviors suggest that fewer than two-thirds of HCT survivors adhere to these recommendations, they said, concluding that further research on the cost-effectiveness of melanoma screening is warranted, as is investigation into whether current approaches are associated with melanoma risk.

This work was supported by the intramural research program of the National Cancer Institute, the National Institutes of Health, and the Department of Health & Human Services. The authors reported having no conflicts of interest.

[email protected]

SOURCE: Herr MM et al. J Am Acad Dermatol. 2019 Oct 22. doi: 10.1016/j.jaad.2019.10.034.




 

Certain myeloablative conditioning regimens are among several novel risk factors for melanoma after allogeneic hematopoietic stem cell transplantation (HCT), according to findings from a nested case-control study.

The study included 140 cases of melanoma and 557 controls matched by age at HCT, sex, primary disease, and survival time. The results showed a significantly increased melanoma risk in HCT survivors who received total body irradiation–based myeloablative conditioning, reduced-intensity conditioning with melphalan, or reduced-intensity conditioning with fludarabine, compared with those who received busulfan-based myeloablative conditioning (odds ratios, 1.77, 2.60, and 2.72, respectively), Megan M. Herr, PhD, of the division of cancer epidemiology and genetics at the National Cancer Institute, and the Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and colleagues reported in the Journal of the American Academy of Dermatology.

Melanoma risk also was increased in patients who experienced acute graft-versus-host disease (GVHD) with stage 2 or greater skin involvement (OR, 1.92 vs. those with no acute GVHD), chronic GVHD without skin involvement (OR, 1.91 vs. those with no chronic GVHD), or keratinocytic carcinoma (OR, 2.37), and in those who resided in areas with higher ambient ultraviolet radiation (OR for the highest vs. lowest tertile, 1.64).

The UV radiation finding was more pronounced for melanomas occurring 6 or more years after transplant (OR, 3.04 for highest vs. lowest tertile), whereas ambient UV radiation was not associated with melanomas occurring earlier (ORs, 1.37 for less than 3 years and 0.98 at 3-6 years), the investigators noted.

The findings, based on large-scale and detailed clinical data from the Center for International Blood and Marrow Transplant Research for HCT performed during 1985-2012, show that melanoma after HCT has a multifactorial etiology that includes patient-, transplant-, and posttransplant-related factors, they said, noting that the findings also underscore the importance of “prioritization of high-risk survivors for adherence to prevention and screening recommendations.”

Those recommendations call for routine skin examination and photoprotective precautions – particularly in HCT survivors at the highest risk – but studies of screening behaviors suggest that fewer than two-thirds of HCT survivors adhere to these recommendations, they said, concluding that further research on the cost-effectiveness of melanoma screening is warranted, as is investigation into whether current approaches are associated with melanoma risk.

This work was supported by the intramural research program of the National Cancer Institute, the National Institutes of Health, and the Department of Health & Human Services. The authors reported having no conflicts of interest.

[email protected]

SOURCE: Herr MM et al. J Am Acad Dermatol. 2019 Oct 22. doi: 10.1016/j.jaad.2019.10.034.




 

BARCELONA – Immune checkpoint inhibitors demonstrate activity in small cell lung cancer (SCLC), but achieving more durable disease control and better survival requires improved understanding of biomarkers and the immune microenvironment.

That was the overarching message from experts speaking at a minisymposium on immunotherapy in SCLC at the World Conference on Lung Cancer.

“None of us are disputing that immunotherapy is clearly active in this space, but I think that we can all agree that the outcomes have been somewhat modest in an unselected population, and there is certainly room to grow,” said Dr. Stephen V. Liu, MD. “Moving forward, while we will look for any advances we can, we also feel strongly that these incremental gains are probably not enough.”
 

The state of the art

Hints that immunotherapy could be clinically efficacious in SCLC emerged in 2016 when interim findings from the CheckMate 032 study showed that the programmed cell death-1 (PD-1) inhibitor nivolumab, either alone or in combination with the anti-CTLA4 antibody ipilimumab, had efficacy in recurrent SCLC. Efficacy was seen regardless of programmed death-ligand 1 (PD-L1) status, which is “a good thing since PD-L1 is expressed much less frequently in SCLC than in non-SCLC,” Scott J. Antonia, MD, of Duke Cancer Institute, Durham, N.C., who was the first author on that study, said during the symposium.

A particularly encouraging finding was that responders included patients with platinum-refractory SCLC for whom treatments in the relapse setting are lacking, Dr Antonia said.

An exploratory analysis of CheckMate 032 also showed better responses among patients in the highest tumor mutation burden (TMB) tertile, especially in the combination therapy group, leading to the hypothesis-generating finding that TMB may predict response, he said.

Another suggestion of nivolumab’s potential came from the randomized CheckMate 331 study comparing the checkpoint inhibitor with chemotherapy in relapsed SCLC patients. As reported in 2018 at the European Society for Medical Oncology (ESMO), no overall survival (OS) benefit was apparent at 12 months (37% vs. 34%), but a separation of the curves at 36 months suggested a possible OS benefit with nivolumab, Dr. Antonia noted, adding that the difference was “obviously small” and requires “a lot more work related to that.”

Subgroup analyses in that study also were “perhaps revealing” in that patients without liver metastases derived benefit (hazard ratio, 0.75), as did those who were platinum resistant (HR, 0.71), he said.

The phase 1b KEYNOTE-028 study showed that the anti–PD-1 monoclonal antibody pembrolizumab also has activity in PD-L1–positive SCLC patients in the relapsed setting, and pooled data from that study and KEYNOTE-158, which included both PD-L1–positive and –negative patients, showed promising antitumor activity and durable responses with pembrolizumab. The pooled data, as presented at the 2019 annual meeting of the American Association for Cancer Research, showed an objective response rate (ORR) of 19%, including complete and partial response rates of 2% and 17%, respectively.

“And there appears to be, at least preliminarily, some durability to the responses,” he said, noting that 9 of 16 patients experienced at least an 18-month response. “Progression-free survival was 2 months, and overall survival was 7.7 months.”

The IMpower133 study showed significantly longer OS and progression-free survival (PFS) with the addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage SCLC (HR, 0.70). Some late merging of the survival curves was apparent, but the data haven’t matured.

“Hopefully there will be some evidence of a lifting of the tail of the survival curve with some durability of responsiveness like we see in non–small cell lung cancer,” he said.

When it comes to “making the next leap” toward improved clinical efficacy with immunotherapy for SCLC, “we need to think about three general categories of how it is that tumors evade rejection by the immune system,” he said.

One category involves SCLC patients with an insufficient numbers of T cells generated within the lymphoid compartment; in those patients, an immunotherapeutic approach directed at the tumor microenvironment won’t lead to a response. Another category includes patients who generate enough T cells within the lymphoid compartment but in whom those cells aren’t driven into the tumor parenchyma. The third involves those whose T cells may make it into the tumor parenchyma, but are inhibited in the tumor microenvironment, he explained.

Strategies to increase the number of T cells generated in the lymphoid compartment – such as vaccines, radiation, adoptive cell therapy with chimeric antigen receptors, to name a few – were a focus of research efforts more than a decade ago, but the pendulum swung more toward addressing the tumor microenvironment.

“I think that the pendulum needs to swing back to the middle, and we do need to develop combination immunotherapies paying attention to the lymphoid compartment as well as the tumor microenvironment,” Dr. Antonia said, listing these “guiding principles” for the development of effective SCLC immunotherapy:

• Combination immunotherapy is necessary.
• Mechanisms exploited by SCLC to evade immune-mediated rejection need to be identified.
• Inclusion of strategies for driving tumor-reactive T cells into the tumor microenvironment should be considered.
• PD-1 blockade should continue.
• Biomarkers should be identified for selecting patients for tumor microenvironment–targeted agents.

Clinical and molecular biomarkers

Indeed, there is much work to do with respect to biomarkers, but their use in the selection of SCLC patients for immunotherapy is “finally starting to evolve and evolve more rapidly,” according to Lauren Averett Byers, MD, of the University of Texas MD Anderson Cancer Center, Houston.

Numerous groups are identifying biomarkers for both targeted therapy and immunotherapy, Dr. Byers said, noting that “this has been a really incredible time for those of us who take care of small cell lung cancer patients.”

“It’s been many decades since we’ve had a new option for our patients ... and so I think with the landmark clinical trials ... we really do have a new option in terms of a new standard of care,” she said of immunotherapy. “But I think we also recognize that there is significant room for further improvement.”

Many patients don’t respond or don’t respond as well as hoped, and therefore an “incredible need” exists for personalized biomarker-driven therapy for SCLC and its distinct molecular subsets, she said.

Emerging and potential biomarkers and other factors to guide treatment decisions include TMB, PD-L1, clinical history/duration of response in immunotherapy-naive relapsed patients, gene expression profile–driven SCLC subgroup identification, and DNA damage response (DDR) inhibitors such as Chk1, PARP, and Wee1 inhibitors.

TMB, as described by Dr. Antonia with respect to the CheckMate 032 findings of improved outcomes in those in the highest TMB tertile, is one potentially helpful biomarker for response.

“In thinking about how we apply this, though, we have to think about what we’re deciding between,” Dr. Byers said, explaining that the responses in patients with medium or low TMB – between 0% and 10% in most studies in the relapsed SCLC setting – aren’t that different from those seen with other treatment options.

“Currently we’re not routinely ordering TMB to decide on immunotherapy because there are still patients that can be as likely to benefit from immunotherapy as they are from chemotherapy, and potentially with more durable responses,” she said. “But certainly, it is a way to potentially identify patients where immunotherapy alone may have very high rates of response.”

IMPower133 showed no difference in hazard ratios for death based on TMB detected in the blood in SCLC patients treated with first-line atezolizumab plus chemotherapy, but “this still supports using the immunotherapy/chemotherapy combination broadly, and also emphasizes the need for an improved – and probably expanded – look at other biomarkers that may help predict response,” she said.

PD-L1 appears to have a role as a biomarker in this setting as well, she said, citing the KEYNOTE-028 findings of numerically improved responses in PD-L1–positive SCLC patients treated with pembrolizumab.

“We should be looking at PD-L1 levels, but we need further information to know how we might use this,” she said.

In immunotherapy-naive patients who relapse after front-line chemotherapy, the most important biomarker is clinical history and duration of response to platinum, which helps guide second-line treatment, Dr. Byers said.

“I think there’s consensus among most of us that patients who have platinum-refractory disease and are unlikely to respond to further platinum therapy or other chemotherapy agents are patients who really should get immunotherapy,” she added, explaining that the available data suggest there is no cross-resistance and that there may actually be enhanced benefit with immunotherapy in such patients.

Using molecular data to identify SCLC subtypes based on gene expression profiles is another area of interest, she said.

In fact, new data presented at the WCLC conference by Carl Gay, MD, PhD, a former fellow in her lab and now a junior faculty member at MD Anderson, identified four specific SCLC subgroups; three were driven by activation of the known transcription factors ASCL1, NEUROD1, and POU2F3, but an additional “inflamed” group without expression of those three transcription factors was also identified.

That “triple-negative” group had significantly higher expression of human leukocyte antigen and very high T-cell activation with expression of multiple immune checkpoints representing candidate targets, she said, adding: “We hypothesize that this group may be the group in SCLC that gets relatively greater benefit from immune checkpoint blockade.”

DDR is also garnering attention.

“Since there was this signal that [patients with] DNA damage ... tend to be more sensitive to immunotherapy ... we looked at whether or not targeted agents that prevented repair of DNA damage and induced increased levels of DNA damage ... might activate the innate immune system through the STING pathway and if that could be a potential approach to enhance immunotherapy response,” she said.

The approach showed promise in cell lines in a mouse model and also in an immunocompetent SCLC mouse model.

“It was really interesting to see how these drugs might potentially enhance response to immunotherapy,” Dr. Byers said, noting that the same phenomenon has been seen with PARP inhibitors in breast and colon cancer models and in other solid tumors.

“So I think that there is something there, and fortunately we’re now at a point now where we can start looking at some of these combinations in the clinic across many different cancer types,” she said. “I think we’ll be learning a lot more about what’s happening with these patients.”

At present, however, “there is more that we don’t know about the immune landscape of small cell lung cancer than what we do know, and that’s a real opportunity where, over the next several years, we will gain a deeper understanding ... that will direct where we’re going in terms of translating that back into the clinic.”
 

The SCLC immune microenvironment

The immune microenvironment will be an integral part of that journey, according to Dr. Liu.

“We consider small cell lung cancer – a carcinogen-associated cancer – to be one that has a high somatic mutation rate, but what we’ve learned over the past few years is that tumor neoantigens are certainly necessary – but not sufficient,” he said, noting that mutational burden represents the potential for immune-mediated antitumor responses, but is not a guarantee.

“As a group, we need to develop strategies to overcome the powerful immunosuppressive microenvironment in small cell lung cancer,” he added.

Lessons learned from studying PD-L1 provided the first insight into the importance of the immune microenvironment: PD-L1 expression, as measured by tumor proportion score (TPS) holds predictive value in non–small cell lung cancer patients treated with PD-1 inhibitors, but the SCLC story is much more complex, he said.

Only 18% of SCLC patients in CheckMate 032 were PD-L1–positive, and “paradoxically, we see responses were better in the PD-L1–negative group,” he explained. The response rates for nivolumab/ipilimumab were 32% in the PD-L1–negative group and 10% in the PD-L1–positive group.

Recent findings regarding the use of the combined positive score (CPS), which unlike the TPS for determining PD-L1 status, includes PD-L1 expression on stromal cells, are also notable. In a phase 2 study of maintenance pembrolizumab in SCLC, for example, 3 of 30 patients were PD-L1 positive by TPS, and 8 of 20 were positive by CPS.

“And that did predict outcomes: We see a higher response rate [38% vs. 8%], better PFS [6.5 vs. 1.3 months], and better overall survival [13 months vs. 8 months] in pretreated small cell lung cancer,” he said.

Similarly, in KEYNOTE-158 when looking at pembrolizumab in previously treated SCLC, the overall response was modest at 18.7%, and median PFS was 2.0 months.

“Again, breaking it down by CPS, we see a different story,” Dr. Liu said. “We see better outcomes in the PD-L1–positive [group] if you’re factoring in expression in the microenvironment.” When assessed by CPS, 39% of patients were PD-L1 positive; those patients, when compared with PD-L1–negative patients, had improved 12-month PFS (28.5% vs. 8.2%, respectively), 12-month OS (53.3% vs. 30.7%), and median OS (14.9 vs. 5.9 months).

Checkpoint expression in tumor-infiltrating lymphocytes (TILs) also has been shown to vary when compared with tumor expression. SCLC tissue microarrays in a study presented at ASCO 2017 (Rivalland et al. Abstract 8569), for example, showed that tumor expression versus TIL expression of PD-L1, TIMS3, and LAG3 was 18% vs. 67%, 0% vs. 59%, and 0% vs. 45%, respectively, and the TIL expression correlated with survival, Dr. Liu said.

“So when we consider things like PD-L1 expression, looking at a narrow scope of just the tumor is not enough. We need to consider the stromal cells, the microenvironment,” he said. “And even larger than that, PD-1/PD-L1 interaction is but a fraction of powerful, dynamic, immunosuppressive factors in small cell lung cancer.

“All of these will need to be accounted for in various patients.”

These findings and others, like those from a recent study showing differentially expressed genes and pathways in the stromal cells of longer- versus shorter-term survivors, raise questions about whether the lymphoid compartment can be manipulated in SCLC to improve immune responses using the strategies discussed by Dr. Antonia and Dr. Byers, he said.

In “cold” tumor phenotypes, one hypothesis has tumor-associated macrophages (TAMs) preventing infiltration of the cytotoxic T lymphocytes, which raises the possibility that TAMs are a therapeutic target, he said.

“At this meeting and others we’ve heard of lurbinectedin as a possible active drug in SCLC,” he said, noting that preclinical data also demonstrate that lurbinectedin targets TAMs. Perhaps the agent’s future role will be that of an immune modulator rather than a cytotoxic agent, he suggested.

Regulatory T cells (Tregs) are another potential immunomodulatory target, but the problem is their redundancy and the lack of good models to identify which ones are active, he said.

“Myeloid-derived suppressor cells [MDSC] are another important part of the microenvironment and could be potential targets to restore immune responses,” he added.

But many questions remain, he said.

For example: How can we overcome an immunosuppressive tumor microenvironment? Can we inhibit arginine or adenosine? Can we restore interleukin-2? Can we target things like LAG3? Can we eliminate the Treg and MDSC population? Which strategies are appropriate? Are they the same in immunotherapy-naive vs. immunotherapy-experienced patients – is intrinsic resistance the same as acquired resistance? Are they the same in each patient, or even throughout each tumor?

And importantly, “how will we choose between these various molecules we have?” he asked.

“At this point we’ve learned that empiric strategies are unlikely to yield meaningful results. We’ve been through empiric strategies in SCLC for years, and it doesn’t work because of that heterogeneity – unless there’s a universal underlying mechanism,” he said. “I think more than likely the studies have to be enriched for the right patients; we need to apply everything we’ve learned from non–small cell lung cancer and apply the principles of targeted therapy to immunotherapy – and that requires the identification of predictive biomarkers.”

It’s a challenging task in SCLC, but “it still needs to be done,” he said, noting that the lack of “perfect models” means relying on cell lines in surgical specimens.

However, while surgical tissue banks are an important resource, there is doubt about whether the specimens are representative of patients in the clinic, he noted.

“At best need to confirm what we know; at worst we may need to rework a lot of the underlying maps,” he said.

Therefore, future SCLC studies “are simply going to need more biopsies,” and that is yet another challenge, he added, explaining that the largely central tumors and fairly aggressive, rapid course of disease in SCLC make it difficult to obtain meaningful biopsies.

“But it’s the only way to move forward,” he said. “As a community we have to stand up and obtain more biopsies and tissue for in-depth analysis.”

As much as that will advance the field, the greatest impact for SCLC will be through prevention, including by smoking cessation, he added.

“Our overarching goal for small cell lung cancer remains achieving durable disease control and long-term survival for our patients,” Dr. Liu said. “That certainly is a lofty goal, but those are probably the only goals worth having.”

Dr. Liu, Dr. Byers, and Dr. Antonia reported relationships with numerous pharmaceutical companies.




 

BARCELONA – Immune checkpoint inhibitors demonstrate activity in small cell lung cancer (SCLC), but achieving more durable disease control and better survival requires improved understanding of biomarkers and the immune microenvironment.

That was the overarching message from experts speaking at a minisymposium on immunotherapy in SCLC at the World Conference on Lung Cancer.

