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Salvage chemo for NSCLC more effective after PD-1/PD-L1 inhibitors
GENEVA – Patients with stage IV non–small cell lung cancer (NSCLC) who have disease progression following treatment with an immune checkpoint inhibitor have a 30% better chance of achieving at least a partial response with salvage chemotherapy compared with patients who had received prior chemotherapy but not immunotherapy, according to Swiss and U.S. investigators.
In a study of 82 patients with advanced NSCLC, 18 of 67 patients (27%) who had progressed on an inhibitor of programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) had a partial response to combination chemotherapy, compared with just 1 of 15 (7%) of patients who had not received a checkpoint inhibitor, reported Sacha Rothschild, MD, PhD, of University Hospital Basel, Switzerland, and colleagues.
“The odds of achieving a partial response to salvage chemotherapy were significantly higher in patients with prior exposure to PD-1/PD-L1 inhibitors. This observed difference, however, warrants confirmation in larger cohorts. Ongoing investigations include the duration of response as well as evaluation of toxicity,” the researchers wrote in a scientific poster presented at the European Lung Cancer Conference.
Immune checkpoint inhibitors have been shown to be active in patients with late-stage NSCLC who have experienced disease progression following chemotherapy. To see whether salvage chemotherapy could offer any additional benefit to patients who had disease progression on immunotherapy, the investigators conducted a retrospective case-control study. They reviewed 355 patient records, and identified 82 patients – 46 men and 36 women – who met the study criteria.
Of this group, 67 patients had received a PD-1/PD-L1 checkpoint inhibitor, either nivolumab (Opdivo, 56 patients), pembrolizumab (Keytruda, 7), or atezolizumab (Tecentriq, 4). These patients were designated as cases. The remaining 15 patients, who had received prior chemotherapy or chemoradiotherapy only, were designated as controls.
Of all 82 patients, 63 (77%) had adenocarcinomas, 18 (22%) had squamous cell carcinomas, and 1 (1%) had a large-cell carcinoma.
Cases had a mean of 2.37 chemotherapy regimens prior to salvage chemotherapy, and controls had a mean of 1.93. Drugs used in the salvage regimens were docetaxel in 62% of patients, pemetrexed in 20%, gemcitabine in 12%, and paclitaxel in 6%.
The odds ratio for achieving a partial response was 0.30 (95% confidence interval, 0.18-0.50, P less than .0001).
In a multiple logistic regression model, neither age, sex, number of prior chemotherapy regimens, tumor histology, smoking status, nor type of salvage chemotherapy regimen were significantly associated with the likelihood of achieving a partial response.
In a poster discussion session, Simon Ekman, MD, of Karolinska Institute in Stockholm, Sweden, the invited discussant, said that the data from the study are convincing, and raise the question of what to do next.
“The question is how do we combine immunotherapy with chemotherapy? Should we use the immune therapy first, like in this trial, or vice versa, or should we combine concurrently” he said.
The strategy of chemotherapy first is supported by research showing that neoantigens crucial for the immune response are released during chemotherapy and radiotherapy, enabling immunotherapeutic agents to work better, he said.
The study was internally funded. Dr. Rothschild and Dr. Ekman reported no conflicts relevant to the research.
GENEVA – Patients with stage IV non–small cell lung cancer (NSCLC) who have disease progression following treatment with an immune checkpoint inhibitor have a 30% better chance of achieving at least a partial response with salvage chemotherapy compared with patients who had received prior chemotherapy but not immunotherapy, according to Swiss and U.S. investigators.
In a study of 82 patients with advanced NSCLC, 18 of 67 patients (27%) who had progressed on an inhibitor of programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) had a partial response to combination chemotherapy, compared with just 1 of 15 (7%) of patients who had not received a checkpoint inhibitor, reported Sacha Rothschild, MD, PhD, of University Hospital Basel, Switzerland, and colleagues.
“The odds of achieving a partial response to salvage chemotherapy were significantly higher in patients with prior exposure to PD-1/PD-L1 inhibitors. This observed difference, however, warrants confirmation in larger cohorts. Ongoing investigations include the duration of response as well as evaluation of toxicity,” the researchers wrote in a scientific poster presented at the European Lung Cancer Conference.
Immune checkpoint inhibitors have been shown to be active in patients with late-stage NSCLC who have experienced disease progression following chemotherapy. To see whether salvage chemotherapy could offer any additional benefit to patients who had disease progression on immunotherapy, the investigators conducted a retrospective case-control study. They reviewed 355 patient records, and identified 82 patients – 46 men and 36 women – who met the study criteria.
Of this group, 67 patients had received a PD-1/PD-L1 checkpoint inhibitor, either nivolumab (Opdivo, 56 patients), pembrolizumab (Keytruda, 7), or atezolizumab (Tecentriq, 4). These patients were designated as cases. The remaining 15 patients, who had received prior chemotherapy or chemoradiotherapy only, were designated as controls.
Of all 82 patients, 63 (77%) had adenocarcinomas, 18 (22%) had squamous cell carcinomas, and 1 (1%) had a large-cell carcinoma.
Cases had a mean of 2.37 chemotherapy regimens prior to salvage chemotherapy, and controls had a mean of 1.93. Drugs used in the salvage regimens were docetaxel in 62% of patients, pemetrexed in 20%, gemcitabine in 12%, and paclitaxel in 6%.
The odds ratio for achieving a partial response was 0.30 (95% confidence interval, 0.18-0.50, P less than .0001).
In a multiple logistic regression model, neither age, sex, number of prior chemotherapy regimens, tumor histology, smoking status, nor type of salvage chemotherapy regimen were significantly associated with the likelihood of achieving a partial response.
In a poster discussion session, Simon Ekman, MD, of Karolinska Institute in Stockholm, Sweden, the invited discussant, said that the data from the study are convincing, and raise the question of what to do next.
“The question is how do we combine immunotherapy with chemotherapy? Should we use the immune therapy first, like in this trial, or vice versa, or should we combine concurrently” he said.
The strategy of chemotherapy first is supported by research showing that neoantigens crucial for the immune response are released during chemotherapy and radiotherapy, enabling immunotherapeutic agents to work better, he said.
The study was internally funded. Dr. Rothschild and Dr. Ekman reported no conflicts relevant to the research.
GENEVA – Patients with stage IV non–small cell lung cancer (NSCLC) who have disease progression following treatment with an immune checkpoint inhibitor have a 30% better chance of achieving at least a partial response with salvage chemotherapy compared with patients who had received prior chemotherapy but not immunotherapy, according to Swiss and U.S. investigators.
In a study of 82 patients with advanced NSCLC, 18 of 67 patients (27%) who had progressed on an inhibitor of programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) had a partial response to combination chemotherapy, compared with just 1 of 15 (7%) of patients who had not received a checkpoint inhibitor, reported Sacha Rothschild, MD, PhD, of University Hospital Basel, Switzerland, and colleagues.
“The odds of achieving a partial response to salvage chemotherapy were significantly higher in patients with prior exposure to PD-1/PD-L1 inhibitors. This observed difference, however, warrants confirmation in larger cohorts. Ongoing investigations include the duration of response as well as evaluation of toxicity,” the researchers wrote in a scientific poster presented at the European Lung Cancer Conference.
Immune checkpoint inhibitors have been shown to be active in patients with late-stage NSCLC who have experienced disease progression following chemotherapy. To see whether salvage chemotherapy could offer any additional benefit to patients who had disease progression on immunotherapy, the investigators conducted a retrospective case-control study. They reviewed 355 patient records, and identified 82 patients – 46 men and 36 women – who met the study criteria.
Of this group, 67 patients had received a PD-1/PD-L1 checkpoint inhibitor, either nivolumab (Opdivo, 56 patients), pembrolizumab (Keytruda, 7), or atezolizumab (Tecentriq, 4). These patients were designated as cases. The remaining 15 patients, who had received prior chemotherapy or chemoradiotherapy only, were designated as controls.
Of all 82 patients, 63 (77%) had adenocarcinomas, 18 (22%) had squamous cell carcinomas, and 1 (1%) had a large-cell carcinoma.