“None of us are disputing that immunotherapy is clearly active in this space, but I think that we can all agree that the outcomes have been somewhat modest in an unselected population, and there is certainly room to grow,” said Dr. Stephen V. Liu, MD. “Moving forward, while we will look for any advances we can, we also feel strongly that these incremental gains are probably not enough.”
 

The state of the art

Hints that immunotherapy could be clinically efficacious in SCLC emerged in 2016 when interim findings from the CheckMate 032 study showed that the programmed cell death-1 (PD-1) inhibitor nivolumab, either alone or in combination with the anti-CTLA4 antibody ipilimumab, had efficacy in recurrent SCLC. Efficacy was seen regardless of programmed death-ligand 1 (PD-L1) status, which is “a good thing since PD-L1 is expressed much less frequently in SCLC than in non-SCLC,” Scott J. Antonia, MD, of Duke Cancer Institute, Durham, N.C., who was the first author on that study, said during the symposium.

A particularly encouraging finding was that responders included patients with platinum-refractory SCLC for whom treatments in the relapse setting are lacking, Dr Antonia said.

An exploratory analysis of CheckMate 032 also showed better responses among patients in the highest tumor mutation burden (TMB) tertile, especially in the combination therapy group, leading to the hypothesis-generating finding that TMB may predict response, he said.

Another suggestion of nivolumab’s potential came from the randomized CheckMate 331 study comparing the checkpoint inhibitor with chemotherapy in relapsed SCLC patients. As reported in 2018 at the European Society for Medical Oncology (ESMO), no overall survival (OS) benefit was apparent at 12 months (37% vs. 34%), but a separation of the curves at 36 months suggested a possible OS benefit with nivolumab, Dr. Antonia noted, adding that the difference was “obviously small” and requires “a lot more work related to that.”

Subgroup analyses in that study also were “perhaps revealing” in that patients without liver metastases derived benefit (hazard ratio, 0.75), as did those who were platinum resistant (HR, 0.71), he said.

The phase 1b KEYNOTE-028 study showed that the anti–PD-1 monoclonal antibody pembrolizumab also has activity in PD-L1–positive SCLC patients in the relapsed setting, and pooled data from that study and KEYNOTE-158, which included both PD-L1–positive and –negative patients, showed promising antitumor activity and durable responses with pembrolizumab. The pooled data, as presented at the 2019 annual meeting of the American Association for Cancer Research, showed an objective response rate (ORR) of 19%, including complete and partial response rates of 2% and 17%, respectively.

“And there appears to be, at least preliminarily, some durability to the responses,” he said, noting that 9 of 16 patients experienced at least an 18-month response. “Progression-free survival was 2 months, and overall survival was 7.7 months.”

The IMpower133 study showed significantly longer OS and progression-free survival (PFS) with the addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage SCLC (HR, 0.70). Some late merging of the survival curves was apparent, but the data haven’t matured.

“Hopefully there will be some evidence of a lifting of the tail of the survival curve with some durability of responsiveness like we see in non–small cell lung cancer,” he said.

When it comes to “making the next leap” toward improved clinical efficacy with immunotherapy for SCLC, “we need to think about three general categories of how it is that tumors evade rejection by the immune system,” he said.

One category involves SCLC patients with an insufficient numbers of T cells generated within the lymphoid compartment; in those patients, an immunotherapeutic approach directed at the tumor microenvironment won’t lead to a response. Another category includes patients who generate enough T cells within the lymphoid compartment but in whom those cells aren’t driven into the tumor parenchyma. The third involves those whose T cells may make it into the tumor parenchyma, but are inhibited in the tumor microenvironment, he explained.

Strategies to increase the number of T cells generated in the lymphoid compartment – such as vaccines, radiation, adoptive cell therapy with chimeric antigen receptors, to name a few – were a focus of research efforts more than a decade ago, but the pendulum swung more toward addressing the tumor microenvironment.

“I think that the pendulum needs to swing back to the middle, and we do need to develop combination immunotherapies paying attention to the lymphoid compartment as well as the tumor microenvironment,” Dr. Antonia said, listing these “guiding principles” for the development of effective SCLC immunotherapy:

• Combination immunotherapy is necessary.
• Mechanisms exploited by SCLC to evade immune-mediated rejection need to be identified.
• Inclusion of strategies for driving tumor-reactive T cells into the tumor microenvironment should be considered.
• PD-1 blockade should continue.
• Biomarkers should be identified for selecting patients for tumor microenvironment–targeted agents.

Clinical and molecular biomarkers

Indeed, there is much work to do with respect to biomarkers, but their use in the selection of SCLC patients for immunotherapy is “finally starting to evolve and evolve more rapidly,” according to Lauren Averett Byers, MD, of the University of Texas MD Anderson Cancer Center, Houston.

Numerous groups are identifying biomarkers for both targeted therapy and immunotherapy, Dr. Byers said, noting that “this has been a really incredible time for those of us who take care of small cell lung cancer patients.”

“It’s been many decades since we’ve had a new option for our patients ... and so I think with the landmark clinical trials ... we really do have a new option in terms of a new standard of care,” she said of immunotherapy. “But I think we also recognize that there is significant room for further improvement.”

Many patients don’t respond or don’t respond as well as hoped, and therefore an “incredible need” exists for personalized biomarker-driven therapy for SCLC and its distinct molecular subsets, she said.

Emerging and potential biomarkers and other factors to guide treatment decisions include TMB, PD-L1, clinical history/duration of response in immunotherapy-naive relapsed patients, gene expression profile–driven SCLC subgroup identification, and DNA damage response (DDR) inhibitors such as Chk1, PARP, and Wee1 inhibitors.

TMB, as described by Dr. Antonia with respect to the CheckMate 032 findings of improved outcomes in those in the highest TMB tertile, is one potentially helpful biomarker for response.

“In thinking about how we apply this, though, we have to think about what we’re deciding between,” Dr. Byers said, explaining that the responses in patients with medium or low TMB – between 0% and 10% in most studies in the relapsed SCLC setting – aren’t that different from those seen with other treatment options.

“Currently we’re not routinely ordering TMB to decide on immunotherapy because there are still patients that can be as likely to benefit from immunotherapy as they are from chemotherapy, and potentially with more durable responses,” she said. “But certainly, it is a way to potentially identify patients where immunotherapy alone may have very high rates of response.”

IMPower133 showed no difference in hazard ratios for death based on TMB detected in the blood in SCLC patients treated with first-line atezolizumab plus chemotherapy, but “this still supports using the immunotherapy/chemotherapy combination broadly, and also emphasizes the need for an improved – and probably expanded – look at other biomarkers that may help predict response,” she said.

PD-L1 appears to have a role as a biomarker in this setting as well, she said, citing the KEYNOTE-028 findings of numerically improved responses in PD-L1–positive SCLC patients treated with pembrolizumab.

“We should be looking at PD-L1 levels, but we need further information to know how we might use this,” she said.

In immunotherapy-naive patients who relapse after front-line chemotherapy, the most important biomarker is clinical history and duration of response to platinum, which helps guide second-line treatment, Dr. Byers said.

“I think there’s consensus among most of us that patients who have platinum-refractory disease and are unlikely to respond to further platinum therapy or other chemotherapy agents are patients who really should get immunotherapy,” she added, explaining that the available data suggest there is no cross-resistance and that there may actually be enhanced benefit with immunotherapy in such patients.

Using molecular data to identify SCLC subtypes based on gene expression profiles is another area of interest, she said.

In fact, new data presented at the WCLC conference by Carl Gay, MD, PhD, a former fellow in her lab and now a junior faculty member at MD Anderson, identified four specific SCLC subgroups; three were driven by activation of the known transcription factors ASCL1, NEUROD1, and POU2F3, but an additional “inflamed” group without expression of those three transcription factors was also identified.

That “triple-negative” group had significantly higher expression of human leukocyte antigen and very high T-cell activation with expression of multiple immune checkpoints representing candidate targets, she said, adding: “We hypothesize that this group may be the group in SCLC that gets relatively greater benefit from immune checkpoint blockade.”

DDR is also garnering attention.

“Since there was this signal that [patients with] DNA damage ... tend to be more sensitive to immunotherapy ... we looked at whether or not targeted agents that prevented repair of DNA damage and induced increased levels of DNA damage ... might activate the innate immune system through the STING pathway and if that could be a potential approach to enhance immunotherapy response,” she said.

The approach showed promise in cell lines in a mouse model and also in an immunocompetent SCLC mouse model.

“It was really interesting to see how these drugs might potentially enhance response to immunotherapy,” Dr. Byers said, noting that the same phenomenon has been seen with PARP inhibitors in breast and colon cancer models and in other solid tumors.

“So I think that there is something there, and fortunately we’re now at a point now where we can start looking at some of these combinations in the clinic across many different cancer types,” she said. “I think we’ll be learning a lot more about what’s happening with these patients.”

At present, however, “there is more that we don’t know about the immune landscape of small cell lung cancer than what we do know, and that’s a real opportunity where, over the next several years, we will gain a deeper understanding ... that will direct where we’re going in terms of translating that back into the clinic.”
 

The SCLC immune microenvironment

The immune microenvironment will be an integral part of that journey, according to Dr. Liu.

“We consider small cell lung cancer – a carcinogen-associated cancer – to be one that has a high somatic mutation rate, but what we’ve learned over the past few years is that tumor neoantigens are certainly necessary – but not sufficient,” he said, noting that mutational burden represents the potential for immune-mediated antitumor responses, but is not a guarantee.

“As a group, we need to develop strategies to overcome the powerful immunosuppressive microenvironment in small cell lung cancer,” he added.

Lessons learned from studying PD-L1 provided the first insight into the importance of the immune microenvironment: PD-L1 expression, as measured by tumor proportion score (TPS) holds predictive value in non–small cell lung cancer patients treated with PD-1 inhibitors, but the SCLC story is much more complex, he said.

Only 18% of SCLC patients in CheckMate 032 were PD-L1–positive, and “paradoxically, we see responses were better in the PD-L1–negative group,” he explained. The response rates for nivolumab/ipilimumab were 32% in the PD-L1–negative group and 10% in the PD-L1–positive group.

Recent findings regarding the use of the combined positive score (CPS), which unlike the TPS for determining PD-L1 status, includes PD-L1 expression on stromal cells, are also notable. In a phase 2 study of maintenance pembrolizumab in SCLC, for example, 3 of 30 patients were PD-L1 positive by TPS, and 8 of 20 were positive by CPS.

“And that did predict outcomes: We see a higher response rate [38% vs. 8%], better PFS [6.5 vs. 1.3 months], and better overall survival [13 months vs. 8 months] in pretreated small cell lung cancer,” he said.

Similarly, in KEYNOTE-158 when looking at pembrolizumab in previously treated SCLC, the overall response was modest at 18.7%, and median PFS was 2.0 months.

“Again, breaking it down by CPS, we see a different story,” Dr. Liu said. “We see better outcomes in the PD-L1–positive [group] if you’re factoring in expression in the microenvironment.” When assessed by CPS, 39% of patients were PD-L1 positive; those patients, when compared with PD-L1–negative patients, had improved 12-month PFS (28.5% vs. 8.2%, respectively), 12-month OS (53.3% vs. 30.7%), and median OS (14.9 vs. 5.9 months).

Checkpoint expression in tumor-infiltrating lymphocytes (TILs) also has been shown to vary when compared with tumor expression. SCLC tissue microarrays in a study presented at ASCO 2017 (Rivalland et al. Abstract 8569), for example, showed that tumor expression versus TIL expression of PD-L1, TIMS3, and LAG3 was 18% vs. 67%, 0% vs. 59%, and 0% vs. 45%, respectively, and the TIL expression correlated with survival, Dr. Liu said.

“So when we consider things like PD-L1 expression, looking at a narrow scope of just the tumor is not enough. We need to consider the stromal cells, the microenvironment,” he said. “And even larger than that, PD-1/PD-L1 interaction is but a fraction of powerful, dynamic, immunosuppressive factors in small cell lung cancer.

“All of these will need to be accounted for in various patients.”

These findings and others, like those from a recent study showing differentially expressed genes and pathways in the stromal cells of longer- versus shorter-term survivors, raise questions about whether the lymphoid compartment can be manipulated in SCLC to improve immune responses using the strategies discussed by Dr. Antonia and Dr. Byers, he said.

In “cold” tumor phenotypes, one hypothesis has tumor-associated macrophages (TAMs) preventing infiltration of the cytotoxic T lymphocytes, which raises the possibility that TAMs are a therapeutic target, he said.

“At this meeting and others we’ve heard of lurbinectedin as a possible active drug in SCLC,” he said, noting that preclinical data also demonstrate that lurbinectedin targets TAMs. Perhaps the agent’s future role will be that of an immune modulator rather than a cytotoxic agent, he suggested.

Regulatory T cells (Tregs) are another potential immunomodulatory target, but the problem is their redundancy and the lack of good models to identify which ones are active, he said.

“Myeloid-derived suppressor cells [MDSC] are another important part of the microenvironment and could be potential targets to restore immune responses,” he added.

But many questions remain, he said.

For example: How can we overcome an immunosuppressive tumor microenvironment? Can we inhibit arginine or adenosine? Can we restore interleukin-2? Can we target things like LAG3? Can we eliminate the Treg and MDSC population? Which strategies are appropriate? Are they the same in immunotherapy-naive vs. immunotherapy-experienced patients – is intrinsic resistance the same as acquired resistance? Are they the same in each patient, or even throughout each tumor?

And importantly, “how will we choose between these various molecules we have?” he asked.

“At this point we’ve learned that empiric strategies are unlikely to yield meaningful results. We’ve been through empiric strategies in SCLC for years, and it doesn’t work because of that heterogeneity – unless there’s a universal underlying mechanism,” he said. “I think more than likely the studies have to be enriched for the right patients; we need to apply everything we’ve learned from non–small cell lung cancer and apply the principles of targeted therapy to immunotherapy – and that requires the identification of predictive biomarkers.”

It’s a challenging task in SCLC, but “it still needs to be done,” he said, noting that the lack of “perfect models” means relying on cell lines in surgical specimens.

However, while surgical tissue banks are an important resource, there is doubt about whether the specimens are representative of patients in the clinic, he noted.

“At best need to confirm what we know; at worst we may need to rework a lot of the underlying maps,” he said.

Therefore, future SCLC studies “are simply going to need more biopsies,” and that is yet another challenge, he added, explaining that the largely central tumors and fairly aggressive, rapid course of disease in SCLC make it difficult to obtain meaningful biopsies.

“But it’s the only way to move forward,” he said. “As a community we have to stand up and obtain more biopsies and tissue for in-depth analysis.”

As much as that will advance the field, the greatest impact for SCLC will be through prevention, including by smoking cessation, he added.

“Our overarching goal for small cell lung cancer remains achieving durable disease control and long-term survival for our patients,” Dr. Liu said. “That certainly is a lofty goal, but those are probably the only goals worth having.”

Dr. Liu, Dr. Byers, and Dr. Antonia reported relationships with numerous pharmaceutical companies.




 

BARCELONA – Immune checkpoint inhibitors demonstrate activity in small cell lung cancer (SCLC), but achieving more durable disease control and better survival requires improved understanding of biomarkers and the immune microenvironment.

That was the overarching message from experts speaking at a minisymposium on immunotherapy in SCLC at the World Conference on Lung Cancer.

“None of us are disputing that immunotherapy is clearly active in this space, but I think that we can all agree that the outcomes have been somewhat modest in an unselected population, and there is certainly room to grow,” said Dr. Stephen V. Liu, MD. “Moving forward, while we will look for any advances we can, we also feel strongly that these incremental gains are probably not enough.”
 

The state of the art

Hints that immunotherapy could be clinically efficacious in SCLC emerged in 2016 when interim findings from the CheckMate 032 study showed that the programmed cell death-1 (PD-1) inhibitor nivolumab, either alone or in combination with the anti-CTLA4 antibody ipilimumab, had efficacy in recurrent SCLC. Efficacy was seen regardless of programmed death-ligand 1 (PD-L1) status, which is “a good thing since PD-L1 is expressed much less frequently in SCLC than in non-SCLC,” Scott J. Antonia, MD, of Duke Cancer Institute, Durham, N.C., who was the first author on that study, said during the symposium.

A particularly encouraging finding was that responders included patients with platinum-refractory SCLC for whom treatments in the relapse setting are lacking, Dr Antonia said.

An exploratory analysis of CheckMate 032 also showed better responses among patients in the highest tumor mutation burden (TMB) tertile, especially in the combination therapy group, leading to the hypothesis-generating finding that TMB may predict response, he said.

Another suggestion of nivolumab’s potential came from the randomized CheckMate 331 study comparing the checkpoint inhibitor with chemotherapy in relapsed SCLC patients. As reported in 2018 at the European Society for Medical Oncology (ESMO), no overall survival (OS) benefit was apparent at 12 months (37% vs. 34%), but a separation of the curves at 36 months suggested a possible OS benefit with nivolumab, Dr. Antonia noted, adding that the difference was “obviously small” and requires “a lot more work related to that.”

Subgroup analyses in that study also were “perhaps revealing” in that patients without liver metastases derived benefit (hazard ratio, 0.75), as did those who were platinum resistant (HR, 0.71), he said.

The phase 1b KEYNOTE-028 study showed that the anti–PD-1 monoclonal antibody pembrolizumab also has activity in PD-L1–positive SCLC patients in the relapsed setting, and pooled data from that study and KEYNOTE-158, which included both PD-L1–positive and –negative patients, showed promising antitumor activity and durable responses with pembrolizumab. The pooled data, as presented at the 2019 annual meeting of the American Association for Cancer Research, showed an objective response rate (ORR) of 19%, including complete and partial response rates of 2% and 17%, respectively.

“And there appears to be, at least preliminarily, some durability to the responses,” he said, noting that 9 of 16 patients experienced at least an 18-month response. “Progression-free survival was 2 months, and overall survival was 7.7 months.”

The IMpower133 study showed significantly longer OS and progression-free survival (PFS) with the addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage SCLC (HR, 0.70). Some late merging of the survival curves was apparent, but the data haven’t matured.

“Hopefully there will be some evidence of a lifting of the tail of the survival curve with some durability of responsiveness like we see in non–small cell lung cancer,” he said.

When it comes to “making the next leap” toward improved clinical efficacy with immunotherapy for SCLC, “we need to think about three general categories of how it is that tumors evade rejection by the immune system,” he said.

One category involves SCLC patients with an insufficient numbers of T cells generated within the lymphoid compartment; in those patients, an immunotherapeutic approach directed at the tumor microenvironment won’t lead to a response. Another category includes patients who generate enough T cells within the lymphoid compartment but in whom those cells aren’t driven into the tumor parenchyma. The third involves those whose T cells may make it into the tumor parenchyma, but are inhibited in the tumor microenvironment, he explained.