Cases had a mean of 2.37 chemotherapy regimens prior to salvage chemotherapy, and controls had a mean of 1.93. Drugs used in the salvage regimens were docetaxel in 62% of patients, pemetrexed in 20%, gemcitabine in 12%, and paclitaxel in 6%.
The odds ratio for achieving a partial response was 0.30 (95% confidence interval, 0.18-0.50, P less than .0001).
In a multiple logistic regression model, neither age, sex, number of prior chemotherapy regimens, tumor histology, smoking status, nor type of salvage chemotherapy regimen were significantly associated with the likelihood of achieving a partial response.
In a poster discussion session, Simon Ekman, MD, of Karolinska Institute in Stockholm, Sweden, the invited discussant, said that the data from the study are convincing, and raise the question of what to do next.
“The question is how do we combine immunotherapy with chemotherapy? Should we use the immune therapy first, like in this trial, or vice versa, or should we combine concurrently” he said.
The strategy of chemotherapy first is supported by research showing that neoantigens crucial for the immune response are released during chemotherapy and radiotherapy, enabling immunotherapeutic agents to work better, he said.
The study was internally funded. Dr. Rothschild and Dr. Ekman reported no conflicts relevant to the research.
FROM ELCC
Key clinical point: Salvage chemotherapy was more effective among patients who had disease progression following immunotherapy in the second line than among patients who received only chemotherapy.
Major finding: Among patients with disease progression while on a checkpoint inhibitor, 18 of 67 had a partial response to salvage chemotherapy, compared with just 1 of 15 controls.
Data source: Retrospective case-control study of 82 patients with advanced NSCLC.
Disclosures: The study was internally funded. Dr. Rothschild and Dr. Ekman reported no conflicts relevant to the research.
Atezolizumab improves OS in NSCLC with brain metastases
GENEVA – Immune checkpoint inhibitors may improve survival in patients with non–small cell lung cancer (NSCLC) and brain metastases compared with chemotherapy, without adding unacceptable toxicities, pooled analyses of clinical trials suggest.
Among 1452 patients with NSCLC treated with the programmed death ligand-1 (PD-L1) inhibitor atezolizumab (Tecentriq), rates of treatment-related serious adverse events (SAEs) were similar between patients with brain metastases at baseline and those without brain metastases, reported Rimas V Lukas, MD, from the University of Chicago.
“Overall, I think that these results support the investigation of atezolizumab in non–small cell lung cancer patients with CNS metastases,” Dr. Lukas said at the European Lung Cancer Conference.
Lung cancer accounts for about 40%-50% of all cases of brain metastases, and approximately 20%-40% of patients with advanced NSCLC will develop metastases, which are associated with poor overall survival, according to Solange Peters, MD, from the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, the invited discussant.
To evaluate the safety and efficacy of the PD-L1 inhibitor in patients with brain metastases at baseline, Lukas et al. looked at pooled safety data on patients enrolled in one of five treatment studies with atezolizumab – PCD4989g; BIRCH, POPLAR, FIR, and OAK – and efficacy data from a subset of patients in OAK.
The pooled analysis included 1452 patients, 79 of whom (5%) had brain metastases at baseline. This analysis showed that, although there was a higher incidence of any neurological AE, treatment-related AE, or treatment–related neurologic AE among patients with brain metastases, treatment-related SAEs and treatment related neurological SAEs were similar between the two groups. The most common neurological AE was headache, reported by 8% of patients with metastases and 3% without.
The efficacy analysis, which included a cohort of the first 850 patients with or without brain metastases treated, showed a significant survival for atezolizumab in the OAK trial, with median overall survival of 20.1 months for patients with brain metastases assigned to the PD-L1 inhibitor, compared with 11.9 months for patients assigned to docetaxel. This translated into a hazard ratio for atezolizumab of 0.54 (P = .0279).
Among the 750 patients without baseline brain metastases in OAK, the respective OS rates were 13.0 months, vs. 9.4 months (HR, 0.75; P = .001).
Although it was not statistically significant, the risk for developing new central nervous system lesions also appeared to be lower with atezolizumab than with docetaxel, with a median time to new lesions not reached, vs. 9.5 months with docetaxel (HR, 0.42; 95% confidence interval, 0.15-1.18).
Among patients without baseline brain metastases, there was also a hint that atezolizumab could delay onset of CNS metastases, although the trend was not significant, the investigators found.
In her commentary on the study, Dr. Peters said that “checkpoint inhibitors demonstrate activity in the brain that remains to be quantified and prospectively compared to systemic activity in larger series, and these are very small series.”
“Limitations in duration and level of activity might exist, however, related to the blood brain barrier and the brain immune system characteristics,” she added.
The study was supported by F. Hoffmann-La Roche/Genentech, a member of the Roche Group. Dr. Lukas disclosed serving on advisory boards for AstraZeneca and Novocure and receiving honoraria from AbbVie. Two coauthors are employees of Genentech, and two are employed by Roche. The remaining author had no disclosures. Dr. Peters reported relationships with Bristol-Myers Squibb, F. Hoffmann-La Roche, Eli Lilly, AstraZeneca, Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Morphotek, Merrimack, Merck Sharp and Dohme, and Merck Serono.
GENEVA – Immune checkpoint inhibitors may improve survival in patients with non–small cell lung cancer (NSCLC) and brain metastases compared with chemotherapy, without adding unacceptable toxicities, pooled analyses of clinical trials suggest.
Among 1452 patients with NSCLC treated with the programmed death ligand-1 (PD-L1) inhibitor atezolizumab (Tecentriq), rates of treatment-related serious adverse events (SAEs) were similar between patients with brain metastases at baseline and those without brain metastases, reported Rimas V Lukas, MD, from the University of Chicago.
“Overall, I think that these results support the investigation of atezolizumab in non–small cell lung cancer patients with CNS metastases,” Dr. Lukas said at the European Lung Cancer Conference.
Lung cancer accounts for about 40%-50% of all cases of brain metastases, and approximately 20%-40% of patients with advanced NSCLC will develop metastases, which are associated with poor overall survival, according to Solange Peters, MD, from the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, the invited discussant.
To evaluate the safety and efficacy of the PD-L1 inhibitor in patients with brain metastases at baseline, Lukas et al. looked at pooled safety data on patients enrolled in one of five treatment studies with atezolizumab – PCD4989g; BIRCH, POPLAR, FIR, and OAK – and efficacy data from a subset of patients in OAK.
The pooled analysis included 1452 patients, 79 of whom (5%) had brain metastases at baseline. This analysis showed that, although there was a higher incidence of any neurological AE, treatment-related AE, or treatment–related neurologic AE among patients with brain metastases, treatment-related SAEs and treatment related neurological SAEs were similar between the two groups. The most common neurological AE was headache, reported by 8% of patients with metastases and 3% without.
The efficacy analysis, which included a cohort of the first 850 patients with or without brain metastases treated, showed a significant survival for atezolizumab in the OAK trial, with median overall survival of 20.1 months for patients with brain metastases assigned to the PD-L1 inhibitor, compared with 11.9 months for patients assigned to docetaxel. This translated into a hazard ratio for atezolizumab of 0.54 (P = .0279).
Among the 750 patients without baseline brain metastases in OAK, the respective OS rates were 13.0 months, vs. 9.4 months (HR, 0.75; P = .001).
Although it was not statistically significant, the risk for developing new central nervous system lesions also appeared to be lower with atezolizumab than with docetaxel, with a median time to new lesions not reached, vs. 9.5 months with docetaxel (HR, 0.42; 95% confidence interval, 0.15-1.18).
Among patients without baseline brain metastases, there was also a hint that atezolizumab could delay onset of CNS metastases, although the trend was not significant, the investigators found.
In her commentary on the study, Dr. Peters said that “checkpoint inhibitors demonstrate activity in the brain that remains to be quantified and prospectively compared to systemic activity in larger series, and these are very small series.”
“Limitations in duration and level of activity might exist, however, related to the blood brain barrier and the brain immune system characteristics,” she added.
The study was supported by F. Hoffmann-La Roche/Genentech, a member of the Roche Group. Dr. Lukas disclosed serving on advisory boards for AstraZeneca and Novocure and receiving honoraria from AbbVie. Two coauthors are employees of Genentech, and two are employed by Roche. The remaining author had no disclosures. Dr. Peters reported relationships with Bristol-Myers Squibb, F. Hoffmann-La Roche, Eli Lilly, AstraZeneca, Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Morphotek, Merrimack, Merck Sharp and Dohme, and Merck Serono.