Strategies to increase the number of T cells generated in the lymphoid compartment – such as vaccines, radiation, adoptive cell therapy with chimeric antigen receptors, to name a few – were a focus of research efforts more than a decade ago, but the pendulum swung more toward addressing the tumor microenvironment.

“I think that the pendulum needs to swing back to the middle, and we do need to develop combination immunotherapies paying attention to the lymphoid compartment as well as the tumor microenvironment,” Dr. Antonia said, listing these “guiding principles” for the development of effective SCLC immunotherapy:

• Combination immunotherapy is necessary.
• Mechanisms exploited by SCLC to evade immune-mediated rejection need to be identified.
• Inclusion of strategies for driving tumor-reactive T cells into the tumor microenvironment should be considered.
• PD-1 blockade should continue.
• Biomarkers should be identified for selecting patients for tumor microenvironment–targeted agents.

Clinical and molecular biomarkers

Indeed, there is much work to do with respect to biomarkers, but their use in the selection of SCLC patients for immunotherapy is “finally starting to evolve and evolve more rapidly,” according to Lauren Averett Byers, MD, of the University of Texas MD Anderson Cancer Center, Houston.

Numerous groups are identifying biomarkers for both targeted therapy and immunotherapy, Dr. Byers said, noting that “this has been a really incredible time for those of us who take care of small cell lung cancer patients.”

“It’s been many decades since we’ve had a new option for our patients ... and so I think with the landmark clinical trials ... we really do have a new option in terms of a new standard of care,” she said of immunotherapy. “But I think we also recognize that there is significant room for further improvement.”

Many patients don’t respond or don’t respond as well as hoped, and therefore an “incredible need” exists for personalized biomarker-driven therapy for SCLC and its distinct molecular subsets, she said.

Emerging and potential biomarkers and other factors to guide treatment decisions include TMB, PD-L1, clinical history/duration of response in immunotherapy-naive relapsed patients, gene expression profile–driven SCLC subgroup identification, and DNA damage response (DDR) inhibitors such as Chk1, PARP, and Wee1 inhibitors.

TMB, as described by Dr. Antonia with respect to the CheckMate 032 findings of improved outcomes in those in the highest TMB tertile, is one potentially helpful biomarker for response.

“In thinking about how we apply this, though, we have to think about what we’re deciding between,” Dr. Byers said, explaining that the responses in patients with medium or low TMB – between 0% and 10% in most studies in the relapsed SCLC setting – aren’t that different from those seen with other treatment options.

“Currently we’re not routinely ordering TMB to decide on immunotherapy because there are still patients that can be as likely to benefit from immunotherapy as they are from chemotherapy, and potentially with more durable responses,” she said. “But certainly, it is a way to potentially identify patients where immunotherapy alone may have very high rates of response.”

IMPower133 showed no difference in hazard ratios for death based on TMB detected in the blood in SCLC patients treated with first-line atezolizumab plus chemotherapy, but “this still supports using the immunotherapy/chemotherapy combination broadly, and also emphasizes the need for an improved – and probably expanded – look at other biomarkers that may help predict response,” she said.

PD-L1 appears to have a role as a biomarker in this setting as well, she said, citing the KEYNOTE-028 findings of numerically improved responses in PD-L1–positive SCLC patients treated with pembrolizumab.

“We should be looking at PD-L1 levels, but we need further information to know how we might use this,” she said.

In immunotherapy-naive patients who relapse after front-line chemotherapy, the most important biomarker is clinical history and duration of response to platinum, which helps guide second-line treatment, Dr. Byers said.

“I think there’s consensus among most of us that patients who have platinum-refractory disease and are unlikely to respond to further platinum therapy or other chemotherapy agents are patients who really should get immunotherapy,” she added, explaining that the available data suggest there is no cross-resistance and that there may actually be enhanced benefit with immunotherapy in such patients.

Using molecular data to identify SCLC subtypes based on gene expression profiles is another area of interest, she said.

In fact, new data presented at the WCLC conference by Carl Gay, MD, PhD, a former fellow in her lab and now a junior faculty member at MD Anderson, identified four specific SCLC subgroups; three were driven by activation of the known transcription factors ASCL1, NEUROD1, and POU2F3, but an additional “inflamed” group without expression of those three transcription factors was also identified.

That “triple-negative” group had significantly higher expression of human leukocyte antigen and very high T-cell activation with expression of multiple immune checkpoints representing candidate targets, she said, adding: “We hypothesize that this group may be the group in SCLC that gets relatively greater benefit from immune checkpoint blockade.”

DDR is also garnering attention.

“Since there was this signal that [patients with] DNA damage ... tend to be more sensitive to immunotherapy ... we looked at whether or not targeted agents that prevented repair of DNA damage and induced increased levels of DNA damage ... might activate the innate immune system through the STING pathway and if that could be a potential approach to enhance immunotherapy response,” she said.

The approach showed promise in cell lines in a mouse model and also in an immunocompetent SCLC mouse model.

“It was really interesting to see how these drugs might potentially enhance response to immunotherapy,” Dr. Byers said, noting that the same phenomenon has been seen with PARP inhibitors in breast and colon cancer models and in other solid tumors.

“So I think that there is something there, and fortunately we’re now at a point now where we can start looking at some of these combinations in the clinic across many different cancer types,” she said. “I think we’ll be learning a lot more about what’s happening with these patients.”

At present, however, “there is more that we don’t know about the immune landscape of small cell lung cancer than what we do know, and that’s a real opportunity where, over the next several years, we will gain a deeper understanding ... that will direct where we’re going in terms of translating that back into the clinic.”
 

The SCLC immune microenvironment

The immune microenvironment will be an integral part of that journey, according to Dr. Liu.

“We consider small cell lung cancer – a carcinogen-associated cancer – to be one that has a high somatic mutation rate, but what we’ve learned over the past few years is that tumor neoantigens are certainly necessary – but not sufficient,” he said, noting that mutational burden represents the potential for immune-mediated antitumor responses, but is not a guarantee.

“As a group, we need to develop strategies to overcome the powerful immunosuppressive microenvironment in small cell lung cancer,” he added.

Lessons learned from studying PD-L1 provided the first insight into the importance of the immune microenvironment: PD-L1 expression, as measured by tumor proportion score (TPS) holds predictive value in non–small cell lung cancer patients treated with PD-1 inhibitors, but the SCLC story is much more complex, he said.

Only 18% of SCLC patients in CheckMate 032 were PD-L1–positive, and “paradoxically, we see responses were better in the PD-L1–negative group,” he explained. The response rates for nivolumab/ipilimumab were 32% in the PD-L1–negative group and 10% in the PD-L1–positive group.

Recent findings regarding the use of the combined positive score (CPS), which unlike the TPS for determining PD-L1 status, includes PD-L1 expression on stromal cells, are also notable. In a phase 2 study of maintenance pembrolizumab in SCLC, for example, 3 of 30 patients were PD-L1 positive by TPS, and 8 of 20 were positive by CPS.

“And that did predict outcomes: We see a higher response rate [38% vs. 8%], better PFS [6.5 vs. 1.3 months], and better overall survival [13 months vs. 8 months] in pretreated small cell lung cancer,” he said.

Similarly, in KEYNOTE-158 when looking at pembrolizumab in previously treated SCLC, the overall response was modest at 18.7%, and median PFS was 2.0 months.

“Again, breaking it down by CPS, we see a different story,” Dr. Liu said. “We see better outcomes in the PD-L1–positive [group] if you’re factoring in expression in the microenvironment.” When assessed by CPS, 39% of patients were PD-L1 positive; those patients, when compared with PD-L1–negative patients, had improved 12-month PFS (28.5% vs. 8.2%, respectively), 12-month OS (53.3% vs. 30.7%), and median OS (14.9 vs. 5.9 months).

Checkpoint expression in tumor-infiltrating lymphocytes (TILs) also has been shown to vary when compared with tumor expression. SCLC tissue microarrays in a study presented at ASCO 2017 (Rivalland et al. Abstract 8569), for example, showed that tumor expression versus TIL expression of PD-L1, TIMS3, and LAG3 was 18% vs. 67%, 0% vs. 59%, and 0% vs. 45%, respectively, and the TIL expression correlated with survival, Dr. Liu said.

“So when we consider things like PD-L1 expression, looking at a narrow scope of just the tumor is not enough. We need to consider the stromal cells, the microenvironment,” he said. “And even larger than that, PD-1/PD-L1 interaction is but a fraction of powerful, dynamic, immunosuppressive factors in small cell lung cancer.

“All of these will need to be accounted for in various patients.”

These findings and others, like those from a recent study showing differentially expressed genes and pathways in the stromal cells of longer- versus shorter-term survivors, raise questions about whether the lymphoid compartment can be manipulated in SCLC to improve immune responses using the strategies discussed by Dr. Antonia and Dr. Byers, he said.

In “cold” tumor phenotypes, one hypothesis has tumor-associated macrophages (TAMs) preventing infiltration of the cytotoxic T lymphocytes, which raises the possibility that TAMs are a therapeutic target, he said.

“At this meeting and others we’ve heard of lurbinectedin as a possible active drug in SCLC,” he said, noting that preclinical data also demonstrate that lurbinectedin targets TAMs. Perhaps the agent’s future role will be that of an immune modulator rather than a cytotoxic agent, he suggested.

Regulatory T cells (Tregs) are another potential immunomodulatory target, but the problem is their redundancy and the lack of good models to identify which ones are active, he said.

“Myeloid-derived suppressor cells [MDSC] are another important part of the microenvironment and could be potential targets to restore immune responses,” he added.

But many questions remain, he said.

For example: How can we overcome an immunosuppressive tumor microenvironment? Can we inhibit arginine or adenosine? Can we restore interleukin-2? Can we target things like LAG3? Can we eliminate the Treg and MDSC population? Which strategies are appropriate? Are they the same in immunotherapy-naive vs. immunotherapy-experienced patients – is intrinsic resistance the same as acquired resistance? Are they the same in each patient, or even throughout each tumor?

And importantly, “how will we choose between these various molecules we have?” he asked.

“At this point we’ve learned that empiric strategies are unlikely to yield meaningful results. We’ve been through empiric strategies in SCLC for years, and it doesn’t work because of that heterogeneity – unless there’s a universal underlying mechanism,” he said. “I think more than likely the studies have to be enriched for the right patients; we need to apply everything we’ve learned from non–small cell lung cancer and apply the principles of targeted therapy to immunotherapy – and that requires the identification of predictive biomarkers.”

It’s a challenging task in SCLC, but “it still needs to be done,” he said, noting that the lack of “perfect models” means relying on cell lines in surgical specimens.

However, while surgical tissue banks are an important resource, there is doubt about whether the specimens are representative of patients in the clinic, he noted.

“At best need to confirm what we know; at worst we may need to rework a lot of the underlying maps,” he said.

Therefore, future SCLC studies “are simply going to need more biopsies,” and that is yet another challenge, he added, explaining that the largely central tumors and fairly aggressive, rapid course of disease in SCLC make it difficult to obtain meaningful biopsies.

“But it’s the only way to move forward,” he said. “As a community we have to stand up and obtain more biopsies and tissue for in-depth analysis.”

As much as that will advance the field, the greatest impact for SCLC will be through prevention, including by smoking cessation, he added.

“Our overarching goal for small cell lung cancer remains achieving durable disease control and long-term survival for our patients,” Dr. Liu said. “That certainly is a lofty goal, but those are probably the only goals worth having.”

Dr. Liu, Dr. Byers, and Dr. Antonia reported relationships with numerous pharmaceutical companies.




 

BARCELONA – Programmed death-ligand 1 (PD-L1) status in patients with advanced triple negative or HER2-positive breast cancer appears to identify distinct disease entities with varying likelihood of benefit from immune checkpoint inhibition, according to Giampaolo Bianchini, MD.

This observation, which contrasts with findings in other solid tumors and expands the road map to improved outcomes with immunotherapy for metastatic breast cancer, is based in part on new findings presented at the European Society for Medical Oncology Congress.

Among additional lessons from those findings: PD-L1 assays are not easily interchangeable, and studies with a “one size fits all” approach should be avoided, Dr. Bianchini, head of the Breast Cancer Group – Medical Oncology and clinical translational and immunotherapy research at Ospedale San Raffaele, Milan, said at the congress.
 

IMPassion130 and PD-L1 assays

In the phase 3 IMpassion130 trial assessing nanoparticle, albumin-bound (nab)-paclitaxel chemotherapy + either the anti-PD-L1 monoclonal antibody atezolizumab or placebo for the first-line treatment of metastatic triple-negative breast cancer (mTNBC), investigators used, and validated, the VENTANA PD-L1 SP142 assay to evaluate PD-L1 expression in immune cells (IC). PD-L1 positivity was defined using a 1% cutoff, meaning that PD-L1-stained IC encompassed at least 1% of the tumor area.

The trial demonstrated significantly improved progression-free survival (PFS) in the atezolizumab arm, both in the intention-to-treat (ITT) analysis (7.2 vs. 5.5 months in the placebo arm; hazard ratio, 0.80), and the PD-L1-positive subgroup (7.5 vs. 5.0 months; HR, 0.62), and the results were published in November 2018 (N Engl J Med. 2018; 379:2108-21).

“IMpassion130 is the first phase 3 trial demonstrating clinical benefit of cancer immunotherapy in patients with PD-L1-positive, metastatic triple-negative breast cancer,” Hope S. Rugo, MD, said at the congress. “The combination of atezolizumab and nab-paclitaxel is now approved in the United States and Europe for this indication.”

Subgroup analyses indicated that PFS and OS benefit with atezolizumab + nab-paclitaxel vs. nab-paclitaxel alone was greater in double-positive patients (those with SP142 positivity and either SP263 or 22C3 positivity) than in patients who were SP263-positive/SP142-negative or 22C3-positive/SP142-negative.

Dr. Rugo and her colleagues also found that the benefits with atezolizumab + nab-paclitaxel in PD-L1-positive patients were apparent regardless of the source of tissue for testing (breast or distant metastases).

They concluded that the findings of the assays are not equivalent; 22C3 and SP263 identified more patients as PD-L1 positive, and SP142-positivity was encompassed in positive tests for both.

“The clinical benefit in the 22C3-positive and the SP263-positive subgroups appear to be driven by the SP142-positive subgroup, and [SP142] identifies patients with the longest median progression-free and overall survival from the addition of atezolizumab to nab-paclitaxel,” she said “The SP142 assay with an IC cutoff of 1% or greater is the approved diagnostic test used to identify patients with metastatic triple-negative breast cancer who are most likely to benefit from the addition of the checkpoint inhibitor atezolizumab to nab-paclitaxel.”

As for whether the SP142 should be the assay of choice in other settings in which it hasn’t been validated, Dr. Rugo said it is advisable to use the assay that has been validated in a positive trial.

“That’s what we would generally do ... however, recognizing that some countries are not using SP142, and some sites may not have access, certainly you encompass that population in the patients whose tumors are positive by both other assays,” she said. “The risk is that you might overtreat, and the cost of treatment is greater.”

Excess toxicity is also a concern in that situation, she said, adding that “hopefully in the future we’ll be able to figure out ways to have even more patients benefit from the addition of immunotherapy so that won’t be an issue.”

“What this data shows is that you can feel secure that you are encompassing the patient population identified by the parent trial to benefit from the addition of atezolizumab by using either of the other two assays; you’re only missing 1% – so that’s very reasonable,” she said. “The risk is that you’re overtreating; it’s quite likely that there’s a population there that isn’t benefiting as much, but that’s a balance.”

The findings from IMPassion130 with regard to OS in the unselected population that included PD-L1-negative patients (18.7 vs. 21.0 months with vs. without atezolizumab; HR, 0.86) underscore the fact that “one size does not fit all” when it comes to immunotherapy benefit, Dr. Bianchini said.

This is further demonstrated by the post hoc analysis comparing IHC assays, he said, explaining that 63% of IMPassion130 patients who were considered PD-L1-negative based on the SP142 “actually scored as PD-L1-positive by the other tests.

“So the very clinically important question is if there is any evidence from the data that [the PD-L1-negative group] benefits in a significant way from the addition of atezolizumab,” he said. “I don’t see evidence for a clinical benefit, I see evidence to look for new biomarkers to identify a potential population who will benefit.”

The “absence of evidence is not evidence of absence,” he stressed, noting that it may be possible – with the right biomarkers – to identify PD-L1-negative patients who would benefit.

What the findings do show, however, is support for the FDA decision to approve the SP142 assay with an IC cutoff of 1% as a companion diagnostic tool, and that PD-L1 is ideally assessed using samples from both the primary and metastatic site, as the IMPassion130 data “do not inform whether PD-L1 assessment in primary and metastatic sites is equally informative,” he said.

In addition, Dr. Bianchini said the findings suggest that more information is needed about using different cutoffs for SP263 and 22C3, and he cautioned against “directly translating these finding to other disease settings or immune combinations.

“Defining new biomarkers to identify who within the PD-L1-negative group might benefit from this combination remains an unmet need,” he said. “For sure, I don’t see a space for the other tests to define this population,” he added.

KEYNOTE-119, KATE2, and future directions

Both the randomized, open-label, phase 3 KEYNOTE-119 study of the checkpoint inhibitor pembrolizumab vs. single-agent chemotherapy for mTNBC, and the phase 2 KATE2 trial of the antibody-drug conjugate trastuzumab emtansine (T-DM1) + either atezolizumab or placebo in previously treated HER2-positive breast cancer patients, failed to meet their respective primary study endpoints.

But the news isn’t all bad, Dr. Bianchini said.

For example, in KEYNOTE-119, second- or third-line pembrolizumab monotherapy did not significantly improve OS vs. chemotherapy for mTNBC, but the pembrolizumab treatment effect increased as PD-L1 enrichment increased, he explained.

Pembrolizumab showed promising antitumor activity and manageable safety in mTNBC in prior trials, and was therefore further assessed in the KEYNOTE-119 study of 601 patients with centrally confirmed TNBC, 1-2 prior systemic treatments for mTNBC, progression on the latest therapy, and a prior anthracycline or taxane, Javier Cortés, MD, PhD, of Instituto Oncológico, Madrid, reported at the congress.

Sharon Worcester/MDedge News

Pembrolizumab was given at a dose of 200 mg every 3 weeks, and chemotherapy was physician’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine.

At a median follow-up of 9.9 months in the pembrolizumab group and 10.9 months in the chemotherapy group, OS did not differ significantly between the groups; this was true overall, in patients with a CPS of 10 or greater, and in those with a CPS of 1 or greater.

In all-comers, the HR for OS was 0.97, compared with 0.78 in patients with CPS of 10 or greater, and 0.86 in those with CPS of 1 or greater, Dr. Cortés said.