GENEVA – Immune checkpoint inhibitors may improve survival in patients with non–small cell lung cancer (NSCLC) and brain metastases compared with chemotherapy, without adding unacceptable toxicities, pooled analyses of clinical trials suggest.
Among 1452 patients with NSCLC treated with the programmed death ligand-1 (PD-L1) inhibitor atezolizumab (Tecentriq), rates of treatment-related serious adverse events (SAEs) were similar between patients with brain metastases at baseline and those without brain metastases, reported Rimas V Lukas, MD, from the University of Chicago.
“Overall, I think that these results support the investigation of atezolizumab in non–small cell lung cancer patients with CNS metastases,” Dr. Lukas said at the European Lung Cancer Conference.
Lung cancer accounts for about 40%-50% of all cases of brain metastases, and approximately 20%-40% of patients with advanced NSCLC will develop metastases, which are associated with poor overall survival, according to Solange Peters, MD, from the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, the invited discussant.
To evaluate the safety and efficacy of the PD-L1 inhibitor in patients with brain metastases at baseline, Lukas et al. looked at pooled safety data on patients enrolled in one of five treatment studies with atezolizumab – PCD4989g; BIRCH, POPLAR, FIR, and OAK – and efficacy data from a subset of patients in OAK.
The pooled analysis included 1452 patients, 79 of whom (5%) had brain metastases at baseline. This analysis showed that, although there was a higher incidence of any neurological AE, treatment-related AE, or treatment–related neurologic AE among patients with brain metastases, treatment-related SAEs and treatment related neurological SAEs were similar between the two groups. The most common neurological AE was headache, reported by 8% of patients with metastases and 3% without.
The efficacy analysis, which included a cohort of the first 850 patients with or without brain metastases treated, showed a significant survival for atezolizumab in the OAK trial, with median overall survival of 20.1 months for patients with brain metastases assigned to the PD-L1 inhibitor, compared with 11.9 months for patients assigned to docetaxel. This translated into a hazard ratio for atezolizumab of 0.54 (P = .0279).
Among the 750 patients without baseline brain metastases in OAK, the respective OS rates were 13.0 months, vs. 9.4 months (HR, 0.75; P = .001).
Although it was not statistically significant, the risk for developing new central nervous system lesions also appeared to be lower with atezolizumab than with docetaxel, with a median time to new lesions not reached, vs. 9.5 months with docetaxel (HR, 0.42; 95% confidence interval, 0.15-1.18).
Among patients without baseline brain metastases, there was also a hint that atezolizumab could delay onset of CNS metastases, although the trend was not significant, the investigators found.
In her commentary on the study, Dr. Peters said that “checkpoint inhibitors demonstrate activity in the brain that remains to be quantified and prospectively compared to systemic activity in larger series, and these are very small series.”
“Limitations in duration and level of activity might exist, however, related to the blood brain barrier and the brain immune system characteristics,” she added.
The study was supported by F. Hoffmann-La Roche/Genentech, a member of the Roche Group. Dr. Lukas disclosed serving on advisory boards for AstraZeneca and Novocure and receiving honoraria from AbbVie. Two coauthors are employees of Genentech, and two are employed by Roche. The remaining author had no disclosures. Dr. Peters reported relationships with Bristol-Myers Squibb, F. Hoffmann-La Roche, Eli Lilly, AstraZeneca, Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Morphotek, Merrimack, Merck Sharp and Dohme, and Merck Serono.
Key clinical point: The PD-L1 inhibitor atezolizumab improved overall survival, vs. docetaxel, in patients with non–small cell lung cancer and brain metastases.
Major finding: The hazard ratio for overall survival was 0.54 for patients assigned to atezolizumab, vs. docetaxel, in the OAK trial.
Data source: Pooled safety analysis of 1452 patients and efficacy analysis of 850 patients with NSCLC with or without brain metastases.
Disclosures: The study was supported by F. Hoffmann-La Roche/Genentech, a member of the Roche Group. Dr. Lukas disclosed serving on advisory boards for AstraZeneca and Novocure and receiving honoraria from AbbVie. Two coauthors are employees of Genentech, and two are employed by Roche. The remaining author had no disclosures. Dr. Peters reported relationships with Bristol-Myers Squibb, F. Hoffmann-La Roche, Eli Lilly, AstraZeneca, Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Morphotek, Merrimack, Merck Sharp and Dohme, and Merck Serono.
FDA approves pembrolizumab for first-line advanced NSCLC
The Food and Drug Administration has granted accelerated approval to checkpoint inhibitor pembrolizumab in combination with pemetrexed and carboplatin for the treatment of patients with previously untreated metastatic nonsquamous non–small cell lung cancer (NSCLC).
The immunotherapy pembrolizumab was approved as a second-line treatment for metastatic NSCLC in 2015.
First-line approval was based on an improved overall response rate (ORR) and progression-free survival (PFS) in a cohort of 123 patients within an open-label, multicohort study (KEYNOTE-21). Enrollees in cohort G1 had locally advanced or metastatic NSCLC and no prior systemic treatment for metastatic disease. They were randomized to receive either pembrolizumab, in combination with pemetrexed and carboplatin (PC) for four cycles followed by pembrolizumab for a maximum of 24 months (n = 60) or PC alone (n = 63). Randomization was stratified by PD-L1 tumor expression (tumor proportion score [TPS] less than 1% vs. TPS greater than or equal to 1%).
The hazard ratio for PFS was 0.53 (95% CI: 0.31, 0.91, P = .0205). The median PFS was 13.0 months for the pembrolizumab plus PC arm and 8.9 months for the PC-alone arm. In the TPS less than 1% subgroup, the ORR was 57% and 13% in the pembrolizumab-plus-PC and in the PC-alone arms, respectively. In the TPS greater-than-or-equal-to-1% subgroup, the ORR was 54% in the pembrolizumab-plus-PC arm and 38% in the pembrolizumab-plus-PC arm, the FDA said.
There were serious adverse events in 41% of the patients in the pembrolizumab-plus-PC arm compared with 28% in the PC-alone arm. Pembrolizumab was discontinued for adverse reactions in 10% of patients, most commonly due to acute kidney injury. The most common grade 3-4 adverse reactions were fatigue, dyspnea, nausea, vomiting, diarrhea, and rash.
The FDA cautioned that immune-mediated adverse reactions can occur with pembrolizumab including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. Based on the severity of the adverse reaction, pembrolizumab should be withheld or discontinued and corticosteroids administered when appropriate. The recommended dose and schedule for NSCLC is 200 mg as an intravenous infusion every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
Pembrolizumab is marketed as Keytruda by Merck.
The Food and Drug Administration has granted accelerated approval to checkpoint inhibitor pembrolizumab in combination with pemetrexed and carboplatin for the treatment of patients with previously untreated metastatic nonsquamous non–small cell lung cancer (NSCLC).
The immunotherapy pembrolizumab was approved as a second-line treatment for metastatic NSCLC in 2015.
First-line approval was based on an improved overall response rate (ORR) and progression-free survival (PFS) in a cohort of 123 patients within an open-label, multicohort study (KEYNOTE-21). Enrollees in cohort G1 had locally advanced or metastatic NSCLC and no prior systemic treatment for metastatic disease. They were randomized to receive either pembrolizumab, in combination with pemetrexed and carboplatin (PC) for four cycles followed by pembrolizumab for a maximum of 24 months (n = 60) or PC alone (n = 63). Randomization was stratified by PD-L1 tumor expression (tumor proportion score [TPS] less than 1% vs. TPS greater than or equal to 1%).
The hazard ratio for PFS was 0.53 (95% CI: 0.31, 0.91, P = .0205). The median PFS was 13.0 months for the pembrolizumab plus PC arm and 8.9 months for the PC-alone arm. In the TPS less than 1% subgroup, the ORR was 57% and 13% in the pembrolizumab-plus-PC and in the PC-alone arms, respectively. In the TPS greater-than-or-equal-to-1% subgroup, the ORR was 54% in the pembrolizumab-plus-PC arm and 38% in the pembrolizumab-plus-PC arm, the FDA said.
There were serious adverse events in 41% of the patients in the pembrolizumab-plus-PC arm compared with 28% in the PC-alone arm. Pembrolizumab was discontinued for adverse reactions in 10% of patients, most commonly due to acute kidney injury. The most common grade 3-4 adverse reactions were fatigue, dyspnea, nausea, vomiting, diarrhea, and rash.
The FDA cautioned that immune-mediated adverse reactions can occur with pembrolizumab including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. Based on the severity of the adverse reaction, pembrolizumab should be withheld or discontinued and corticosteroids administered when appropriate. The recommended dose and schedule for NSCLC is 200 mg as an intravenous infusion every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
Pembrolizumab is marketed as Keytruda by Merck.
The Food and Drug Administration has granted accelerated approval to checkpoint inhibitor pembrolizumab in combination with pemetrexed and carboplatin for the treatment of patients with previously untreated metastatic nonsquamous non–small cell lung cancer (NSCLC).
The immunotherapy pembrolizumab was approved as a second-line treatment for metastatic NSCLC in 2015.
First-line approval was based on an improved overall response rate (ORR) and progression-free survival (PFS) in a cohort of 123 patients within an open-label, multicohort study (KEYNOTE-21). Enrollees in cohort G1 had locally advanced or metastatic NSCLC and no prior systemic treatment for metastatic disease. They were randomized to receive either pembrolizumab, in combination with pemetrexed and carboplatin (PC) for four cycles followed by pembrolizumab for a maximum of 24 months (n = 60) or PC alone (n = 63). Randomization was stratified by PD-L1 tumor expression (tumor proportion score [TPS] less than 1% vs. TPS greater than or equal to 1%).
The hazard ratio for PFS was 0.53 (95% CI: 0.31, 0.91, P = .0205). The median PFS was 13.0 months for the pembrolizumab plus PC arm and 8.9 months for the PC-alone arm. In the TPS less than 1% subgroup, the ORR was 57% and 13% in the pembrolizumab-plus-PC and in the PC-alone arms, respectively. In the TPS greater-than-or-equal-to-1% subgroup, the ORR was 54% in the pembrolizumab-plus-PC arm and 38% in the pembrolizumab-plus-PC arm, the FDA said.
There were serious adverse events in 41% of the patients in the pembrolizumab-plus-PC arm compared with 28% in the PC-alone arm. Pembrolizumab was discontinued for adverse reactions in 10% of patients, most commonly due to acute kidney injury. The most common grade 3-4 adverse reactions were fatigue, dyspnea, nausea, vomiting, diarrhea, and rash.
The FDA cautioned that immune-mediated adverse reactions can occur with pembrolizumab including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. Based on the severity of the adverse reaction, pembrolizumab should be withheld or discontinued and corticosteroids administered when appropriate. The recommended dose and schedule for NSCLC is 200 mg as an intravenous infusion every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
Pembrolizumab is marketed as Keytruda by Merck.
SLE linked to subsequent risk of malignant melanoma
PORTLAND, ORE. – A diagnosis of systemic lupus erythematosus (SLE) significantly increases the risk of a subsequent diagnosis of malignant melanoma, according to the results of a large, first-in-kind, single-center longitudinal analysis of electronic medical records.
This finding expands the list of known associations between SLE and cancer, and highlights the need for careful surveillance of this population, Solomiya Grushchak, of the department of dermatology at Northwestern University, Chicago, and her associates, reported in a poster presented at the annual meeting of the Society for Investigative Dermatology.
SLE is increasingly being treated with immune checkpoint inhibitors, which can aggressively disrupt immune reactivity and trigger uncontrolled cellular responses in patients with SLE, Ms. Grushchak noted. “The findings in this large population warrant further exploration of the association between malignant melanoma and SLE to promote optimal patient management, especially in light of recent advances [in the use of] checkpoint inhibitors,” she added.
Past work has linked SLE with several other malignancies, including nonmelanoma skin cancers, non-Hodgkin and Hodgkin lymphomas, and cancers of the larynx, lungs, liver, vulva, vagina, and thyroid gland. Even when patients are not receiving checkpoint inhibitors, SLE causes chronic inflammation and is known to increase cellular dysplasia, which can ultimately trigger uncontrolled proliferation of tumor cells. In 2015, a meta-analysis showed that SLE was associated with a decreased risk of melanoma, but no studies had conclusively evaluated this relationship (PLoS One. 2015;10[4]:e0122964).
Therefore, Ms. Grushchak and her associates analyzed medical records from 2,351 patients from the urban Midwest with SLE diagnosed by a dermatologist or rheumatologist between 2000 and 2016. The data source was the Northwestern Enterprise Data Warehouse, which integrates clinical and research information from more than 50 health data systems used by the Northwestern University Feinberg School of Medicine and its health care partners. To avoid detection bias, the researchers constructed a comparison group from the same database of 1,676 patients diagnosed with systemic sclerosis.
Ten patients (0.4%) with a diagnostic code for SLE were later diagnosed with malignant melanoma, compared with one patient with systemic sclerosis (0.06%), the investigators reported. A Fisher’s exact test confirmed a statistically significant difference between these rates (P = .03). Among the 10 SLE patients with melanoma, 7 were white, 2 were black, and 1 was of Asian ancestry. Nine were females, and one was male. The patient with systemic sclerosis and melanoma was a white male.
The study had several limitations. The investigators did not report how much time elapsed between the diagnoses of SLE and melanoma, or the rates or cumulative exposure to checkpoint inhibitors.
The National Institutes of Health provides support to the Northwestern Enterprise Data Warehouse. The investigators had no relevant financial conflicts.
PORTLAND, ORE. – A diagnosis of systemic lupus erythematosus (SLE) significantly increases the risk of a subsequent diagnosis of malignant melanoma, according to the results of a large, first-in-kind, single-center longitudinal analysis of electronic medical records.
This finding expands the list of known associations between SLE and cancer, and highlights the need for careful surveillance of this population, Solomiya Grushchak, of the department of dermatology at Northwestern University, Chicago, and her associates, reported in a poster presented at the annual meeting of the Society for Investigative Dermatology.
SLE is increasingly being treated with immune checkpoint inhibitors, which can aggressively disrupt immune reactivity and trigger uncontrolled cellular responses in patients with SLE, Ms. Grushchak noted. “The findings in this large population warrant further exploration of the association between malignant melanoma and SLE to promote optimal patient management, especially in light of recent advances [in the use of] checkpoint inhibitors,” she added.
Past work has linked SLE with several other malignancies, including nonmelanoma skin cancers, non-Hodgkin and Hodgkin lymphomas, and cancers of the larynx, lungs, liver, vulva, vagina, and thyroid gland. Even when patients are not receiving checkpoint inhibitors, SLE causes chronic inflammation and is known to increase cellular dysplasia, which can ultimately trigger uncontrolled proliferation of tumor cells. In 2015, a meta-analysis showed that SLE was associated with a decreased risk of melanoma, but no studies had conclusively evaluated this relationship (PLoS One. 2015;10[4]:e0122964).
Therefore, Ms. Grushchak and her associates analyzed medical records from 2,351 patients from the urban Midwest with SLE diagnosed by a dermatologist or rheumatologist between 2000 and 2016. The data source was the Northwestern Enterprise Data Warehouse, which integrates clinical and research information from more than 50 health data systems used by the Northwestern University Feinberg School of Medicine and its health care partners. To avoid detection bias, the researchers constructed a comparison group from the same database of 1,676 patients diagnosed with systemic sclerosis.
Ten patients (0.4%) with a diagnostic code for SLE were later diagnosed with malignant melanoma, compared with one patient with systemic sclerosis (0.06%), the investigators reported. A Fisher’s exact test confirmed a statistically significant difference between these rates (P = .03). Among the 10 SLE patients with melanoma, 7 were white, 2 were black, and 1 was of Asian ancestry. Nine were females, and one was male. The patient with systemic sclerosis and melanoma was a white male.
The study had several limitations. The investigators did not report how much time elapsed between the diagnoses of SLE and melanoma, or the rates or cumulative exposure to checkpoint inhibitors.