“One of the most interesting exploratory analyses was OS in those patients with CPS of 20 or higher,” he said, noting that median OS in that group was 14.9 vs.12.5 months with pembrolizumab vs. with chemotherapy (HR, 0.58).

Pembrolizumab did not improve overall PFS, but again, the rates improved with higher CPS. Duration of response, however, was longer with pembrolizumab vs. chemotherapy (12.2 vs. 8.3 months overall; 12.2 vs. 6.5 months for CPS of 1 or greater; and not reached vs. 7.1 months for CPS of 10 or greater).

Grade 3-5 AEs occurred in 35% vs. 49% of patients in the pembrolizumab vs. chemotherapy groups, with nine deaths occurring in each, Dr. Cortés said, adding that treatment-related AEs occurred in 14% (with one death) and 36% (with two deaths), respectively, and grade 3-4 immune-mediated AEs and infusion reactions occurred in 3.2% vs. 1.0% (no deaths), respectively.

In the double-blind, signal-seeking KATE2 trial, as reported in 2018 at the San Antonio Breast Cancer Symposium, no overall PFS improvement was seen with atezolizumab + T-DM1 (median of 8.2 vs. 6.8 months; HR, 0.82; 12-month PFS 38% vs. 34%), but again, a possible benefit was seen in PD-L1-positive patients (8.5 vs. 4.1 months; HR, 0.60).

KATE2 included 202 patients with advanced HER2-positive breast cancer that progressed after treatment with T-DM1 and a taxane. They were randomized 2:1 to receive intravenous T-DM1 at a dose of 3.6 mg/kg plus atezolizumab (1,200 mg) or placebo every 3 weeks until loss of clinical benefit or intolerable toxicity.

The “overall survival and final safety results” show that at a median follow-up of 19.0 months in the atezolizumab arm and 18.2 months in the placebo arm, with 52 OS events reported, median OS was not reached in either arm and 1-year survival was similar in the two groups (89.1% and 89.0%), Leisha A. Emens, MD, PhD, professor of medicine in hematology/oncology and co-leader of the Hillman Cancer Immunology and Immunotherapy Program at Hillman Cancer Center, University of Pittsburgh Medical Center (UPMC) reported at the congress.

“And when you look at duration of response, you see an increase not just in the number ... but the quality of the response,” he said, noting that for PFS, as well, a trend toward superiority is seen “that is consistent with all the other endpoints.”

“So overall, the application of incrementally restrictive cut-off of CPS lends weight to the exploratory analysis showing better survival from pembrolizumab in tumors with CPS more than 20,” Dr. Bianchini said, noting that the “real question,” however, is whether the finding “is worth clinical implementation.

“We know a lot about the primary tumor and immune infiltration. We’ve learned ... that if you wait and look ahead at immune infiltration in the advanced stage, you find that the tumor becomes smart,” he said, explaining that tumor/immune co-evolution leads to increased immuno-editing and immune subversion and it becomes “much harder to just hit the tumor with PD-L1, because this is not the only mechanism of immune escape.”

A review of several studies shows that in similar populations defined by biomarkers, response rates in patients treated with checkpoint inhibitors decrease in the second- and third-line setting vs. the first-line setting, he said.

For example, pembrolizumab response rates in the first-line and second-line or greater setting in cohort B of the KEYNOTE-086 study were 21.4% and 5.7%, respectively, compared with 12.3% in the second- to third-line setting in KEYNOTE-119, he said.

Another consideration is whether monotherapy or combination therapy is preferable, and the data suggest that regardless of how PD-L1-positivity is defined (by CPS cutoff of 1 vs. 20, for example), most patients treated with monotherapy progress within the first 3 months, he said.

“I don’t see that this is a safe approach for the majority of these patients. So without better biomarkers, combinations should always be preferred, at least to avoid early progression,” Dr. Bianchini said, adding that the open question, then, is: “If we set the new standard in the first-line as the combination of nab-paclitaxel and atezolizumab for PD-L1-positive patients defined by the VENTANA [SP142 assay], should we continue with immune checkpoint [inhibition] using different combinations?”

“Of course, at the time the trial was designed, the results of IMpassion were not available, but it’s very important, because [the findings] add to the evidence that immunotherapy is extremely relevant for some patients,” he said.

KATE2 further demonstrated the importance of PD-L1 status, he said, adding that due to its limitations, including small sample size and short follow-up, longer follow-up is needed to better evaluate duration of response and PFS.

“Despite the trial limitations, the qualitative effect seen in all clinical endpoints – overall response rate, progression-free survival, overall survival – in PD-L1-positive tumors defined by SP142 ... provided strong and robust signals supporting the investigation of immune checkpoint inhibitors in HER-positive breast cancer,” he said, noting that “many trials are ongoing in the early setting and the advanced setting.”

In addition to the lessons of these trials with respect to the interchangeability of PD-L1 IHC assays and the value of PD-L1 assessment for identifying the likelihood of benefit from immune checkpoint inhibitors, the findings highlight the possibility that PD-L1-negative tumors require different immunotherapy approaches or alternative therapeutic strategies, and underscore that the benefit of immunotherapy in PD-L1-positive patients is still restricted to a minority.

“So new studies and approaches with immuno-oncology are needed, and we need more effective biomarkers, because we need to have precision oncology applied – we need to go in that direction,” he concluded.

Dr. Bianchini reported consultancy/honorarium and or advisory board activity associated with Roche, MSD, AstraZeneca, Pfizer, Chugai, EISAI, Lilly, Novartis, Amgen, Sanofi, Neopharm, and Genomic Health. The IMPassion30 trial was funded by F. Hoffmann-La Roche Ltd.; Dr. Rugo reported research grants, other funding, and or travel/accommodation/expenses from Pfizer, Novartis, Eli Lilly, Merck, OBI, EISAI, Plexxikon, Genentech/Roche, MacroGenics, PUMA, Mylan, Immunomedics, Daiichi Sankyo, and Celltrion. KEYNOTE-119 was funded by Merck Sharp & Dohme Corp.; Dr. Cortés and Dr. Emens reported numerous funding relationships but none with F. Hoffman-La Roche. KATE2 was funded by F. Hoffmann-La Roche.
 

Sources: IMPassion130; ESMO Abstract LBA20; KEYNOTE-119: ESMO Abstract LBA21; KATE2: ESMO Abstract 305O.

BARCELONA – Programmed death-ligand 1 (PD-L1) status in patients with advanced triple negative or HER2-positive breast cancer appears to identify distinct disease entities with varying likelihood of benefit from immune checkpoint inhibition, according to Giampaolo Bianchini, MD.

This observation, which contrasts with findings in other solid tumors and expands the road map to improved outcomes with immunotherapy for metastatic breast cancer, is based in part on new findings presented at the European Society for Medical Oncology Congress.

Among additional lessons from those findings: PD-L1 assays are not easily interchangeable, and studies with a “one size fits all” approach should be avoided, Dr. Bianchini, head of the Breast Cancer Group – Medical Oncology and clinical translational and immunotherapy research at Ospedale San Raffaele, Milan, said at the congress.
 

IMPassion130 and PD-L1 assays

In the phase 3 IMpassion130 trial assessing nanoparticle, albumin-bound (nab)-paclitaxel chemotherapy + either the anti-PD-L1 monoclonal antibody atezolizumab or placebo for the first-line treatment of metastatic triple-negative breast cancer (mTNBC), investigators used, and validated, the VENTANA PD-L1 SP142 assay to evaluate PD-L1 expression in immune cells (IC). PD-L1 positivity was defined using a 1% cutoff, meaning that PD-L1-stained IC encompassed at least 1% of the tumor area.

The trial demonstrated significantly improved progression-free survival (PFS) in the atezolizumab arm, both in the intention-to-treat (ITT) analysis (7.2 vs. 5.5 months in the placebo arm; hazard ratio, 0.80), and the PD-L1-positive subgroup (7.5 vs. 5.0 months; HR, 0.62), and the results were published in November 2018 (N Engl J Med. 2018; 379:2108-21).

“IMpassion130 is the first phase 3 trial demonstrating clinical benefit of cancer immunotherapy in patients with PD-L1-positive, metastatic triple-negative breast cancer,” Hope S. Rugo, MD, said at the congress. “The combination of atezolizumab and nab-paclitaxel is now approved in the United States and Europe for this indication.”

Subgroup analyses indicated that PFS and OS benefit with atezolizumab + nab-paclitaxel vs. nab-paclitaxel alone was greater in double-positive patients (those with SP142 positivity and either SP263 or 22C3 positivity) than in patients who were SP263-positive/SP142-negative or 22C3-positive/SP142-negative.

Dr. Rugo and her colleagues also found that the benefits with atezolizumab + nab-paclitaxel in PD-L1-positive patients were apparent regardless of the source of tissue for testing (breast or distant metastases).

They concluded that the findings of the assays are not equivalent; 22C3 and SP263 identified more patients as PD-L1 positive, and SP142-positivity was encompassed in positive tests for both.

“The clinical benefit in the 22C3-positive and the SP263-positive subgroups appear to be driven by the SP142-positive subgroup, and [SP142] identifies patients with the longest median progression-free and overall survival from the addition of atezolizumab to nab-paclitaxel,” she said “The SP142 assay with an IC cutoff of 1% or greater is the approved diagnostic test used to identify patients with metastatic triple-negative breast cancer who are most likely to benefit from the addition of the checkpoint inhibitor atezolizumab to nab-paclitaxel.”

As for whether the SP142 should be the assay of choice in other settings in which it hasn’t been validated, Dr. Rugo said it is advisable to use the assay that has been validated in a positive trial.

“That’s what we would generally do ... however, recognizing that some countries are not using SP142, and some sites may not have access, certainly you encompass that population in the patients whose tumors are positive by both other assays,” she said. “The risk is that you might overtreat, and the cost of treatment is greater.”

Excess toxicity is also a concern in that situation, she said, adding that “hopefully in the future we’ll be able to figure out ways to have even more patients benefit from the addition of immunotherapy so that won’t be an issue.”

“What this data shows is that you can feel secure that you are encompassing the patient population identified by the parent trial to benefit from the addition of atezolizumab by using either of the other two assays; you’re only missing 1% – so that’s very reasonable,” she said. “The risk is that you’re overtreating; it’s quite likely that there’s a population there that isn’t benefiting as much, but that’s a balance.”

The findings from IMPassion130 with regard to OS in the unselected population that included PD-L1-negative patients (18.7 vs. 21.0 months with vs. without atezolizumab; HR, 0.86) underscore the fact that “one size does not fit all” when it comes to immunotherapy benefit, Dr. Bianchini said.

This is further demonstrated by the post hoc analysis comparing IHC assays, he said, explaining that 63% of IMPassion130 patients who were considered PD-L1-negative based on the SP142 “actually scored as PD-L1-positive by the other tests.

“So the very clinically important question is if there is any evidence from the data that [the PD-L1-negative group] benefits in a significant way from the addition of atezolizumab,” he said. “I don’t see evidence for a clinical benefit, I see evidence to look for new biomarkers to identify a potential population who will benefit.”

The “absence of evidence is not evidence of absence,” he stressed, noting that it may be possible – with the right biomarkers – to identify PD-L1-negative patients who would benefit.

What the findings do show, however, is support for the FDA decision to approve the SP142 assay with an IC cutoff of 1% as a companion diagnostic tool, and that PD-L1 is ideally assessed using samples from both the primary and metastatic site, as the IMPassion130 data “do not inform whether PD-L1 assessment in primary and metastatic sites is equally informative,” he said.

In addition, Dr. Bianchini said the findings suggest that more information is needed about using different cutoffs for SP263 and 22C3, and he cautioned against “directly translating these finding to other disease settings or immune combinations.

“Defining new biomarkers to identify who within the PD-L1-negative group might benefit from this combination remains an unmet need,” he said. “For sure, I don’t see a space for the other tests to define this population,” he added.

KEYNOTE-119, KATE2, and future directions

Both the randomized, open-label, phase 3 KEYNOTE-119 study of the checkpoint inhibitor pembrolizumab vs. single-agent chemotherapy for mTNBC, and the phase 2 KATE2 trial of the antibody-drug conjugate trastuzumab emtansine (T-DM1) + either atezolizumab or placebo in previously treated HER2-positive breast cancer patients, failed to meet their respective primary study endpoints.

But the news isn’t all bad, Dr. Bianchini said.

For example, in KEYNOTE-119, second- or third-line pembrolizumab monotherapy did not significantly improve OS vs. chemotherapy for mTNBC, but the pembrolizumab treatment effect increased as PD-L1 enrichment increased, he explained.

Pembrolizumab showed promising antitumor activity and manageable safety in mTNBC in prior trials, and was therefore further assessed in the KEYNOTE-119 study of 601 patients with centrally confirmed TNBC, 1-2 prior systemic treatments for mTNBC, progression on the latest therapy, and a prior anthracycline or taxane, Javier Cortés, MD, PhD, of Instituto Oncológico, Madrid, reported at the congress.

Sharon Worcester/MDedge News

Pembrolizumab was given at a dose of 200 mg every 3 weeks, and chemotherapy was physician’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine.

At a median follow-up of 9.9 months in the pembrolizumab group and 10.9 months in the chemotherapy group, OS did not differ significantly between the groups; this was true overall, in patients with a CPS of 10 or greater, and in those with a CPS of 1 or greater.

In all-comers, the HR for OS was 0.97, compared with 0.78 in patients with CPS of 10 or greater, and 0.86 in those with CPS of 1 or greater, Dr. Cortés said.

“One of the most interesting exploratory analyses was OS in those patients with CPS of 20 or higher,” he said, noting that median OS in that group was 14.9 vs.12.5 months with pembrolizumab vs. with chemotherapy (HR, 0.58).

Pembrolizumab did not improve overall PFS, but again, the rates improved with higher CPS. Duration of response, however, was longer with pembrolizumab vs. chemotherapy (12.2 vs. 8.3 months overall; 12.2 vs. 6.5 months for CPS of 1 or greater; and not reached vs. 7.1 months for CPS of 10 or greater).

Grade 3-5 AEs occurred in 35% vs. 49% of patients in the pembrolizumab vs. chemotherapy groups, with nine deaths occurring in each, Dr. Cortés said, adding that treatment-related AEs occurred in 14% (with one death) and 36% (with two deaths), respectively, and grade 3-4 immune-mediated AEs and infusion reactions occurred in 3.2% vs. 1.0% (no deaths), respectively.

In the double-blind, signal-seeking KATE2 trial, as reported in 2018 at the San Antonio Breast Cancer Symposium, no overall PFS improvement was seen with atezolizumab + T-DM1 (median of 8.2 vs. 6.8 months; HR, 0.82; 12-month PFS 38% vs. 34%), but again, a possible benefit was seen in PD-L1-positive patients (8.5 vs. 4.1 months; HR, 0.60).

KATE2 included 202 patients with advanced HER2-positive breast cancer that progressed after treatment with T-DM1 and a taxane. They were randomized 2:1 to receive intravenous T-DM1 at a dose of 3.6 mg/kg plus atezolizumab (1,200 mg) or placebo every 3 weeks until loss of clinical benefit or intolerable toxicity.

The “overall survival and final safety results” show that at a median follow-up of 19.0 months in the atezolizumab arm and 18.2 months in the placebo arm, with 52 OS events reported, median OS was not reached in either arm and 1-year survival was similar in the two groups (89.1% and 89.0%), Leisha A. Emens, MD, PhD, professor of medicine in hematology/oncology and co-leader of the Hillman Cancer Immunology and Immunotherapy Program at Hillman Cancer Center, University of Pittsburgh Medical Center (UPMC) reported at the congress.

“And when you look at duration of response, you see an increase not just in the number ... but the quality of the response,” he said, noting that for PFS, as well, a trend toward superiority is seen “that is consistent with all the other endpoints.”

“So overall, the application of incrementally restrictive cut-off of CPS lends weight to the exploratory analysis showing better survival from pembrolizumab in tumors with CPS more than 20,” Dr. Bianchini said, noting that the “real question,” however, is whether the finding “is worth clinical implementation.

“We know a lot about the primary tumor and immune infiltration. We’ve learned ... that if you wait and look ahead at immune infiltration in the advanced stage, you find that the tumor becomes smart,” he said, explaining that tumor/immune co-evolution leads to increased immuno-editing and immune subversion and it becomes “much harder to just hit the tumor with PD-L1, because this is not the only mechanism of immune escape.”

A review of several studies shows that in similar populations defined by biomarkers, response rates in patients treated with checkpoint inhibitors decrease in the second- and third-line setting vs. the first-line setting, he said.

For example, pembrolizumab response rates in the first-line and second-line or greater setting in cohort B of the KEYNOTE-086 study were 21.4% and 5.7%, respectively, compared with 12.3% in the second- to third-line setting in KEYNOTE-119, he said.

Another consideration is whether monotherapy or combination therapy is preferable, and the data suggest that regardless of how PD-L1-positivity is defined (by CPS cutoff of 1 vs. 20, for example), most patients treated with monotherapy progress within the first 3 months, he said.

“I don’t see that this is a safe approach for the majority of these patients. So without better biomarkers, combinations should always be preferred, at least to avoid early progression,” Dr. Bianchini said, adding that the open question, then, is: “If we set the new standard in the first-line as the combination of nab-paclitaxel and atezolizumab for PD-L1-positive patients defined by the VENTANA [SP142 assay], should we continue with immune checkpoint [inhibition] using different combinations?”

“Of course, at the time the trial was designed, the results of IMpassion were not available, but it’s very important, because [the findings] add to the evidence that immunotherapy is extremely relevant for some patients,” he said.

KATE2 further demonstrated the importance of PD-L1 status, he said, adding that due to its limitations, including small sample size and short follow-up, longer follow-up is needed to better evaluate duration of response and PFS.

“Despite the trial limitations, the qualitative effect seen in all clinical endpoints – overall response rate, progression-free survival, overall survival – in PD-L1-positive tumors defined by SP142 ... provided strong and robust signals supporting the investigation of immune checkpoint inhibitors in HER-positive breast cancer,” he said, noting that “many trials are ongoing in the early setting and the advanced setting.”

In addition to the lessons of these trials with respect to the interchangeability of PD-L1 IHC assays and the value of PD-L1 assessment for identifying the likelihood of benefit from immune checkpoint inhibitors, the findings highlight the possibility that PD-L1-negative tumors require different immunotherapy approaches or alternative therapeutic strategies, and underscore that the benefit of immunotherapy in PD-L1-positive patients is still restricted to a minority.

“So new studies and approaches with immuno-oncology are needed, and we need more effective biomarkers, because we need to have precision oncology applied – we need to go in that direction,” he concluded.