The National Institutes of Health provides support to the Northwestern Enterprise Data Warehouse. The investigators had no relevant financial conflicts.
PORTLAND, ORE. – A diagnosis of systemic lupus erythematosus (SLE) significantly increases the risk of a subsequent diagnosis of malignant melanoma, according to the results of a large, first-in-kind, single-center longitudinal analysis of electronic medical records.
This finding expands the list of known associations between SLE and cancer, and highlights the need for careful surveillance of this population, Solomiya Grushchak, of the department of dermatology at Northwestern University, Chicago, and her associates, reported in a poster presented at the annual meeting of the Society for Investigative Dermatology.
SLE is increasingly being treated with immune checkpoint inhibitors, which can aggressively disrupt immune reactivity and trigger uncontrolled cellular responses in patients with SLE, Ms. Grushchak noted. “The findings in this large population warrant further exploration of the association between malignant melanoma and SLE to promote optimal patient management, especially in light of recent advances [in the use of] checkpoint inhibitors,” she added.
Past work has linked SLE with several other malignancies, including nonmelanoma skin cancers, non-Hodgkin and Hodgkin lymphomas, and cancers of the larynx, lungs, liver, vulva, vagina, and thyroid gland. Even when patients are not receiving checkpoint inhibitors, SLE causes chronic inflammation and is known to increase cellular dysplasia, which can ultimately trigger uncontrolled proliferation of tumor cells. In 2015, a meta-analysis showed that SLE was associated with a decreased risk of melanoma, but no studies had conclusively evaluated this relationship (PLoS One. 2015;10[4]:e0122964).
Therefore, Ms. Grushchak and her associates analyzed medical records from 2,351 patients from the urban Midwest with SLE diagnosed by a dermatologist or rheumatologist between 2000 and 2016. The data source was the Northwestern Enterprise Data Warehouse, which integrates clinical and research information from more than 50 health data systems used by the Northwestern University Feinberg School of Medicine and its health care partners. To avoid detection bias, the researchers constructed a comparison group from the same database of 1,676 patients diagnosed with systemic sclerosis.
Ten patients (0.4%) with a diagnostic code for SLE were later diagnosed with malignant melanoma, compared with one patient with systemic sclerosis (0.06%), the investigators reported. A Fisher’s exact test confirmed a statistically significant difference between these rates (P = .03). Among the 10 SLE patients with melanoma, 7 were white, 2 were black, and 1 was of Asian ancestry. Nine were females, and one was male. The patient with systemic sclerosis and melanoma was a white male.
The study had several limitations. The investigators did not report how much time elapsed between the diagnoses of SLE and melanoma, or the rates or cumulative exposure to checkpoint inhibitors.
The National Institutes of Health provides support to the Northwestern Enterprise Data Warehouse. The investigators had no relevant financial conflicts.
AT SID 2017
Key clinical point: Compared with controls, patients with systemic lupus erythematosus (SLE) were at significantly increased risk of later being diagnosed with malignant melanoma.
Major finding: Ten patients with SLE (0.4%) were later diagnosed with malignant melanoma, compared with one patient with systemic sclerosis (0.06%), a statistically significant difference (P = .03).
Data source: Electronic medical record reviews of 2,351 patients with SLE and 1,676 patients with systemic sclerosis (controls) between 2000 and 2016.
Disclosures: The National Institutes of Health provides support to the Northwestern Enterprise Data Warehouse. The investigators had no relevant financial conflicts.
Flu shots may spark immune adverse events in PD-1 blockade for NSCLC
GENEVA – The influenza vaccine may interact with immune checkpoint inhibitors in patients with lung cancer, results of a small study suggest.
Among 23 patients with non–small cell lung cancer (NSCLC) treated with a drug targeted against programmed death-1 (PD-1), the seasonal flu vaccine appeared to produce good serologic protection against infection, but at the possible cost of an increase in the rate of immune-related adverse events (IrAE), reported Sacha Rothschild, MD, PhD, of University Hospital Basel (Switzerland) at the European Lung Cancer Conference.
Among 23 patients with lung cancer treated with a PD-1 inhibitor, 12 (52.2%) had one or more IrAEs. In contrast, the most frequent IrAE in a key registration trial for nivolumab (Opdivo) was skin rash, which occurred in 9% of patients (N Engl J Med. 2015 Jul 9;373:1627-39).
“It’s a very small study, but it raises some concern that there might be an interaction between the vaccine and PD-1 blockade,” Dr. Rothschild said.
To see whether blocking the PD-1/PD–ligand-1 (PD-L1) axis might induce an overactive immune response, the investigators prospectively studied 23 patients with NSCLC who were undergoing treatment with a PD-1 inhibitor – 22 with nivolumab and 1 with pembrolizumab (Keytruda) – who were also vaccinated with a trivalent influenza vaccine in October or November 2015. They used the partners of the patients, also vaccinated, for an age-matched cohort of healthy controls.
The investigators looked at antibody titers against flu strains covered by the vaccine, measured inflammatory chemokines and assessed the vaccine’s safety and the frequency of IrAEs.
None of the patients came down with the flu during the 2015-2016 season. There were no major differences over time in the generation of antibodies against all three viral strains tested.
However, at both 30 and 60 days after vaccination, a hemagglutination inhibition assay showed slightly elevated antibody titers among patients, compared with controls. Antibody titers against H1N1 virus also appeared to increase somewhat more rapidly among patients than among controls, the authors found.
The patients appeared to tolerate the vaccine well, and no serious adverse events were reported within 30 days of vaccination.
When they looked at the incidence of IrAEs, however, the investigators found that six patients had grade 1 or 2 IrAEs, and six had grade 3 or 4 events.
The events included skin rash and arthritis in three patients each, colitis and encephalitis in two patients each, and hypothyroidism, pneumonitis, and neuropathy in one patient each.
“We looked into inflammatory chemokines to understand if there was a high rate of systemic inflammation, and we didn’t find any differences in this regard. So far, we have no clue about why the immune-related adverse event rate in this group is higher,” Dr. Rothschild said.
Although the sample size was small, the IrAE effect they saw was large enough to warrant concern, and it should be studied in a larger population sample, he said.
Egbert Smit, MD, PhD, of the Netherlands Cancer Institute in Amsterdam, who was not involved in the study, commented that “it shows how much we still have to learn about the optimal use of checkpoint inhibitors in lung cancer patients. The study is important as it is the first to investigate the impact of influenza vaccination in such patients, and there is a hint that we actually put them at increased risk for serious toxicities, including encephalitis. However, until we have data on a larger cohort, preferably in a controlled, prospective study, in my institution, we advocate influenza vaccination irrespective of concurrent treatment with immune-checkpoint inhibitors.”
The study was supported by institutional funding. The investigators and Dr. Smit reported no relevant conflicts of interest.
GENEVA – The influenza vaccine may interact with immune checkpoint inhibitors in patients with lung cancer, results of a small study suggest.
Among 23 patients with non–small cell lung cancer (NSCLC) treated with a drug targeted against programmed death-1 (PD-1), the seasonal flu vaccine appeared to produce good serologic protection against infection, but at the possible cost of an increase in the rate of immune-related adverse events (IrAE), reported Sacha Rothschild, MD, PhD, of University Hospital Basel (Switzerland) at the European Lung Cancer Conference.
Among 23 patients with lung cancer treated with a PD-1 inhibitor, 12 (52.2%) had one or more IrAEs. In contrast, the most frequent IrAE in a key registration trial for nivolumab (Opdivo) was skin rash, which occurred in 9% of patients (N Engl J Med. 2015 Jul 9;373:1627-39).
“It’s a very small study, but it raises some concern that there might be an interaction between the vaccine and PD-1 blockade,” Dr. Rothschild said.
To see whether blocking the PD-1/PD–ligand-1 (PD-L1) axis might induce an overactive immune response, the investigators prospectively studied 23 patients with NSCLC who were undergoing treatment with a PD-1 inhibitor – 22 with nivolumab and 1 with pembrolizumab (Keytruda) – who were also vaccinated with a trivalent influenza vaccine in October or November 2015. They used the partners of the patients, also vaccinated, for an age-matched cohort of healthy controls.
The investigators looked at antibody titers against flu strains covered by the vaccine, measured inflammatory chemokines and assessed the vaccine’s safety and the frequency of IrAEs.
None of the patients came down with the flu during the 2015-2016 season. There were no major differences over time in the generation of antibodies against all three viral strains tested.
However, at both 30 and 60 days after vaccination, a hemagglutination inhibition assay showed slightly elevated antibody titers among patients, compared with controls. Antibody titers against H1N1 virus also appeared to increase somewhat more rapidly among patients than among controls, the authors found.
The patients appeared to tolerate the vaccine well, and no serious adverse events were reported within 30 days of vaccination.
When they looked at the incidence of IrAEs, however, the investigators found that six patients had grade 1 or 2 IrAEs, and six had grade 3 or 4 events.
The events included skin rash and arthritis in three patients each, colitis and encephalitis in two patients each, and hypothyroidism, pneumonitis, and neuropathy in one patient each.
“We looked into inflammatory chemokines to understand if there was a high rate of systemic inflammation, and we didn’t find any differences in this regard. So far, we have no clue about why the immune-related adverse event rate in this group is higher,” Dr. Rothschild said.
Although the sample size was small, the IrAE effect they saw was large enough to warrant concern, and it should be studied in a larger population sample, he said.
Egbert Smit, MD, PhD, of the Netherlands Cancer Institute in Amsterdam, who was not involved in the study, commented that “it shows how much we still have to learn about the optimal use of checkpoint inhibitors in lung cancer patients. The study is important as it is the first to investigate the impact of influenza vaccination in such patients, and there is a hint that we actually put them at increased risk for serious toxicities, including encephalitis. However, until we have data on a larger cohort, preferably in a controlled, prospective study, in my institution, we advocate influenza vaccination irrespective of concurrent treatment with immune-checkpoint inhibitors.”
The study was supported by institutional funding. The investigators and Dr. Smit reported no relevant conflicts of interest.
GENEVA – The influenza vaccine may interact with immune checkpoint inhibitors in patients with lung cancer, results of a small study suggest.
Among 23 patients with non–small cell lung cancer (NSCLC) treated with a drug targeted against programmed death-1 (PD-1), the seasonal flu vaccine appeared to produce good serologic protection against infection, but at the possible cost of an increase in the rate of immune-related adverse events (IrAE), reported Sacha Rothschild, MD, PhD, of University Hospital Basel (Switzerland) at the European Lung Cancer Conference.
Among 23 patients with lung cancer treated with a PD-1 inhibitor, 12 (52.2%) had one or more IrAEs. In contrast, the most frequent IrAE in a key registration trial for nivolumab (Opdivo) was skin rash, which occurred in 9% of patients (N Engl J Med. 2015 Jul 9;373:1627-39).
“It’s a very small study, but it raises some concern that there might be an interaction between the vaccine and PD-1 blockade,” Dr. Rothschild said.
To see whether blocking the PD-1/PD–ligand-1 (PD-L1) axis might induce an overactive immune response, the investigators prospectively studied 23 patients with NSCLC who were undergoing treatment with a PD-1 inhibitor – 22 with nivolumab and 1 with pembrolizumab (Keytruda) – who were also vaccinated with a trivalent influenza vaccine in October or November 2015. They used the partners of the patients, also vaccinated, for an age-matched cohort of healthy controls.
The investigators looked at antibody titers against flu strains covered by the vaccine, measured inflammatory chemokines and assessed the vaccine’s safety and the frequency of IrAEs.
None of the patients came down with the flu during the 2015-2016 season. There were no major differences over time in the generation of antibodies against all three viral strains tested.
However, at both 30 and 60 days after vaccination, a hemagglutination inhibition assay showed slightly elevated antibody titers among patients, compared with controls. Antibody titers against H1N1 virus also appeared to increase somewhat more rapidly among patients than among controls, the authors found.
The patients appeared to tolerate the vaccine well, and no serious adverse events were reported within 30 days of vaccination.
When they looked at the incidence of IrAEs, however, the investigators found that six patients had grade 1 or 2 IrAEs, and six had grade 3 or 4 events.
The events included skin rash and arthritis in three patients each, colitis and encephalitis in two patients each, and hypothyroidism, pneumonitis, and neuropathy in one patient each.
“We looked into inflammatory chemokines to understand if there was a high rate of systemic inflammation, and we didn’t find any differences in this regard. So far, we have no clue about why the immune-related adverse event rate in this group is higher,” Dr. Rothschild said.
Although the sample size was small, the IrAE effect they saw was large enough to warrant concern, and it should be studied in a larger population sample, he said.
Egbert Smit, MD, PhD, of the Netherlands Cancer Institute in Amsterdam, who was not involved in the study, commented that “it shows how much we still have to learn about the optimal use of checkpoint inhibitors in lung cancer patients. The study is important as it is the first to investigate the impact of influenza vaccination in such patients, and there is a hint that we actually put them at increased risk for serious toxicities, including encephalitis. However, until we have data on a larger cohort, preferably in a controlled, prospective study, in my institution, we advocate influenza vaccination irrespective of concurrent treatment with immune-checkpoint inhibitors.”
The study was supported by institutional funding. The investigators and Dr. Smit reported no relevant conflicts of interest.
AT ELCC
Key clinical point:
Major finding: Of 23 patients who were vaccinated, 12 developed IrAEs, including 6 grade 1/2 and 6 grade 3/4 events.
Data source: Prospective study of 23 patients with NSCLC and 23 healthy controls.
Disclosures: The study was supported by institutional funding. The investigators reported no relevant conflicts of interest.
Pembrolizumab advances in relapsed/refractory classic Hodgkin lymphoma
The immune checkpoint inhibitor pembrolizumab has good antitumor activity and a favorable safety profile when used to treat relapsed or refractory classic Hodgkin lymphoma, according to findings from the KEYNOTE-087 trial.
Pembrolizumab has garnered interest for this population because Hodgkin Reed-Sternberg cells have a chromosomal alteration leading to overexpression of both programmed death ligand 1 and programmed death ligand 2.
Programmed death 1 “blockade with pembrolizumab demonstrated substantial clinical activity in subsets of heavily pretreated patients with [classic Hodgkin lymphoma], with most responses observed at the first disease assessment and ongoing at the time of data cutoff,” Craig H. Moskowitz, MD, clinical director of the division of hematologic oncology at the Memorial Sloan-Kettering Cancer Center in New York, and his coinvestigators wrote. Thus, pembrolizumab offers “a new treatment paradigm for this disease.”
The findings have led to initiation of a randomized phase III trial, comparing pembrolizumab with brentuximab vedotin in this population (KEYNOTE-204), they noted.
Patients treated in KEYNOTE-087, a multicenter, single-arm phase II trial supported by Merck, fell into three cohorts, based on the timing of progression. Cohort 1 experienced progression after autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (69 patients); cohort 2 after salvage chemotherapy and brentuximab vedotin, which made them ineligible for ASCT because of chemoresistant disease (81 patients); and cohort 3 after ASCT but without posttransplantation brentuximab vedotin (60 patients).
All patients were treated with pembrolizumab (Keytruda) 200 mg every 3 weeks and underwent response assessment every 12 weeks.
After a median follow-up of 10.1 months (with receipt of a median of 13 treatment cycles), the overall response rate according to central review was 69%, and the complete response rate was 22%, trial results show. At the 6-month mark, overall survival was 99.5% and progression-free survival was 72.4%.
The overall response rate was consistently high across cohorts: 74% for cohort 1, 64% for cohort 2, and 70% for cohort 3. Moreover, 31 patients had a response lasting at least 6 months.
The leading treatment-related adverse events of any grade were hypothyroidism (12%) and fever (11%), and the leading grade 3 or 4 treatment-related adverse events were neutropenia (2%), dyspnea (1%), and diarrhea (1%). Immune-mediated adverse events – most often hypothyroidism – and infusion-related reactions were seen in 29% of patients.
Dr. Moskowitz has ties to Celgene, Genentech, BioOncology, Merck, Pharmacyclics, and Seattle Genetics. The trial was supported by Merck.
The immune checkpoint inhibitor pembrolizumab has good antitumor activity and a favorable safety profile when used to treat relapsed or refractory classic Hodgkin lymphoma, according to findings from the KEYNOTE-087 trial.