Dr. Bianchini reported consultancy/honorarium and or advisory board activity associated with Roche, MSD, AstraZeneca, Pfizer, Chugai, EISAI, Lilly, Novartis, Amgen, Sanofi, Neopharm, and Genomic Health. The IMPassion30 trial was funded by F. Hoffmann-La Roche Ltd.; Dr. Rugo reported research grants, other funding, and or travel/accommodation/expenses from Pfizer, Novartis, Eli Lilly, Merck, OBI, EISAI, Plexxikon, Genentech/Roche, MacroGenics, PUMA, Mylan, Immunomedics, Daiichi Sankyo, and Celltrion. KEYNOTE-119 was funded by Merck Sharp & Dohme Corp.; Dr. Cortés and Dr. Emens reported numerous funding relationships but none with F. Hoffman-La Roche. KATE2 was funded by F. Hoffmann-La Roche.
 

Sources: IMPassion130; ESMO Abstract LBA20; KEYNOTE-119: ESMO Abstract LBA21; KATE2: ESMO Abstract 305O.

BARCELONA – Programmed death-ligand 1 (PD-L1) status in patients with advanced triple negative or HER2-positive breast cancer appears to identify distinct disease entities with varying likelihood of benefit from immune checkpoint inhibition, according to Giampaolo Bianchini, MD.

This observation, which contrasts with findings in other solid tumors and expands the road map to improved outcomes with immunotherapy for metastatic breast cancer, is based in part on new findings presented at the European Society for Medical Oncology Congress.

Among additional lessons from those findings: PD-L1 assays are not easily interchangeable, and studies with a “one size fits all” approach should be avoided, Dr. Bianchini, head of the Breast Cancer Group – Medical Oncology and clinical translational and immunotherapy research at Ospedale San Raffaele, Milan, said at the congress.
 

IMPassion130 and PD-L1 assays

In the phase 3 IMpassion130 trial assessing nanoparticle, albumin-bound (nab)-paclitaxel chemotherapy + either the anti-PD-L1 monoclonal antibody atezolizumab or placebo for the first-line treatment of metastatic triple-negative breast cancer (mTNBC), investigators used, and validated, the VENTANA PD-L1 SP142 assay to evaluate PD-L1 expression in immune cells (IC). PD-L1 positivity was defined using a 1% cutoff, meaning that PD-L1-stained IC encompassed at least 1% of the tumor area.

The trial demonstrated significantly improved progression-free survival (PFS) in the atezolizumab arm, both in the intention-to-treat (ITT) analysis (7.2 vs. 5.5 months in the placebo arm; hazard ratio, 0.80), and the PD-L1-positive subgroup (7.5 vs. 5.0 months; HR, 0.62), and the results were published in November 2018 (N Engl J Med. 2018; 379:2108-21).

“IMpassion130 is the first phase 3 trial demonstrating clinical benefit of cancer immunotherapy in patients with PD-L1-positive, metastatic triple-negative breast cancer,” Hope S. Rugo, MD, said at the congress. “The combination of atezolizumab and nab-paclitaxel is now approved in the United States and Europe for this indication.”

Subgroup analyses indicated that PFS and OS benefit with atezolizumab + nab-paclitaxel vs. nab-paclitaxel alone was greater in double-positive patients (those with SP142 positivity and either SP263 or 22C3 positivity) than in patients who were SP263-positive/SP142-negative or 22C3-positive/SP142-negative.

Dr. Rugo and her colleagues also found that the benefits with atezolizumab + nab-paclitaxel in PD-L1-positive patients were apparent regardless of the source of tissue for testing (breast or distant metastases).

They concluded that the findings of the assays are not equivalent; 22C3 and SP263 identified more patients as PD-L1 positive, and SP142-positivity was encompassed in positive tests for both.

“The clinical benefit in the 22C3-positive and the SP263-positive subgroups appear to be driven by the SP142-positive subgroup, and [SP142] identifies patients with the longest median progression-free and overall survival from the addition of atezolizumab to nab-paclitaxel,” she said “The SP142 assay with an IC cutoff of 1% or greater is the approved diagnostic test used to identify patients with metastatic triple-negative breast cancer who are most likely to benefit from the addition of the checkpoint inhibitor atezolizumab to nab-paclitaxel.”

As for whether the SP142 should be the assay of choice in other settings in which it hasn’t been validated, Dr. Rugo said it is advisable to use the assay that has been validated in a positive trial.

“That’s what we would generally do ... however, recognizing that some countries are not using SP142, and some sites may not have access, certainly you encompass that population in the patients whose tumors are positive by both other assays,” she said. “The risk is that you might overtreat, and the cost of treatment is greater.”

Excess toxicity is also a concern in that situation, she said, adding that “hopefully in the future we’ll be able to figure out ways to have even more patients benefit from the addition of immunotherapy so that won’t be an issue.”

“What this data shows is that you can feel secure that you are encompassing the patient population identified by the parent trial to benefit from the addition of atezolizumab by using either of the other two assays; you’re only missing 1% – so that’s very reasonable,” she said. “The risk is that you’re overtreating; it’s quite likely that there’s a population there that isn’t benefiting as much, but that’s a balance.”

The findings from IMPassion130 with regard to OS in the unselected population that included PD-L1-negative patients (18.7 vs. 21.0 months with vs. without atezolizumab; HR, 0.86) underscore the fact that “one size does not fit all” when it comes to immunotherapy benefit, Dr. Bianchini said.

This is further demonstrated by the post hoc analysis comparing IHC assays, he said, explaining that 63% of IMPassion130 patients who were considered PD-L1-negative based on the SP142 “actually scored as PD-L1-positive by the other tests.

“So the very clinically important question is if there is any evidence from the data that [the PD-L1-negative group] benefits in a significant way from the addition of atezolizumab,” he said. “I don’t see evidence for a clinical benefit, I see evidence to look for new biomarkers to identify a potential population who will benefit.”

The “absence of evidence is not evidence of absence,” he stressed, noting that it may be possible – with the right biomarkers – to identify PD-L1-negative patients who would benefit.

What the findings do show, however, is support for the FDA decision to approve the SP142 assay with an IC cutoff of 1% as a companion diagnostic tool, and that PD-L1 is ideally assessed using samples from both the primary and metastatic site, as the IMPassion130 data “do not inform whether PD-L1 assessment in primary and metastatic sites is equally informative,” he said.

In addition, Dr. Bianchini said the findings suggest that more information is needed about using different cutoffs for SP263 and 22C3, and he cautioned against “directly translating these finding to other disease settings or immune combinations.

“Defining new biomarkers to identify who within the PD-L1-negative group might benefit from this combination remains an unmet need,” he said. “For sure, I don’t see a space for the other tests to define this population,” he added.

KEYNOTE-119, KATE2, and future directions

Both the randomized, open-label, phase 3 KEYNOTE-119 study of the checkpoint inhibitor pembrolizumab vs. single-agent chemotherapy for mTNBC, and the phase 2 KATE2 trial of the antibody-drug conjugate trastuzumab emtansine (T-DM1) + either atezolizumab or placebo in previously treated HER2-positive breast cancer patients, failed to meet their respective primary study endpoints.

But the news isn’t all bad, Dr. Bianchini said.

For example, in KEYNOTE-119, second- or third-line pembrolizumab monotherapy did not significantly improve OS vs. chemotherapy for mTNBC, but the pembrolizumab treatment effect increased as PD-L1 enrichment increased, he explained.

Pembrolizumab showed promising antitumor activity and manageable safety in mTNBC in prior trials, and was therefore further assessed in the KEYNOTE-119 study of 601 patients with centrally confirmed TNBC, 1-2 prior systemic treatments for mTNBC, progression on the latest therapy, and a prior anthracycline or taxane, Javier Cortés, MD, PhD, of Instituto Oncológico, Madrid, reported at the congress.

Sharon Worcester/MDedge News

Pembrolizumab was given at a dose of 200 mg every 3 weeks, and chemotherapy was physician’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine.

At a median follow-up of 9.9 months in the pembrolizumab group and 10.9 months in the chemotherapy group, OS did not differ significantly between the groups; this was true overall, in patients with a CPS of 10 or greater, and in those with a CPS of 1 or greater.

In all-comers, the HR for OS was 0.97, compared with 0.78 in patients with CPS of 10 or greater, and 0.86 in those with CPS of 1 or greater, Dr. Cortés said.

“One of the most interesting exploratory analyses was OS in those patients with CPS of 20 or higher,” he said, noting that median OS in that group was 14.9 vs.12.5 months with pembrolizumab vs. with chemotherapy (HR, 0.58).

Pembrolizumab did not improve overall PFS, but again, the rates improved with higher CPS. Duration of response, however, was longer with pembrolizumab vs. chemotherapy (12.2 vs. 8.3 months overall; 12.2 vs. 6.5 months for CPS of 1 or greater; and not reached vs. 7.1 months for CPS of 10 or greater).

Grade 3-5 AEs occurred in 35% vs. 49% of patients in the pembrolizumab vs. chemotherapy groups, with nine deaths occurring in each, Dr. Cortés said, adding that treatment-related AEs occurred in 14% (with one death) and 36% (with two deaths), respectively, and grade 3-4 immune-mediated AEs and infusion reactions occurred in 3.2% vs. 1.0% (no deaths), respectively.

In the double-blind, signal-seeking KATE2 trial, as reported in 2018 at the San Antonio Breast Cancer Symposium, no overall PFS improvement was seen with atezolizumab + T-DM1 (median of 8.2 vs. 6.8 months; HR, 0.82; 12-month PFS 38% vs. 34%), but again, a possible benefit was seen in PD-L1-positive patients (8.5 vs. 4.1 months; HR, 0.60).

KATE2 included 202 patients with advanced HER2-positive breast cancer that progressed after treatment with T-DM1 and a taxane. They were randomized 2:1 to receive intravenous T-DM1 at a dose of 3.6 mg/kg plus atezolizumab (1,200 mg) or placebo every 3 weeks until loss of clinical benefit or intolerable toxicity.

The “overall survival and final safety results” show that at a median follow-up of 19.0 months in the atezolizumab arm and 18.2 months in the placebo arm, with 52 OS events reported, median OS was not reached in either arm and 1-year survival was similar in the two groups (89.1% and 89.0%), Leisha A. Emens, MD, PhD, professor of medicine in hematology/oncology and co-leader of the Hillman Cancer Immunology and Immunotherapy Program at Hillman Cancer Center, University of Pittsburgh Medical Center (UPMC) reported at the congress.

“And when you look at duration of response, you see an increase not just in the number ... but the quality of the response,” he said, noting that for PFS, as well, a trend toward superiority is seen “that is consistent with all the other endpoints.”

“So overall, the application of incrementally restrictive cut-off of CPS lends weight to the exploratory analysis showing better survival from pembrolizumab in tumors with CPS more than 20,” Dr. Bianchini said, noting that the “real question,” however, is whether the finding “is worth clinical implementation.

“We know a lot about the primary tumor and immune infiltration. We’ve learned ... that if you wait and look ahead at immune infiltration in the advanced stage, you find that the tumor becomes smart,” he said, explaining that tumor/immune co-evolution leads to increased immuno-editing and immune subversion and it becomes “much harder to just hit the tumor with PD-L1, because this is not the only mechanism of immune escape.”

A review of several studies shows that in similar populations defined by biomarkers, response rates in patients treated with checkpoint inhibitors decrease in the second- and third-line setting vs. the first-line setting, he said.

For example, pembrolizumab response rates in the first-line and second-line or greater setting in cohort B of the KEYNOTE-086 study were 21.4% and 5.7%, respectively, compared with 12.3% in the second- to third-line setting in KEYNOTE-119, he said.

Another consideration is whether monotherapy or combination therapy is preferable, and the data suggest that regardless of how PD-L1-positivity is defined (by CPS cutoff of 1 vs. 20, for example), most patients treated with monotherapy progress within the first 3 months, he said.

“I don’t see that this is a safe approach for the majority of these patients. So without better biomarkers, combinations should always be preferred, at least to avoid early progression,” Dr. Bianchini said, adding that the open question, then, is: “If we set the new standard in the first-line as the combination of nab-paclitaxel and atezolizumab for PD-L1-positive patients defined by the VENTANA [SP142 assay], should we continue with immune checkpoint [inhibition] using different combinations?”

“Of course, at the time the trial was designed, the results of IMpassion were not available, but it’s very important, because [the findings] add to the evidence that immunotherapy is extremely relevant for some patients,” he said.

KATE2 further demonstrated the importance of PD-L1 status, he said, adding that due to its limitations, including small sample size and short follow-up, longer follow-up is needed to better evaluate duration of response and PFS.

“Despite the trial limitations, the qualitative effect seen in all clinical endpoints – overall response rate, progression-free survival, overall survival – in PD-L1-positive tumors defined by SP142 ... provided strong and robust signals supporting the investigation of immune checkpoint inhibitors in HER-positive breast cancer,” he said, noting that “many trials are ongoing in the early setting and the advanced setting.”

In addition to the lessons of these trials with respect to the interchangeability of PD-L1 IHC assays and the value of PD-L1 assessment for identifying the likelihood of benefit from immune checkpoint inhibitors, the findings highlight the possibility that PD-L1-negative tumors require different immunotherapy approaches or alternative therapeutic strategies, and underscore that the benefit of immunotherapy in PD-L1-positive patients is still restricted to a minority.

“So new studies and approaches with immuno-oncology are needed, and we need more effective biomarkers, because we need to have precision oncology applied – we need to go in that direction,” he concluded.

Dr. Bianchini reported consultancy/honorarium and or advisory board activity associated with Roche, MSD, AstraZeneca, Pfizer, Chugai, EISAI, Lilly, Novartis, Amgen, Sanofi, Neopharm, and Genomic Health. The IMPassion30 trial was funded by F. Hoffmann-La Roche Ltd.; Dr. Rugo reported research grants, other funding, and or travel/accommodation/expenses from Pfizer, Novartis, Eli Lilly, Merck, OBI, EISAI, Plexxikon, Genentech/Roche, MacroGenics, PUMA, Mylan, Immunomedics, Daiichi Sankyo, and Celltrion. KEYNOTE-119 was funded by Merck Sharp & Dohme Corp.; Dr. Cortés and Dr. Emens reported numerous funding relationships but none with F. Hoffman-La Roche. KATE2 was funded by F. Hoffmann-La Roche.
 

Sources: IMPassion130; ESMO Abstract LBA20; KEYNOTE-119: ESMO Abstract LBA21; KATE2: ESMO Abstract 305O.

EDINBURGH – Impaired renal function may indicate excess risk of tumor lysis syndrome (TLS) in venetoclax-treated chronic lymphocytic leukemia (CLL) patients and should be considered when assessing TLS risk, according to findings from a retrospective cohort study.

Complex karyotype may also affect TLS risk, Anthony Mato, MD, reported at the International Workshop on Chronic Lymphocytic Leukemia.

Of 339 CLL patients who were treated with venetoclax, 38%, 34%, and 28% were considered to have low, medium, or high risk for TLS, respectively, according to the standard definition based on absolute lymphocyte count as a measure of tumor burden and/or lymph node size.

TLS occurred in 35 patients (10%), including 26 cases of laboratory-confirmed TLS and 9 clinical TLS cases; 1 patient required dialysis and 1 death occurred, which was attributable to the TLS, Dr. Mato of Memorial Sloan Kettering Cancer Center, New York, and colleagues reported in a poster at the workshop.

Univariate analysis was performed to “understand baseline factors associated with TLS development during dose escalation,” and it examined sex, creatinine clearance (CrCl), complex karyotype, immunoglobulin heavy chain variable mutation status, prior ibrutinib exposure, venetoclax monotherapy vs. combination therapy, and TLS risk group. The investigators observed no significant difference between the low- and medium-risk patients, therefore those two groups were combined and compared with the high-risk patients.

The univariate analysis showed significant associations between TLS and CrCl (odds ratio, 2.9 for 80 mL/min or less vs. greater than 80 mL/min), complex karyotype (OR, 2.2), and low/medium vs. high TLS risk based on the standard definition (OR, 2.56).

A multivariable analysis of the predictors identified as significant in the univariate analyses showed that standard TLS risk group and CrCl remained independent predictors of TLS.

“Although the odds ratio for complex karyotype suggested potential clinical significance, this did not meet the threshold for statistical significance and was not included in the final model,” they wrote.

The area under the receiver operating characteristic curve for a model including TLS risk group and CrCl was 74.6%, compared with 65% for the area under the ROC curve using the standard tumor burden/lymph node size approach for defining TLS risk, which is described in the venetoclax package insert.

Patients included in the study had a median age of 67 years at venetoclax initiation, 69% were men, 85% were white, and 13% were treated on a clinical trial. Complex karyotype was present in 39%, del(17p) in 43%, and 84% had immunoglobulin heavy chain variable–unmutated disease.

Most patients received venetoclax monotherapy (79%), had relapsed/refractory disease (94%), and had previously received ibrutinib (78%). The median number of prior therapies was 3, but the number ranged from 0-15, the investigators noted.

The findings of this study suggest that, in addition to defining risk based on absolute lymphocyte count and lymph node size, patients with CrCl less than 80 mL/min – indicating impaired renal function – have excess risk of TLS.

Although complex karyotype did not reach statistical significance as an independent predictor of TLS, the findings in this study suggest it “may impact TLS risk and is worthy of further study in larger samples,” they said, concluding that consideration of baseline renal function, and possibly karyotype, could “further guide practitioners in their approach to prophylaxis and patient counseling, allowing for improved safety in the use of this effective agent in CLL.”

Additional planned analyses will focus on TLS risk score development and further refinement of TLS risk stratification, they noted.

Dr. Mato has received grant support, consulting fees, and/or fees for serving on a data and safety monitoring board or advisory board from AbbVie, AstraZeneca, Celgene, Janssen, TG Therapeutics, Pharmacyclics, Loxo, Sunesis, prIME Oncology, Pfizer, Johnson & Johnson, and Regeneron.

[email protected]

EDINBURGH – Impaired renal function may indicate excess risk of tumor lysis syndrome (TLS) in venetoclax-treated chronic lymphocytic leukemia (CLL) patients and should be considered when assessing TLS risk, according to findings from a retrospective cohort study.

Complex karyotype may also affect TLS risk, Anthony Mato, MD, reported at the International Workshop on Chronic Lymphocytic Leukemia.

Of 339 CLL patients who were treated with venetoclax, 38%, 34%, and 28% were considered to have low, medium, or high risk for TLS, respectively, according to the standard definition based on absolute lymphocyte count as a measure of tumor burden and/or lymph node size.

TLS occurred in 35 patients (10%), including 26 cases of laboratory-confirmed TLS and 9 clinical TLS cases; 1 patient required dialysis and 1 death occurred, which was attributable to the TLS, Dr. Mato of Memorial Sloan Kettering Cancer Center, New York, and colleagues reported in a poster at the workshop.

Univariate analysis was performed to “understand baseline factors associated with TLS development during dose escalation,” and it examined sex, creatinine clearance (CrCl), complex karyotype, immunoglobulin heavy chain variable mutation status, prior ibrutinib exposure, venetoclax monotherapy vs. combination therapy, and TLS risk group. The investigators observed no significant difference between the low- and medium-risk patients, therefore those two groups were combined and compared with the high-risk patients.

The univariate analysis showed significant associations between TLS and CrCl (odds ratio, 2.9 for 80 mL/min or less vs. greater than 80 mL/min), complex karyotype (OR, 2.2), and low/medium vs. high TLS risk based on the standard definition (OR, 2.56).

A multivariable analysis of the predictors identified as significant in the univariate analyses showed that standard TLS risk group and CrCl remained independent predictors of TLS.

“Although the odds ratio for complex karyotype suggested potential clinical significance, this did not meet the threshold for statistical significance and was not included in the final model,” they wrote.

The area under the receiver operating characteristic curve for a model including TLS risk group and CrCl was 74.6%, compared with 65% for the area under the ROC curve using the standard tumor burden/lymph node size approach for defining TLS risk, which is described in the venetoclax package insert.

Patients included in the study had a median age of 67 years at venetoclax initiation, 69% were men, 85% were white, and 13% were treated on a clinical trial. Complex karyotype was present in 39%, del(17p) in 43%, and 84% had immunoglobulin heavy chain variable–unmutated disease.

Most patients received venetoclax monotherapy (79%), had relapsed/refractory disease (94%), and had previously received ibrutinib (78%). The median number of prior therapies was 3, but the number ranged from 0-15, the investigators noted.

The findings of this study suggest that, in addition to defining risk based on absolute lymphocyte count and lymph node size, patients with CrCl less than 80 mL/min – indicating impaired renal function – have excess risk of TLS.

Although complex karyotype did not reach statistical significance as an independent predictor of TLS, the findings in this study suggest it “may impact TLS risk and is worthy of further study in larger samples,” they said, concluding that consideration of baseline renal function, and possibly karyotype, could “further guide practitioners in their approach to prophylaxis and patient counseling, allowing for improved safety in the use of this effective agent in CLL.”

Additional planned analyses will focus on TLS risk score development and further refinement of TLS risk stratification, they noted.

Dr. Mato has received grant support, consulting fees, and/or fees for serving on a data and safety monitoring board or advisory board from AbbVie, AstraZeneca, Celgene, Janssen, TG Therapeutics, Pharmacyclics, Loxo, Sunesis, prIME Oncology, Pfizer, Johnson & Johnson, and Regeneron.

[email protected]

EDINBURGH – Impaired renal function may indicate excess risk of tumor lysis syndrome (TLS) in venetoclax-treated chronic lymphocytic leukemia (CLL) patients and should be considered when assessing TLS risk, according to findings from a retrospective cohort study.

Complex karyotype may also affect TLS risk, Anthony Mato, MD, reported at the International Workshop on Chronic Lymphocytic Leukemia.

Of 339 CLL patients who were treated with venetoclax, 38%, 34%, and 28% were considered to have low, medium, or high risk for TLS, respectively, according to the standard definition based on absolute lymphocyte count as a measure of tumor burden and/or lymph node size.

TLS occurred in 35 patients (10%), including 26 cases of laboratory-confirmed TLS and 9 clinical TLS cases; 1 patient required dialysis and 1 death occurred, which was attributable to the TLS, Dr. Mato of Memorial Sloan Kettering Cancer Center, New York, and colleagues reported in a poster at the workshop.

Univariate analysis was performed to “understand baseline factors associated with TLS development during dose escalation,” and it examined sex, creatinine clearance (CrCl), complex karyotype, immunoglobulin heavy chain variable mutation status, prior ibrutinib exposure, venetoclax monotherapy vs. combination therapy, and TLS risk group. The investigators observed no significant difference between the low- and medium-risk patients, therefore those two groups were combined and compared with the high-risk patients.

The univariate analysis showed significant associations between TLS and CrCl (odds ratio, 2.9 for 80 mL/min or less vs. greater than 80 mL/min), complex karyotype (OR, 2.2), and low/medium vs. high TLS risk based on the standard definition (OR, 2.56).

A multivariable analysis of the predictors identified as significant in the univariate analyses showed that standard TLS risk group and CrCl remained independent predictors of TLS.

“Although the odds ratio for complex karyotype suggested potential clinical significance, this did not meet the threshold for statistical significance and was not included in the final model,” they wrote.

The area under the receiver operating characteristic curve for a model including TLS risk group and CrCl was 74.6%, compared with 65% for the area under the ROC curve using the standard tumor burden/lymph node size approach for defining TLS risk, which is described in the venetoclax package insert.

Patients included in the study had a median age of 67 years at venetoclax initiation, 69% were men, 85% were white, and 13% were treated on a clinical trial. Complex karyotype was present in 39%, del(17p) in 43%, and 84% had immunoglobulin heavy chain variable–unmutated disease.

Most patients received venetoclax monotherapy (79%), had relapsed/refractory disease (94%), and had previously received ibrutinib (78%). The median number of prior therapies was 3, but the number ranged from 0-15, the investigators noted.

The findings of this study suggest that, in addition to defining risk based on absolute lymphocyte count and lymph node size, patients with CrCl less than 80 mL/min – indicating impaired renal function – have excess risk of TLS.

Although complex karyotype did not reach statistical significance as an independent predictor of TLS, the findings in this study suggest it “may impact TLS risk and is worthy of further study in larger samples,” they said, concluding that consideration of baseline renal function, and possibly karyotype, could “further guide practitioners in their approach to prophylaxis and patient counseling, allowing for improved safety in the use of this effective agent in CLL.”

Additional planned analyses will focus on TLS risk score development and further refinement of TLS risk stratification, they noted.

Dr. Mato has received grant support, consulting fees, and/or fees for serving on a data and safety monitoring board or advisory board from AbbVie, AstraZeneca, Celgene, Janssen, TG Therapeutics, Pharmacyclics, Loxo, Sunesis, prIME Oncology, Pfizer, Johnson & Johnson, and Regeneron.

[email protected]

Mortality risk associated with neurodegenerative disease is higher, and mortality risk associated with other causes lower, among former Scottish professional soccer players versus matched controls, findings from a retrospective epidemiologic analysis suggest.

Nikada/Getty Images

Former professional soccer players included in the analysis also received more dementia-related medication prescriptions than did controls, Daniel F. Mackay, PhD, of the Institute of Health and Wellbeing at the University of Glasgow (Scotland) and his colleagues reported online Oct. 21 in The New England Journal of Medicine.

Overall mortality during a median follow-up of 18 years from study entry at the age of 40 years was 15.4% among 7,676 former players, and 16.5% among 23,028 controls matched based on age, sex, and degree of social deprivation. All-cause mortality was lower among players versus controls before age 70 years, and was higher thereafter, and the mortality rates associated with ischemic heart disease and lung cancer were lower among the players (hazard ratios, 0.80 and 0.53, respectively), the investigators found.

Mortality rates from stroke or cerebrovascular disease were similar in the players and controls (HR, 0.88), they noted.

However, mortality with neurodegenerative disease listed as the primary cause was 1.7% in players versus 0.5% in controls (HR adjusted for competing risks of death, 3.45), they said. The estimated risk of death with neurodegenerative disease was highest among those with Alzheimer’s disease and lowest for those with Parkinson’s disease (HRs, 5.07 and 2.15, respectively).

Dementia-related medications also were prescribed more frequently for players vs. controls (odds ratio, 4.90).

A subgroup analysis showed no significant difference between goalkeepers and outfielders with respect to mortality with neurodegenerative disease listed as a factor (HR, 0.73), but dementia-related medications were prescribed less often to goalkeepers (OR, 0.41).

Concerns about the risk of neurodegenerative diseases among participants in contact sports have been raised, in part because of the recognition of pathologic changes of chronic traumatic encephalopathy among participants across a range of such sports, the investigators explained, noting that data regarding the risk of neurodegenerative disease among former professional soccer players are limited.

The findings of the current study, in terms of lower all-cause mortality up to the age of 70 years, are similar to those in previous studies involving elite athletes across a range of sports, and “may reflect higher levels of physical activity and lower levels of obesity and smoking in elite athletes than in the general population,” they noted.

“In contrast, mortality from neurodegenerative disease was higher among former soccer players, a finding consistent with studies involving former players in the U.S. National Football League,” they added, concluding that the findings, which “may be valuable to inform the management of risks in the sport,” require confirmation in prospective studies.

This study was supported by the Football Association and Professional Footballers’ Association, and by an NHS Research Scotland Career Researcher Fellowship. Dr. Mackay reported having no relevant financial disclosures.

[email protected]

SOURCE: Mackay D et al. N Engl J Med. 2019 Oct 21. doi: 10.1056/NEJMoa1908483.

Mortality risk associated with neurodegenerative disease is higher, and mortality risk associated with other causes lower, among former Scottish professional soccer players versus matched controls, findings from a retrospective epidemiologic analysis suggest.

Nikada/Getty Images

Former professional soccer players included in the analysis also received more dementia-related medication prescriptions than did controls, Daniel F. Mackay, PhD, of the Institute of Health and Wellbeing at the University of Glasgow (Scotland) and his colleagues reported online Oct. 21 in The New England Journal of Medicine.

Overall mortality during a median follow-up of 18 years from study entry at the age of 40 years was 15.4% among 7,676 former players, and 16.5% among 23,028 controls matched based on age, sex, and degree of social deprivation. All-cause mortality was lower among players versus controls before age 70 years, and was higher thereafter, and the mortality rates associated with ischemic heart disease and lung cancer were lower among the players (hazard ratios, 0.80 and 0.53, respectively), the investigators found.

Mortality rates from stroke or cerebrovascular disease were similar in the players and controls (HR, 0.88), they noted.

However, mortality with neurodegenerative disease listed as the primary cause was 1.7% in players versus 0.5% in controls (HR adjusted for competing risks of death, 3.45), they said. The estimated risk of death with neurodegenerative disease was highest among those with Alzheimer’s disease and lowest for those with Parkinson’s disease (HRs, 5.07 and 2.15, respectively).

Dementia-related medications also were prescribed more frequently for players vs. controls (odds ratio, 4.90).

A subgroup analysis showed no significant difference between goalkeepers and outfielders with respect to mortality with neurodegenerative disease listed as a factor (HR, 0.73), but dementia-related medications were prescribed less often to goalkeepers (OR, 0.41).

Concerns about the risk of neurodegenerative diseases among participants in contact sports have been raised, in part because of the recognition of pathologic changes of chronic traumatic encephalopathy among participants across a range of such sports, the investigators explained, noting that data regarding the risk of neurodegenerative disease among former professional soccer players are limited.

The findings of the current study, in terms of lower all-cause mortality up to the age of 70 years, are similar to those in previous studies involving elite athletes across a range of sports, and “may reflect higher levels of physical activity and lower levels of obesity and smoking in elite athletes than in the general population,” they noted.

“In contrast, mortality from neurodegenerative disease was higher among former soccer players, a finding consistent with studies involving former players in the U.S. National Football League,” they added, concluding that the findings, which “may be valuable to inform the management of risks in the sport,” require confirmation in prospective studies.

This study was supported by the Football Association and Professional Footballers’ Association, and by an NHS Research Scotland Career Researcher Fellowship. Dr. Mackay reported having no relevant financial disclosures.

[email protected]

SOURCE: Mackay D et al. N Engl J Med. 2019 Oct 21. doi: 10.1056/NEJMoa1908483.

Mortality risk associated with neurodegenerative disease is higher, and mortality risk associated with other causes lower, among former Scottish professional soccer players versus matched controls, findings from a retrospective epidemiologic analysis suggest.

Nikada/Getty Images

Former professional soccer players included in the analysis also received more dementia-related medication prescriptions than did controls, Daniel F. Mackay, PhD, of the Institute of Health and Wellbeing at the University of Glasgow (Scotland) and his colleagues reported online Oct. 21 in The New England Journal of Medicine.

Overall mortality during a median follow-up of 18 years from study entry at the age of 40 years was 15.4% among 7,676 former players, and 16.5% among 23,028 controls matched based on age, sex, and degree of social deprivation. All-cause mortality was lower among players versus controls before age 70 years, and was higher thereafter, and the mortality rates associated with ischemic heart disease and lung cancer were lower among the players (hazard ratios, 0.80 and 0.53, respectively), the investigators found.

Mortality rates from stroke or cerebrovascular disease were similar in the players and controls (HR, 0.88), they noted.

However, mortality with neurodegenerative disease listed as the primary cause was 1.7% in players versus 0.5% in controls (HR adjusted for competing risks of death, 3.45), they said. The estimated risk of death with neurodegenerative disease was highest among those with Alzheimer’s disease and lowest for those with Parkinson’s disease (HRs, 5.07 and 2.15, respectively).

Dementia-related medications also were prescribed more frequently for players vs. controls (odds ratio, 4.90).

A subgroup analysis showed no significant difference between goalkeepers and outfielders with respect to mortality with neurodegenerative disease listed as a factor (HR, 0.73), but dementia-related medications were prescribed less often to goalkeepers (OR, 0.41).

Concerns about the risk of neurodegenerative diseases among participants in contact sports have been raised, in part because of the recognition of pathologic changes of chronic traumatic encephalopathy among participants across a range of such sports, the investigators explained, noting that data regarding the risk of neurodegenerative disease among former professional soccer players are limited.

The findings of the current study, in terms of lower all-cause mortality up to the age of 70 years, are similar to those in previous studies involving elite athletes across a range of sports, and “may reflect higher levels of physical activity and lower levels of obesity and smoking in elite athletes than in the general population,” they noted.

“In contrast, mortality from neurodegenerative disease was higher among former soccer players, a finding consistent with studies involving former players in the U.S. National Football League,” they added, concluding that the findings, which “may be valuable to inform the management of risks in the sport,” require confirmation in prospective studies.

This study was supported by the Football Association and Professional Footballers’ Association, and by an NHS Research Scotland Career Researcher Fellowship. Dr. Mackay reported having no relevant financial disclosures.

[email protected]

SOURCE: Mackay D et al. N Engl J Med. 2019 Oct 21. doi: 10.1056/NEJMoa1908483.

BARCELONA – Adding veliparib to chemotherapy improved progression-free survival and provided a more durable benefit than did chemotherapy alone for HER2-negative advanced germline BRCA-associated breast cancer in the randomized, placebo-controlled, phase 3 BROCADE3 study.

Investigator-assessed median progression-free survival (PFS), the primary study endpoint, was 14.5 vs. 12.6 months in 337 patients randomized to receive the poly (ADP-ribose) polymerase inhibitor (PARPi) veliparib along with carboplatin/paclitaxel (CP) and 172 who received placebo and CP (hazard ratio, 0.71), Veronique C. Diéras, MD, reported at the European Society for Medical Oncology Congress.

“The benefit looks durable; more patients in the veliparib arm were still progression free at 2 years (34% vs. 20%), and at 3 years (26% vs. 11%),” said Dr. Diéras of Institut Curie, Paris, and Centre Eugene Marquis, Rennes, France.

The PFS benefit was confirmed by independent central review, and was apparent in all subgroups analyzed, except perhaps in patients with prior brain metastases, who comprised a very small group, she noted.

Among the secondary study endpoints were median overall survival (33.5 vs. 28.2 months at an interim analysis; HR, 0.95), clinical benefit rate (90.7% and 93.2% at 24 weeks), and objective response rate (75.8% and 74.1%).

“This is very important to note,” she said, referring to the high percentage of patients who benefited from CP alone. “But, again, if we look at the duration of response, in the veliparib arm the median duration of response was 14.7 months, whereas it was 11 months in the placebo arm.”

Participants in the double-blind trial were adults with a median age of 47 years who were randomized 2:1 to CP with veliparib or placebo for the treatment of germline BRCA1- or BRCA2-mutated metastatic breast cancer and had received no more than two prior lines of cytotoxic therapy; 48% were estrogen receptor– and/or progesterone receptor–negative, 8% had prior platinum therapy, 4% had a history of central nervous system metastases, and 19% had prior chemotherapy for metastatic disease.

They received placebo or veliparib at an oral dose of 120 mg twice daily on days −2 to 5 with carboplatin (area under the curve 6 on day 1) and weekly paclitaxel (80 mg/m² on days 1, 8, and 15) in 21-day cycles until disease progression, and as allowed per study protocol, 44% crossed over from the placebo to veliparib group, Dr. Diéras said.

Common adverse events in the veliparib and placebo groups, respectively, included neutropenia (in 89% and 91% of patients), thrombocytopenia (81% and 71%), anemia (80% and 70%), and nausea (73% and 64%), she said, adding that the most common grade 3 adverse events were anemia (42% and 40%), neutropenia (81% and 84%), and thrombocytopenia (40% and 28%).

However, less than 10% of patients discontinued the study drug because of adverse events, she noted.

“In fact, the addition of veliparib to cytotoxic chemotherapy didn’t impair the administration of cytotoxic chemotherapy,” she said, adding that the mean number of CP cycles was 11 in both arms.

Select adverse events of special interest in the veliparib and placebo groups, respectively, included infection within 14 days of neutropenia (any grade, 37% and 36%; grade 3+, 5.4% and 1.8%), hemorrhage within 14 days of thrombocytopenia (any grade, 10% and 7%; grade 3+, 0.3% and 0%), and myelodysplastic syndromes (0.3% in both groups, with 0 grade 3+ events), she said.

“We know that germline BRCA-mutated breast cancers have increased sensitivity to platinum agents. Moreover, according to the concept of synthetic lethality, we do know also that these mutated tumors are very good candidates for PARP inhibition, so there is a strong rationale to combine a PARP inhibitor with cytotoxic chemotherapy with platinum,” she said.

Early studies of such combinations have been challenging because of exacerbation of myelosuppression, which may be the result of “the PARP trapping activity of some compounds,” but veliparib potently inhibits PARP with minimal PARP trapping, and thus may be better tolerated in combination with CP, she explained.

“In fact, in a phase 2 randomized trial – BROCADE2 – we did observe numerical increases in PFS and overall survival with [veliparib+CP],” she said.

In BROCADE3, the addition to veliparib to CP provided “a statistically significant and clinically meaningful benefit in patients with HER-negative advanced breast cancer and a germline BRCA mutation” without substantially altering the toxicity profile of C/P, she said.