Pembrolizumab has garnered interest for this population because Hodgkin Reed-Sternberg cells have a chromosomal alteration leading to overexpression of both programmed death ligand 1 and programmed death ligand 2.
Programmed death 1 “blockade with pembrolizumab demonstrated substantial clinical activity in subsets of heavily pretreated patients with [classic Hodgkin lymphoma], with most responses observed at the first disease assessment and ongoing at the time of data cutoff,” Craig H. Moskowitz, MD, clinical director of the division of hematologic oncology at the Memorial Sloan-Kettering Cancer Center in New York, and his coinvestigators wrote. Thus, pembrolizumab offers “a new treatment paradigm for this disease.”
The findings have led to initiation of a randomized phase III trial, comparing pembrolizumab with brentuximab vedotin in this population (KEYNOTE-204), they noted.
Patients treated in KEYNOTE-087, a multicenter, single-arm phase II trial supported by Merck, fell into three cohorts, based on the timing of progression. Cohort 1 experienced progression after autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (69 patients); cohort 2 after salvage chemotherapy and brentuximab vedotin, which made them ineligible for ASCT because of chemoresistant disease (81 patients); and cohort 3 after ASCT but without posttransplantation brentuximab vedotin (60 patients).
All patients were treated with pembrolizumab (Keytruda) 200 mg every 3 weeks and underwent response assessment every 12 weeks.
After a median follow-up of 10.1 months (with receipt of a median of 13 treatment cycles), the overall response rate according to central review was 69%, and the complete response rate was 22%, trial results show. At the 6-month mark, overall survival was 99.5% and progression-free survival was 72.4%.
The overall response rate was consistently high across cohorts: 74% for cohort 1, 64% for cohort 2, and 70% for cohort 3. Moreover, 31 patients had a response lasting at least 6 months.
The leading treatment-related adverse events of any grade were hypothyroidism (12%) and fever (11%), and the leading grade 3 or 4 treatment-related adverse events were neutropenia (2%), dyspnea (1%), and diarrhea (1%). Immune-mediated adverse events – most often hypothyroidism – and infusion-related reactions were seen in 29% of patients.
Dr. Moskowitz has ties to Celgene, Genentech, BioOncology, Merck, Pharmacyclics, and Seattle Genetics. The trial was supported by Merck.
The immune checkpoint inhibitor pembrolizumab has good antitumor activity and a favorable safety profile when used to treat relapsed or refractory classic Hodgkin lymphoma, according to findings from the KEYNOTE-087 trial.
Pembrolizumab has garnered interest for this population because Hodgkin Reed-Sternberg cells have a chromosomal alteration leading to overexpression of both programmed death ligand 1 and programmed death ligand 2.
Programmed death 1 “blockade with pembrolizumab demonstrated substantial clinical activity in subsets of heavily pretreated patients with [classic Hodgkin lymphoma], with most responses observed at the first disease assessment and ongoing at the time of data cutoff,” Craig H. Moskowitz, MD, clinical director of the division of hematologic oncology at the Memorial Sloan-Kettering Cancer Center in New York, and his coinvestigators wrote. Thus, pembrolizumab offers “a new treatment paradigm for this disease.”
The findings have led to initiation of a randomized phase III trial, comparing pembrolizumab with brentuximab vedotin in this population (KEYNOTE-204), they noted.
Patients treated in KEYNOTE-087, a multicenter, single-arm phase II trial supported by Merck, fell into three cohorts, based on the timing of progression. Cohort 1 experienced progression after autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (69 patients); cohort 2 after salvage chemotherapy and brentuximab vedotin, which made them ineligible for ASCT because of chemoresistant disease (81 patients); and cohort 3 after ASCT but without posttransplantation brentuximab vedotin (60 patients).
All patients were treated with pembrolizumab (Keytruda) 200 mg every 3 weeks and underwent response assessment every 12 weeks.
After a median follow-up of 10.1 months (with receipt of a median of 13 treatment cycles), the overall response rate according to central review was 69%, and the complete response rate was 22%, trial results show. At the 6-month mark, overall survival was 99.5% and progression-free survival was 72.4%.
The overall response rate was consistently high across cohorts: 74% for cohort 1, 64% for cohort 2, and 70% for cohort 3. Moreover, 31 patients had a response lasting at least 6 months.
The leading treatment-related adverse events of any grade were hypothyroidism (12%) and fever (11%), and the leading grade 3 or 4 treatment-related adverse events were neutropenia (2%), dyspnea (1%), and diarrhea (1%). Immune-mediated adverse events – most often hypothyroidism – and infusion-related reactions were seen in 29% of patients.
Dr. Moskowitz has ties to Celgene, Genentech, BioOncology, Merck, Pharmacyclics, and Seattle Genetics. The trial was supported by Merck.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point:
Major finding: The overall response rate was 69%, and the safety profile was as expected and favorable.
Data source: KEYNOTE-087, a multicenter, single-arm phase II trial of pembrolizumab in 210 patients with relapsed or refractory classic Hodgkin lymphoma.
Disclosures: Dr. Moskowitz has ties to Celgene, Genentech BioOncology, Merck, Pharmacyclics, and Seattle Genetics. The trial was supported by Merck.
Durvalumab approved for advanced urothelial carcinoma
for patients with locally advanced or metastatic urothelial carcinoma who have disease progression after prior treatment with a platinum-containing chemotherapy.
The agency also approved a complementary diagnostic for the assessment of the PD-L1 protein the tumor tissue.
The most common adverse reactions were fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and urinary tract infection. Pneumonitis, hepatitis, colitis, thyroid disease, adrenal insufficiency, and diabetes also occurred in patients taking durvalumab.
The recommended dose of durvalumab is 10 mg/kg IV over a period of 60 minutes, every 2 weeks, until disease progression or unacceptable toxicity occurs. Full prescribing information is available here.
Durvalumab is marketed as Imfinzi by AstraZeneca. The complementary diagnostic is the Ventana PD-L1 (SP263) Assay from Ventana Medical Systems.
for patients with locally advanced or metastatic urothelial carcinoma who have disease progression after prior treatment with a platinum-containing chemotherapy.
The agency also approved a complementary diagnostic for the assessment of the PD-L1 protein the tumor tissue.
The most common adverse reactions were fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and urinary tract infection. Pneumonitis, hepatitis, colitis, thyroid disease, adrenal insufficiency, and diabetes also occurred in patients taking durvalumab.
The recommended dose of durvalumab is 10 mg/kg IV over a period of 60 minutes, every 2 weeks, until disease progression or unacceptable toxicity occurs. Full prescribing information is available here.
Durvalumab is marketed as Imfinzi by AstraZeneca. The complementary diagnostic is the Ventana PD-L1 (SP263) Assay from Ventana Medical Systems.
for patients with locally advanced or metastatic urothelial carcinoma who have disease progression after prior treatment with a platinum-containing chemotherapy.
The agency also approved a complementary diagnostic for the assessment of the PD-L1 protein the tumor tissue.
The most common adverse reactions were fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and urinary tract infection. Pneumonitis, hepatitis, colitis, thyroid disease, adrenal insufficiency, and diabetes also occurred in patients taking durvalumab.
The recommended dose of durvalumab is 10 mg/kg IV over a period of 60 minutes, every 2 weeks, until disease progression or unacceptable toxicity occurs. Full prescribing information is available here.
Durvalumab is marketed as Imfinzi by AstraZeneca. The complementary diagnostic is the Ventana PD-L1 (SP263) Assay from Ventana Medical Systems.
Nivolumab boosts 5-year survival in advanced NSCLC
Early data show that treatment with the immune checkpoint inhibitor nivolumab (Opdivo) resulted in a 5-year overall survival rate of 16% among patients with advanced non–small-cell lung cancer (NSCLC).
In comparison, the 5-year survival rate for patients with advanced lung and bronchus cancer, according to SEER data, is 4.3%, and for those with advanced NSCLC, 4.9%.
“This is the first report of the long-term survival rate in patients with metastatic NSCLC treated with an immune checkpoint inhibitor,” said Julie Brahmer, MD, of the Bloomberg Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore.