“Considering these results, in my opinion, patients harboring BRCA mutations with advanced breast cancer [who are] candidates for chemotherapy should be offered this treatment option,” she concluded.

Invited discussant Sherene Loi, MBBS, PhD, head of the Translational Breast Cancer Genomics and Therapeutics Laboratory at Peter MacCallum Cancer Center, Victoria, Australia, said the investigators should be commended for conducting this phase 3 trial, and agreed that the approach is “reasonable to consider in a patient who does need chemotherapy.”

However, Dr. Loi said, it remains unclear if the PFS benefit seen in BROCADE3 is “due to the combination upfront and/or the monotherapy,” and suggested waiting for additional data before considering veliparib + CP as the new standard of care for germline BRCA1- and BRCA2-mutated advanced breast cancer.

“Current ESMO guidelines advise that single-agent chemotherapy be given sequentially in the absence of visceral crisis, therefore I think it’s important to await further for mature OS data and patient-reported outcomes,” she said, adding that it is also important to wait for the correlative analyses to “try to understand the rate of BRCA reversions and other resistance mechanisms in plasma.”

BROCADE3 was funded by AbbVie. Dr. Diéras reported advisory/consultancy roles for several pharmaceutical companies including AbbVie. Dr. Loi reported relationships with numerous pharmaceutical companies.

[email protected]

SOURCE: Diéras V et al. ESMO 2019, Abstract LBA9.

BARCELONA – Adding veliparib to chemotherapy improved progression-free survival and provided a more durable benefit than did chemotherapy alone for HER2-negative advanced germline BRCA-associated breast cancer in the randomized, placebo-controlled, phase 3 BROCADE3 study.

Investigator-assessed median progression-free survival (PFS), the primary study endpoint, was 14.5 vs. 12.6 months in 337 patients randomized to receive the poly (ADP-ribose) polymerase inhibitor (PARPi) veliparib along with carboplatin/paclitaxel (CP) and 172 who received placebo and CP (hazard ratio, 0.71), Veronique C. Diéras, MD, reported at the European Society for Medical Oncology Congress.

“The benefit looks durable; more patients in the veliparib arm were still progression free at 2 years (34% vs. 20%), and at 3 years (26% vs. 11%),” said Dr. Diéras of Institut Curie, Paris, and Centre Eugene Marquis, Rennes, France.

The PFS benefit was confirmed by independent central review, and was apparent in all subgroups analyzed, except perhaps in patients with prior brain metastases, who comprised a very small group, she noted.

Among the secondary study endpoints were median overall survival (33.5 vs. 28.2 months at an interim analysis; HR, 0.95), clinical benefit rate (90.7% and 93.2% at 24 weeks), and objective response rate (75.8% and 74.1%).

“This is very important to note,” she said, referring to the high percentage of patients who benefited from CP alone. “But, again, if we look at the duration of response, in the veliparib arm the median duration of response was 14.7 months, whereas it was 11 months in the placebo arm.”

Participants in the double-blind trial were adults with a median age of 47 years who were randomized 2:1 to CP with veliparib or placebo for the treatment of germline BRCA1- or BRCA2-mutated metastatic breast cancer and had received no more than two prior lines of cytotoxic therapy; 48% were estrogen receptor– and/or progesterone receptor–negative, 8% had prior platinum therapy, 4% had a history of central nervous system metastases, and 19% had prior chemotherapy for metastatic disease.

They received placebo or veliparib at an oral dose of 120 mg twice daily on days −2 to 5 with carboplatin (area under the curve 6 on day 1) and weekly paclitaxel (80 mg/m² on days 1, 8, and 15) in 21-day cycles until disease progression, and as allowed per study protocol, 44% crossed over from the placebo to veliparib group, Dr. Diéras said.

Common adverse events in the veliparib and placebo groups, respectively, included neutropenia (in 89% and 91% of patients), thrombocytopenia (81% and 71%), anemia (80% and 70%), and nausea (73% and 64%), she said, adding that the most common grade 3 adverse events were anemia (42% and 40%), neutropenia (81% and 84%), and thrombocytopenia (40% and 28%).

However, less than 10% of patients discontinued the study drug because of adverse events, she noted.

“In fact, the addition of veliparib to cytotoxic chemotherapy didn’t impair the administration of cytotoxic chemotherapy,” she said, adding that the mean number of CP cycles was 11 in both arms.

Select adverse events of special interest in the veliparib and placebo groups, respectively, included infection within 14 days of neutropenia (any grade, 37% and 36%; grade 3+, 5.4% and 1.8%), hemorrhage within 14 days of thrombocytopenia (any grade, 10% and 7%; grade 3+, 0.3% and 0%), and myelodysplastic syndromes (0.3% in both groups, with 0 grade 3+ events), she said.

“We know that germline BRCA-mutated breast cancers have increased sensitivity to platinum agents. Moreover, according to the concept of synthetic lethality, we do know also that these mutated tumors are very good candidates for PARP inhibition, so there is a strong rationale to combine a PARP inhibitor with cytotoxic chemotherapy with platinum,” she said.

Early studies of such combinations have been challenging because of exacerbation of myelosuppression, which may be the result of “the PARP trapping activity of some compounds,” but veliparib potently inhibits PARP with minimal PARP trapping, and thus may be better tolerated in combination with CP, she explained.

“In fact, in a phase 2 randomized trial – BROCADE2 – we did observe numerical increases in PFS and overall survival with [veliparib+CP],” she said.

In BROCADE3, the addition to veliparib to CP provided “a statistically significant and clinically meaningful benefit in patients with HER-negative advanced breast cancer and a germline BRCA mutation” without substantially altering the toxicity profile of C/P, she said.

“Considering these results, in my opinion, patients harboring BRCA mutations with advanced breast cancer [who are] candidates for chemotherapy should be offered this treatment option,” she concluded.

Invited discussant Sherene Loi, MBBS, PhD, head of the Translational Breast Cancer Genomics and Therapeutics Laboratory at Peter MacCallum Cancer Center, Victoria, Australia, said the investigators should be commended for conducting this phase 3 trial, and agreed that the approach is “reasonable to consider in a patient who does need chemotherapy.”

However, Dr. Loi said, it remains unclear if the PFS benefit seen in BROCADE3 is “due to the combination upfront and/or the monotherapy,” and suggested waiting for additional data before considering veliparib + CP as the new standard of care for germline BRCA1- and BRCA2-mutated advanced breast cancer.

“Current ESMO guidelines advise that single-agent chemotherapy be given sequentially in the absence of visceral crisis, therefore I think it’s important to await further for mature OS data and patient-reported outcomes,” she said, adding that it is also important to wait for the correlative analyses to “try to understand the rate of BRCA reversions and other resistance mechanisms in plasma.”

BROCADE3 was funded by AbbVie. Dr. Diéras reported advisory/consultancy roles for several pharmaceutical companies including AbbVie. Dr. Loi reported relationships with numerous pharmaceutical companies.

[email protected]

SOURCE: Diéras V et al. ESMO 2019, Abstract LBA9.

BARCELONA – Adding veliparib to chemotherapy improved progression-free survival and provided a more durable benefit than did chemotherapy alone for HER2-negative advanced germline BRCA-associated breast cancer in the randomized, placebo-controlled, phase 3 BROCADE3 study.

Investigator-assessed median progression-free survival (PFS), the primary study endpoint, was 14.5 vs. 12.6 months in 337 patients randomized to receive the poly (ADP-ribose) polymerase inhibitor (PARPi) veliparib along with carboplatin/paclitaxel (CP) and 172 who received placebo and CP (hazard ratio, 0.71), Veronique C. Diéras, MD, reported at the European Society for Medical Oncology Congress.

“The benefit looks durable; more patients in the veliparib arm were still progression free at 2 years (34% vs. 20%), and at 3 years (26% vs. 11%),” said Dr. Diéras of Institut Curie, Paris, and Centre Eugene Marquis, Rennes, France.

The PFS benefit was confirmed by independent central review, and was apparent in all subgroups analyzed, except perhaps in patients with prior brain metastases, who comprised a very small group, she noted.

Among the secondary study endpoints were median overall survival (33.5 vs. 28.2 months at an interim analysis; HR, 0.95), clinical benefit rate (90.7% and 93.2% at 24 weeks), and objective response rate (75.8% and 74.1%).

“This is very important to note,” she said, referring to the high percentage of patients who benefited from CP alone. “But, again, if we look at the duration of response, in the veliparib arm the median duration of response was 14.7 months, whereas it was 11 months in the placebo arm.”

Participants in the double-blind trial were adults with a median age of 47 years who were randomized 2:1 to CP with veliparib or placebo for the treatment of germline BRCA1- or BRCA2-mutated metastatic breast cancer and had received no more than two prior lines of cytotoxic therapy; 48% were estrogen receptor– and/or progesterone receptor–negative, 8% had prior platinum therapy, 4% had a history of central nervous system metastases, and 19% had prior chemotherapy for metastatic disease.

They received placebo or veliparib at an oral dose of 120 mg twice daily on days −2 to 5 with carboplatin (area under the curve 6 on day 1) and weekly paclitaxel (80 mg/m² on days 1, 8, and 15) in 21-day cycles until disease progression, and as allowed per study protocol, 44% crossed over from the placebo to veliparib group, Dr. Diéras said.

Common adverse events in the veliparib and placebo groups, respectively, included neutropenia (in 89% and 91% of patients), thrombocytopenia (81% and 71%), anemia (80% and 70%), and nausea (73% and 64%), she said, adding that the most common grade 3 adverse events were anemia (42% and 40%), neutropenia (81% and 84%), and thrombocytopenia (40% and 28%).

However, less than 10% of patients discontinued the study drug because of adverse events, she noted.

“In fact, the addition of veliparib to cytotoxic chemotherapy didn’t impair the administration of cytotoxic chemotherapy,” she said, adding that the mean number of CP cycles was 11 in both arms.

Select adverse events of special interest in the veliparib and placebo groups, respectively, included infection within 14 days of neutropenia (any grade, 37% and 36%; grade 3+, 5.4% and 1.8%), hemorrhage within 14 days of thrombocytopenia (any grade, 10% and 7%; grade 3+, 0.3% and 0%), and myelodysplastic syndromes (0.3% in both groups, with 0 grade 3+ events), she said.

“We know that germline BRCA-mutated breast cancers have increased sensitivity to platinum agents. Moreover, according to the concept of synthetic lethality, we do know also that these mutated tumors are very good candidates for PARP inhibition, so there is a strong rationale to combine a PARP inhibitor with cytotoxic chemotherapy with platinum,” she said.

Early studies of such combinations have been challenging because of exacerbation of myelosuppression, which may be the result of “the PARP trapping activity of some compounds,” but veliparib potently inhibits PARP with minimal PARP trapping, and thus may be better tolerated in combination with CP, she explained.

“In fact, in a phase 2 randomized trial – BROCADE2 – we did observe numerical increases in PFS and overall survival with [veliparib+CP],” she said.

In BROCADE3, the addition to veliparib to CP provided “a statistically significant and clinically meaningful benefit in patients with HER-negative advanced breast cancer and a germline BRCA mutation” without substantially altering the toxicity profile of C/P, she said.

“Considering these results, in my opinion, patients harboring BRCA mutations with advanced breast cancer [who are] candidates for chemotherapy should be offered this treatment option,” she concluded.

Invited discussant Sherene Loi, MBBS, PhD, head of the Translational Breast Cancer Genomics and Therapeutics Laboratory at Peter MacCallum Cancer Center, Victoria, Australia, said the investigators should be commended for conducting this phase 3 trial, and agreed that the approach is “reasonable to consider in a patient who does need chemotherapy.”

However, Dr. Loi said, it remains unclear if the PFS benefit seen in BROCADE3 is “due to the combination upfront and/or the monotherapy,” and suggested waiting for additional data before considering veliparib + CP as the new standard of care for germline BRCA1- and BRCA2-mutated advanced breast cancer.

“Current ESMO guidelines advise that single-agent chemotherapy be given sequentially in the absence of visceral crisis, therefore I think it’s important to await further for mature OS data and patient-reported outcomes,” she said, adding that it is also important to wait for the correlative analyses to “try to understand the rate of BRCA reversions and other resistance mechanisms in plasma.”

BROCADE3 was funded by AbbVie. Dr. Diéras reported advisory/consultancy roles for several pharmaceutical companies including AbbVie. Dr. Loi reported relationships with numerous pharmaceutical companies.

[email protected]

SOURCE: Diéras V et al. ESMO 2019, Abstract LBA9.

BARCELONA – Adding veliparib to frontline chemotherapy and maintenance therapy significantly extended progression-free survival in women with high-grade serous epithelial ovarian cancer (HGSC) in the phase 3 VELIA/GOG-3005 trial.

The benefit associated with the oral poly (ADP-ribose) polymerase (PARP) inhibitor was seen in all women with newly diagnosed HGSC included in the randomized, placebo-controlled trial, regardless of BRCA mutation (BRCAm) status or homologous recombination deficiency (HRD) status, Robert L. Coleman, MD, reported at the European Society for Medical Oncology Congress.

Of 1,140 patients enrolled in the international, multicenter trial, 26% had a BRCAm and 55% were HRD positive. In the intent-to-treat population, median progression-free survival (PFS) was 23.5 months in 382 patients who received carboplatin/paclitaxel (CP) plus veliparib followed by veliparib maintenance (veliparib group 1) versus 17.3 months in 375 patients treated with CP alone followed by placebo maintenance (the control group) (hazard ratio, 0.68), according to Dr. Coleman, professor and Ann Rife Cox Chair in Gynecology in the department of gynecologic oncology and reproductive medicine in the division of surgery at the University of Texas MD Anderson Cancer Center, Houston.

Among 200 patients with a deleterious BRCAm, including 108 in the veliparib 1 group and 92 in the control group, median PFS was 34.7 and 22.0 months, respectively (HR, 0.44), and among 421 patients with HRD and BRCAm, including 214 in the veliparib 1 group and 207 in the control group, median PFS was 31.9 versus 20.5 months (HR, 0.57).

In the non-HRD population of 249 patients (125 in the veliparib 1 arm and 124 in the control arm), median PFS was 15.0 and 11.5 months, respectively.

The PFS for an additional group of 383 patients treated with CP plus veliparib followed by placebo maintenance (veliparib group 2) didn’t differ significantly from either the veliparib 1 or the control group (HR, 1.07 vs. the control group in the intent-to-treat population), and the PFS rates were also similar for the BRCAm and HRD-positive patients in the veliparib 2 group and control group, he noted, explaining that the main focus of his presentation was the primary study endpoint of median PFS in the veliparib 1 versus control group.

The overall response rates at the end of treatment in the intent-to-treat populations were 84% in the veliparib 1 group, 74% in the control group, and 79% in the veliparib 2 group, Dr. Coleman said, adding that response rates were numerically higher in both veliparib-containing arms.

Additional analyses, including overall survival, will be reported at a future date, he noted.

Study participants were adults with a mean age of 62 years who had previously untreated stage III-IV HGSC. Treatment included six cycles of CP at 21-day intervals, with paclitaxel given either weekly or every 3 weeks following primary cytoreduction or neoadjuvant chemotherapy with interval cytoreduction. The veliparib dose when given with CP was 150 mg twice daily, and the veliparib maintenance dose was 400 mg twice daily for 30 cycles.

Relative CP dose intensities were similar between arms, and grade 3-4 adverse events were similar in the veliparib 1 and control groups during CP – with the exception of thrombocytopenia, which occurred in 27% and 8% of patients in the groups, respectively. During maintenance, the rates of any grade 3-4 adverse events were higher in the veliparib 1 group versus the control group (45% vs. 32%), but serious adverse event rates were similar in the groups (17% and 19%).

Observed toxicities were consistent with the known veliparib safety profile, Dr. Coleman said.

The findings are notable, as PARP inhibitors have proven effective in ovarian cancer, but their use in combination with chemotherapy has been challenging because of hematologic toxicity, he added, explaining, however, that veliparib has not only been shown to have single agent activity in germline BRCAm recurrent ovarian cancer patients, but also has binding characteristics – namely increased protein poly ADP-ribosylation and decreased PARP trapping – that could allow for its use in combination with chemotherapy.

VELIA/GOG-3005 is the first randomized trial designed to enroll only untreated patients with advanced-stage HGSC regardless of BRCA status, surgical management, or response to treatment, and the findings suggest that veliparib can be safely administered with CP and should be considered a new treatment option for women with newly diagnosed, advanced-stage serous ovarian cancer, he concluded.

In an ESMO press release, Ana Oaknin, MD, PhD, head of the gynecologic cancer program at Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, said that this trial, along with others such as the SOLO-1 trial, the PAOLA-1/ENGOT-Ov25 trial, and the PRIMA/ENGOT-OV26/GOG-3012 trial, which each looked at integrating PARP inhibitors into first-line treatment, represents “a milestone for patients.”

“After decades studying different chemotherapy approaches, it is the first time we have meaningfully prolonged progression free survival and hopefully we will improve long-term outcome,” she said.

The study was sponsored by AbbVie. Dr. Coleman and Dr. Oaknin reported relationships with numerous pharmaceutical companies.

SOURCE: Coleman RL et al. ESMO 2019, Abstract LBA3-PR.

BARCELONA – Adding veliparib to frontline chemotherapy and maintenance therapy significantly extended progression-free survival in women with high-grade serous epithelial ovarian cancer (HGSC) in the phase 3 VELIA/GOG-3005 trial.

The benefit associated with the oral poly (ADP-ribose) polymerase (PARP) inhibitor was seen in all women with newly diagnosed HGSC included in the randomized, placebo-controlled trial, regardless of BRCA mutation (BRCAm) status or homologous recombination deficiency (HRD) status, Robert L. Coleman, MD, reported at the European Society for Medical Oncology Congress.

Of 1,140 patients enrolled in the international, multicenter trial, 26% had a BRCAm and 55% were HRD positive. In the intent-to-treat population, median progression-free survival (PFS) was 23.5 months in 382 patients who received carboplatin/paclitaxel (CP) plus veliparib followed by veliparib maintenance (veliparib group 1) versus 17.3 months in 375 patients treated with CP alone followed by placebo maintenance (the control group) (hazard ratio, 0.68), according to Dr. Coleman, professor and Ann Rife Cox Chair in Gynecology in the department of gynecologic oncology and reproductive medicine in the division of surgery at the University of Texas MD Anderson Cancer Center, Houston.

Among 200 patients with a deleterious BRCAm, including 108 in the veliparib 1 group and 92 in the control group, median PFS was 34.7 and 22.0 months, respectively (HR, 0.44), and among 421 patients with HRD and BRCAm, including 214 in the veliparib 1 group and 207 in the control group, median PFS was 31.9 versus 20.5 months (HR, 0.57).

In the non-HRD population of 249 patients (125 in the veliparib 1 arm and 124 in the control arm), median PFS was 15.0 and 11.5 months, respectively.

The PFS for an additional group of 383 patients treated with CP plus veliparib followed by placebo maintenance (veliparib group 2) didn’t differ significantly from either the veliparib 1 or the control group (HR, 1.07 vs. the control group in the intent-to-treat population), and the PFS rates were also similar for the BRCAm and HRD-positive patients in the veliparib 2 group and control group, he noted, explaining that the main focus of his presentation was the primary study endpoint of median PFS in the veliparib 1 versus control group.

The overall response rates at the end of treatment in the intent-to-treat populations were 84% in the veliparib 1 group, 74% in the control group, and 79% in the veliparib 2 group, Dr. Coleman said, adding that response rates were numerically higher in both veliparib-containing arms.

Additional analyses, including overall survival, will be reported at a future date, he noted.

Study participants were adults with a mean age of 62 years who had previously untreated stage III-IV HGSC. Treatment included six cycles of CP at 21-day intervals, with paclitaxel given either weekly or every 3 weeks following primary cytoreduction or neoadjuvant chemotherapy with interval cytoreduction. The veliparib dose when given with CP was 150 mg twice daily, and the veliparib maintenance dose was 400 mg twice daily for 30 cycles.

Relative CP dose intensities were similar between arms, and grade 3-4 adverse events were similar in the veliparib 1 and control groups during CP – with the exception of thrombocytopenia, which occurred in 27% and 8% of patients in the groups, respectively. During maintenance, the rates of any grade 3-4 adverse events were higher in the veliparib 1 group versus the control group (45% vs. 32%), but serious adverse event rates were similar in the groups (17% and 19%).

Observed toxicities were consistent with the known veliparib safety profile, Dr. Coleman said.

The findings are notable, as PARP inhibitors have proven effective in ovarian cancer, but their use in combination with chemotherapy has been challenging because of hematologic toxicity, he added, explaining, however, that veliparib has not only been shown to have single agent activity in germline BRCAm recurrent ovarian cancer patients, but also has binding characteristics – namely increased protein poly ADP-ribosylation and decreased PARP trapping – that could allow for its use in combination with chemotherapy.

VELIA/GOG-3005 is the first randomized trial designed to enroll only untreated patients with advanced-stage HGSC regardless of BRCA status, surgical management, or response to treatment, and the findings suggest that veliparib can be safely administered with CP and should be considered a new treatment option for women with newly diagnosed, advanced-stage serous ovarian cancer, he concluded.

In an ESMO press release, Ana Oaknin, MD, PhD, head of the gynecologic cancer program at Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, said that this trial, along with others such as the SOLO-1 trial, the PAOLA-1/ENGOT-Ov25 trial, and the PRIMA/ENGOT-OV26/GOG-3012 trial, which each looked at integrating PARP inhibitors into first-line treatment, represents “a milestone for patients.”

“After decades studying different chemotherapy approaches, it is the first time we have meaningfully prolonged progression free survival and hopefully we will improve long-term outcome,” she said.

The study was sponsored by AbbVie. Dr. Coleman and Dr. Oaknin reported relationships with numerous pharmaceutical companies.

SOURCE: Coleman RL et al. ESMO 2019, Abstract LBA3-PR.

BARCELONA – Adding veliparib to frontline chemotherapy and maintenance therapy significantly extended progression-free survival in women with high-grade serous epithelial ovarian cancer (HGSC) in the phase 3 VELIA/GOG-3005 trial.

The benefit associated with the oral poly (ADP-ribose) polymerase (PARP) inhibitor was seen in all women with newly diagnosed HGSC included in the randomized, placebo-controlled trial, regardless of BRCA mutation (BRCAm) status or homologous recombination deficiency (HRD) status, Robert L. Coleman, MD, reported at the European Society for Medical Oncology Congress.

Of 1,140 patients enrolled in the international, multicenter trial, 26% had a BRCAm and 55% were HRD positive. In the intent-to-treat population, median progression-free survival (PFS) was 23.5 months in 382 patients who received carboplatin/paclitaxel (CP) plus veliparib followed by veliparib maintenance (veliparib group 1) versus 17.3 months in 375 patients treated with CP alone followed by placebo maintenance (the control group) (hazard ratio, 0.68), according to Dr. Coleman, professor and Ann Rife Cox Chair in Gynecology in the department of gynecologic oncology and reproductive medicine in the division of surgery at the University of Texas MD Anderson Cancer Center, Houston.

Among 200 patients with a deleterious BRCAm, including 108 in the veliparib 1 group and 92 in the control group, median PFS was 34.7 and 22.0 months, respectively (HR, 0.44), and among 421 patients with HRD and BRCAm, including 214 in the veliparib 1 group and 207 in the control group, median PFS was 31.9 versus 20.5 months (HR, 0.57).

In the non-HRD population of 249 patients (125 in the veliparib 1 arm and 124 in the control arm), median PFS was 15.0 and 11.5 months, respectively.

The PFS for an additional group of 383 patients treated with CP plus veliparib followed by placebo maintenance (veliparib group 2) didn’t differ significantly from either the veliparib 1 or the control group (HR, 1.07 vs. the control group in the intent-to-treat population), and the PFS rates were also similar for the BRCAm and HRD-positive patients in the veliparib 2 group and control group, he noted, explaining that the main focus of his presentation was the primary study endpoint of median PFS in the veliparib 1 versus control group.

The overall response rates at the end of treatment in the intent-to-treat populations were 84% in the veliparib 1 group, 74% in the control group, and 79% in the veliparib 2 group, Dr. Coleman said, adding that response rates were numerically higher in both veliparib-containing arms.

Additional analyses, including overall survival, will be reported at a future date, he noted.

Study participants were adults with a mean age of 62 years who had previously untreated stage III-IV HGSC. Treatment included six cycles of CP at 21-day intervals, with paclitaxel given either weekly or every 3 weeks following primary cytoreduction or neoadjuvant chemotherapy with interval cytoreduction. The veliparib dose when given with CP was 150 mg twice daily, and the veliparib maintenance dose was 400 mg twice daily for 30 cycles.

Relative CP dose intensities were similar between arms, and grade 3-4 adverse events were similar in the veliparib 1 and control groups during CP – with the exception of thrombocytopenia, which occurred in 27% and 8% of patients in the groups, respectively. During maintenance, the rates of any grade 3-4 adverse events were higher in the veliparib 1 group versus the control group (45% vs. 32%), but serious adverse event rates were similar in the groups (17% and 19%).

Observed toxicities were consistent with the known veliparib safety profile, Dr. Coleman said.

The findings are notable, as PARP inhibitors have proven effective in ovarian cancer, but their use in combination with chemotherapy has been challenging because of hematologic toxicity, he added, explaining, however, that veliparib has not only been shown to have single agent activity in germline BRCAm recurrent ovarian cancer patients, but also has binding characteristics – namely increased protein poly ADP-ribosylation and decreased PARP trapping – that could allow for its use in combination with chemotherapy.

VELIA/GOG-3005 is the first randomized trial designed to enroll only untreated patients with advanced-stage HGSC regardless of BRCA status, surgical management, or response to treatment, and the findings suggest that veliparib can be safely administered with CP and should be considered a new treatment option for women with newly diagnosed, advanced-stage serous ovarian cancer, he concluded.

In an ESMO press release, Ana Oaknin, MD, PhD, head of the gynecologic cancer program at Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, said that this trial, along with others such as the SOLO-1 trial, the PAOLA-1/ENGOT-Ov25 trial, and the PRIMA/ENGOT-OV26/GOG-3012 trial, which each looked at integrating PARP inhibitors into first-line treatment, represents “a milestone for patients.”

“After decades studying different chemotherapy approaches, it is the first time we have meaningfully prolonged progression free survival and hopefully we will improve long-term outcome,” she said.

The study was sponsored by AbbVie. Dr. Coleman and Dr. Oaknin reported relationships with numerous pharmaceutical companies.

SOURCE: Coleman RL et al. ESMO 2019, Abstract LBA3-PR.

EDINBURGH – Routine empiric prophylaxis against pneumocystis jiroveci pneumonia (PJP) may be unwarranted in chronic lymphocytic leukemia patients initiating Bruton tyrosine kinase (BTK) inhibitor therapy, a retrospective chart review suggests.

Among 212 patients with chronic lymphocytic leukemia (CLL) who were treated with ibrutinib or acalabrutinib either as monotherapy or as part of a combination regimen for at least 30 days between Jan. 1, 2010, and Feb. 1, 2019, at Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, 125 (59%) received PJP prophylaxis, including either trimethoprim-sulfamethoxazole (74%) or atovaquone (26%), Christine Ryan, MD, reported at the International Workshop on CLL.

Two PJP cases occurred in the 120 patients on single-agent ibrutinib, including one in a previously untreated patient and one in a patient with relapsed/refractory CLL. Neither patient had received PJP prophylaxis, said Dr. Ryan, a senior resident at Brigham and Women’s Hospital.

No PJP cases occurred in the 21 patients who received acalabrutinib monotherapy or in the 14 patients who received acalabrutinib combination therapy, and 1 occurred in a trial cohort of 57 patients receiving frontline ibrutinib plus fludarabine-based chemotherapy (FCR). The latter had been prescribed PJP prophylaxis, but “unfortunately self-discontinued the prophylaxis” 2 months prior to the infection, Dr. Ryan said.

“The overall prevalence of PJP in patients not on prophylaxis was 3.4%, there were no cases of PJP in patients on prophylaxis, and the incidence rate in patients not on prophylaxis was 1.9 per 100 person-years, with a number needed to treat to prevent 1 case of PJP calculated to be 42 patients,” she said.

In addition to PJP, three cases of proven or probable invasive fungal infections (IFI) occurred, including one case of pulmonary histoplasmosis in the ibrutinib plus FCR trial cohort and two cases of aspergillosis, including a pulmonary case and a brain abscess, in an ibrutinib plus umbralisib trial cohort.

“The overall prevalence of aspergillosis or histoplasmosis in our entire cohort was 1.4%, and notably there were no cases of IFI in the single-agent therapy cohort, but the prevalence in the ibrutinib-combination therapy patients was 4.2%,” Dr. Ryan said.

Patients included in the review were adults with a median age of 64.8 years, and 64% were men. The median duration of BTK inhibitor therapy was 23.2 months.

“We know that CLL patients treated with fludarabine have an increased risk of PJP,” she said. “As such, it is routinely recommended that patients receiving fludarabine-containing chemotherapy regimens are prescribed PJP prophylaxis.”

Additionally, the increasing use of oral BTK inhibitors has raised concerns about the potential risk of PJP or other IFIs in patients on those agents, Dr. Ryan explained, noting that existing case reports and case series looking at PJP have shown varying prevalence rates, and little is known about the effects of prophylaxis.

“At present, there are no international guidelines regarding the use of antimicrobial prophylaxis in CLL patients treated with BTK inhibitors, and prophylaxis practices vary widely across countries and institutions,” she said.

The findings of the current study demonstrate that such variation exists “even within our own institution,” Dr. Ryan added.

The findings also show an overall low PJP prevalence of 3.4% in patients not receiving prophylaxis, which falls below the “commonly accepted threshold of 5%, above which routine prophylaxis becomes recommended,” she said.

“Overall, our data suggest that routine PJP or IFI prophylaxis in patients receiving BTK inhibitors may not be needed, but this is definitely an area that requires further study, ideally with a prospective trial with a larger sample size and multiple institutions, to support the development of consensus guidelines on this issue,” she said.

Dr. Ryan reported having no financial disclosures.

[email protected]

EDINBURGH – Routine empiric prophylaxis against pneumocystis jiroveci pneumonia (PJP) may be unwarranted in chronic lymphocytic leukemia patients initiating Bruton tyrosine kinase (BTK) inhibitor therapy, a retrospective chart review suggests.

Among 212 patients with chronic lymphocytic leukemia (CLL) who were treated with ibrutinib or acalabrutinib either as monotherapy or as part of a combination regimen for at least 30 days between Jan. 1, 2010, and Feb. 1, 2019, at Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, 125 (59%) received PJP prophylaxis, including either trimethoprim-sulfamethoxazole (74%) or atovaquone (26%), Christine Ryan, MD, reported at the International Workshop on CLL.

Two PJP cases occurred in the 120 patients on single-agent ibrutinib, including one in a previously untreated patient and one in a patient with relapsed/refractory CLL. Neither patient had received PJP prophylaxis, said Dr. Ryan, a senior resident at Brigham and Women’s Hospital.

No PJP cases occurred in the 21 patients who received acalabrutinib monotherapy or in the 14 patients who received acalabrutinib combination therapy, and 1 occurred in a trial cohort of 57 patients receiving frontline ibrutinib plus fludarabine-based chemotherapy (FCR). The latter had been prescribed PJP prophylaxis, but “unfortunately self-discontinued the prophylaxis” 2 months prior to the infection, Dr. Ryan said.

“The overall prevalence of PJP in patients not on prophylaxis was 3.4%, there were no cases of PJP in patients on prophylaxis, and the incidence rate in patients not on prophylaxis was 1.9 per 100 person-years, with a number needed to treat to prevent 1 case of PJP calculated to be 42 patients,” she said.

In addition to PJP, three cases of proven or probable invasive fungal infections (IFI) occurred, including one case of pulmonary histoplasmosis in the ibrutinib plus FCR trial cohort and two cases of aspergillosis, including a pulmonary case and a brain abscess, in an ibrutinib plus umbralisib trial cohort.

“The overall prevalence of aspergillosis or histoplasmosis in our entire cohort was 1.4%, and notably there were no cases of IFI in the single-agent therapy cohort, but the prevalence in the ibrutinib-combination therapy patients was 4.2%,” Dr. Ryan said.

Patients included in the review were adults with a median age of 64.8 years, and 64% were men. The median duration of BTK inhibitor therapy was 23.2 months.

“We know that CLL patients treated with fludarabine have an increased risk of PJP,” she said. “As such, it is routinely recommended that patients receiving fludarabine-containing chemotherapy regimens are prescribed PJP prophylaxis.”

Additionally, the increasing use of oral BTK inhibitors has raised concerns about the potential risk of PJP or other IFIs in patients on those agents, Dr. Ryan explained, noting that existing case reports and case series looking at PJP have shown varying prevalence rates, and little is known about the effects of prophylaxis.

“At present, there are no international guidelines regarding the use of antimicrobial prophylaxis in CLL patients treated with BTK inhibitors, and prophylaxis practices vary widely across countries and institutions,” she said.

The findings of the current study demonstrate that such variation exists “even within our own institution,” Dr. Ryan added.

The findings also show an overall low PJP prevalence of 3.4% in patients not receiving prophylaxis, which falls below the “commonly accepted threshold of 5%, above which routine prophylaxis becomes recommended,” she said.

“Overall, our data suggest that routine PJP or IFI prophylaxis in patients receiving BTK inhibitors may not be needed, but this is definitely an area that requires further study, ideally with a prospective trial with a larger sample size and multiple institutions, to support the development of consensus guidelines on this issue,” she said.

Dr. Ryan reported having no financial disclosures.

[email protected]

EDINBURGH – Routine empiric prophylaxis against pneumocystis jiroveci pneumonia (PJP) may be unwarranted in chronic lymphocytic leukemia patients initiating Bruton tyrosine kinase (BTK) inhibitor therapy, a retrospective chart review suggests.

Among 212 patients with chronic lymphocytic leukemia (CLL) who were treated with ibrutinib or acalabrutinib either as monotherapy or as part of a combination regimen for at least 30 days between Jan. 1, 2010, and Feb. 1, 2019, at Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, 125 (59%) received PJP prophylaxis, including either trimethoprim-sulfamethoxazole (74%) or atovaquone (26%), Christine Ryan, MD, reported at the International Workshop on CLL.

Two PJP cases occurred in the 120 patients on single-agent ibrutinib, including one in a previously untreated patient and one in a patient with relapsed/refractory CLL. Neither patient had received PJP prophylaxis, said Dr. Ryan, a senior resident at Brigham and Women’s Hospital.

No PJP cases occurred in the 21 patients who received acalabrutinib monotherapy or in the 14 patients who received acalabrutinib combination therapy, and 1 occurred in a trial cohort of 57 patients receiving frontline ibrutinib plus fludarabine-based chemotherapy (FCR). The latter had been prescribed PJP prophylaxis, but “unfortunately self-discontinued the prophylaxis” 2 months prior to the infection, Dr. Ryan said.

“The overall prevalence of PJP in patients not on prophylaxis was 3.4%, there were no cases of PJP in patients on prophylaxis, and the incidence rate in patients not on prophylaxis was 1.9 per 100 person-years, with a number needed to treat to prevent 1 case of PJP calculated to be 42 patients,” she said.

In addition to PJP, three cases of proven or probable invasive fungal infections (IFI) occurred, including one case of pulmonary histoplasmosis in the ibrutinib plus FCR trial cohort and two cases of aspergillosis, including a pulmonary case and a brain abscess, in an ibrutinib plus umbralisib trial cohort.

“The overall prevalence of aspergillosis or histoplasmosis in our entire cohort was 1.4%, and notably there were no cases of IFI in the single-agent therapy cohort, but the prevalence in the ibrutinib-combination therapy patients was 4.2%,” Dr. Ryan said.

Patients included in the review were adults with a median age of 64.8 years, and 64% were men. The median duration of BTK inhibitor therapy was 23.2 months.

“We know that CLL patients treated with fludarabine have an increased risk of PJP,” she said. “As such, it is routinely recommended that patients receiving fludarabine-containing chemotherapy regimens are prescribed PJP prophylaxis.”

Additionally, the increasing use of oral BTK inhibitors has raised concerns about the potential risk of PJP or other IFIs in patients on those agents, Dr. Ryan explained, noting that existing case reports and case series looking at PJP have shown varying prevalence rates, and little is known about the effects of prophylaxis.

“At present, there are no international guidelines regarding the use of antimicrobial prophylaxis in CLL patients treated with BTK inhibitors, and prophylaxis practices vary widely across countries and institutions,” she said.

The findings of the current study demonstrate that such variation exists “even within our own institution,” Dr. Ryan added.

The findings also show an overall low PJP prevalence of 3.4% in patients not receiving prophylaxis, which falls below the “commonly accepted threshold of 5%, above which routine prophylaxis becomes recommended,” she said.

“Overall, our data suggest that routine PJP or IFI prophylaxis in patients receiving BTK inhibitors may not be needed, but this is definitely an area that requires further study, ideally with a prospective trial with a larger sample size and multiple institutions, to support the development of consensus guidelines on this issue,” she said.

Dr. Ryan reported having no financial disclosures.

[email protected]