For a small subset of patients, immunotherapy can work for a very long time, explained Dr. Brahmer, who discussed her findings during a presscast at the annual meeting of the American Association for Cancer Research.
The 5-year overall survival rate that was reported in this study was much higher than what has been seen for this patient population who receive the standard of care. Statistics show that the majority of patients with advanced disease will die within a year of their diagnosis, Dr. Brahmer pointed out.
The findings presented at the meeting are updated results from the phase Ib CA209-003 dose-escalation cohort expansion trial that comprised 129 patients with heavily pretreated, advanced NSCLC . The cohort was randomized to receive nivolumab once every 2 weeks for up to 2 years at one of three dose levels: 1 mg/kg, 3 mg/kg, or 10 mg/kg.
A previous analysis of the data showed promising activity, and findings from subsequent clinical trials led to the approval of nivolumab for use in the second line setting of advanced NSCLC.
Dr. Brahmer now reported findings based on 5-year results of this phase Ib trial. “This analysis is based on a minimum follow up of 58 months,” she said.
The overall 5-year survival rates for squamous NSCLC were 16%, and the rates for nonsquamous were 15%.
At 1 year, overall survival was 42%. At 2 years, it was 24%, and at 3 years, 18%.
“After 3 years, the survival curve has plateaued out, which is similar to what has been seen in the past in other diseases treated with immunotherapy,” Dr. Brahmer noted.
Within the cohort, there were 16 patients who had survived for at least 5 years. Of this group, 12 achieved a partial response, 2 patients had stable disease, and 2 had progressive disease.
Dr. Brahmer pointed out that there was nothing different or unusual among the 16 patients who survived for 5 years, compared with the rest of the cohort. Their characteristics were similar to others in the study, most of them were former smokers, and they had very similar rates of different histologies.
One interesting note was that within that group, there were two patients with EGFR mutations. “We usually don’t expect them to do well with immunotherapy,” she said.
Dr. Brahmer received research funding from, and is an adviser to, Bristol-Myers Squibb, which funded the study.
Early data show that treatment with the immune checkpoint inhibitor nivolumab (Opdivo) resulted in a 5-year overall survival rate of 16% among patients with advanced non–small-cell lung cancer (NSCLC).
In comparison, the 5-year survival rate for patients with advanced lung and bronchus cancer, according to SEER data, is 4.3%, and for those with advanced NSCLC, 4.9%.
“This is the first report of the long-term survival rate in patients with metastatic NSCLC treated with an immune checkpoint inhibitor,” said Julie Brahmer, MD, of the Bloomberg Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore.
For a small subset of patients, immunotherapy can work for a very long time, explained Dr. Brahmer, who discussed her findings during a presscast at the annual meeting of the American Association for Cancer Research.
The 5-year overall survival rate that was reported in this study was much higher than what has been seen for this patient population who receive the standard of care. Statistics show that the majority of patients with advanced disease will die within a year of their diagnosis, Dr. Brahmer pointed out.
The findings presented at the meeting are updated results from the phase Ib CA209-003 dose-escalation cohort expansion trial that comprised 129 patients with heavily pretreated, advanced NSCLC . The cohort was randomized to receive nivolumab once every 2 weeks for up to 2 years at one of three dose levels: 1 mg/kg, 3 mg/kg, or 10 mg/kg.
A previous analysis of the data showed promising activity, and findings from subsequent clinical trials led to the approval of nivolumab for use in the second line setting of advanced NSCLC.
Dr. Brahmer now reported findings based on 5-year results of this phase Ib trial. “This analysis is based on a minimum follow up of 58 months,” she said.
The overall 5-year survival rates for squamous NSCLC were 16%, and the rates for nonsquamous were 15%.
At 1 year, overall survival was 42%. At 2 years, it was 24%, and at 3 years, 18%.
“After 3 years, the survival curve has plateaued out, which is similar to what has been seen in the past in other diseases treated with immunotherapy,” Dr. Brahmer noted.
Within the cohort, there were 16 patients who had survived for at least 5 years. Of this group, 12 achieved a partial response, 2 patients had stable disease, and 2 had progressive disease.
Dr. Brahmer pointed out that there was nothing different or unusual among the 16 patients who survived for 5 years, compared with the rest of the cohort. Their characteristics were similar to others in the study, most of them were former smokers, and they had very similar rates of different histologies.
One interesting note was that within that group, there were two patients with EGFR mutations. “We usually don’t expect them to do well with immunotherapy,” she said.
Dr. Brahmer received research funding from, and is an adviser to, Bristol-Myers Squibb, which funded the study.
Early data show that treatment with the immune checkpoint inhibitor nivolumab (Opdivo) resulted in a 5-year overall survival rate of 16% among patients with advanced non–small-cell lung cancer (NSCLC).
In comparison, the 5-year survival rate for patients with advanced lung and bronchus cancer, according to SEER data, is 4.3%, and for those with advanced NSCLC, 4.9%.
“This is the first report of the long-term survival rate in patients with metastatic NSCLC treated with an immune checkpoint inhibitor,” said Julie Brahmer, MD, of the Bloomberg Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore.
For a small subset of patients, immunotherapy can work for a very long time, explained Dr. Brahmer, who discussed her findings during a presscast at the annual meeting of the American Association for Cancer Research.
The 5-year overall survival rate that was reported in this study was much higher than what has been seen for this patient population who receive the standard of care. Statistics show that the majority of patients with advanced disease will die within a year of their diagnosis, Dr. Brahmer pointed out.
The findings presented at the meeting are updated results from the phase Ib CA209-003 dose-escalation cohort expansion trial that comprised 129 patients with heavily pretreated, advanced NSCLC . The cohort was randomized to receive nivolumab once every 2 weeks for up to 2 years at one of three dose levels: 1 mg/kg, 3 mg/kg, or 10 mg/kg.
A previous analysis of the data showed promising activity, and findings from subsequent clinical trials led to the approval of nivolumab for use in the second line setting of advanced NSCLC.
Dr. Brahmer now reported findings based on 5-year results of this phase Ib trial. “This analysis is based on a minimum follow up of 58 months,” she said.
The overall 5-year survival rates for squamous NSCLC were 16%, and the rates for nonsquamous were 15%.
At 1 year, overall survival was 42%. At 2 years, it was 24%, and at 3 years, 18%.
“After 3 years, the survival curve has plateaued out, which is similar to what has been seen in the past in other diseases treated with immunotherapy,” Dr. Brahmer noted.
Within the cohort, there were 16 patients who had survived for at least 5 years. Of this group, 12 achieved a partial response, 2 patients had stable disease, and 2 had progressive disease.
Dr. Brahmer pointed out that there was nothing different or unusual among the 16 patients who survived for 5 years, compared with the rest of the cohort. Their characteristics were similar to others in the study, most of them were former smokers, and they had very similar rates of different histologies.
One interesting note was that within that group, there were two patients with EGFR mutations. “We usually don’t expect them to do well with immunotherapy,” she said.
Dr. Brahmer received research funding from, and is an adviser to, Bristol-Myers Squibb, which funded the study.
Key clinical point: Treatment with nivolumab resulted in a 5-year overall survival rate that is much higher than what is reported for this patient population receiving standard-of-care treatment.
Major finding: Nivolumab yielded a 5-year survival rate of 16% in a cohort of patients with advanced NSCLC.
Data source: Updated results from a phase Ib study that included 129 patients with advanced NSCLC.
Disclosures: Dr. Brahmer received research funding from, and is an adviser to, Bristol-Myers Squibb, which funded the study.
Get ready for cancer immunotherapy-induced rheumatic diseases
SNOWMASS, COLO. – Physicians can expect to encounter more and more patients with inflammatory arthritis and other rheumatic adverse events induced by immune checkpoint inhibitors as a result of anticipated exponential growth in the use of these drugs to treat an expanding list of cancers, Clifton O. Bingham III, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
These cancer immunotherapy–induced rheumatic diseases may superficially look like the classic forms of familiar autoimmune diseases, but they have highly atypical features that will affect treatment decisions.
“What we’ve seen consistently is that the normal doses of prednisone we would use to treat an inflammatory arthritis are really ineffective in most of these patients. We’ve had to use super doses – up to 120 mg/day – for initial control, and then 7.5-40 mg daily for maintenance of response,” according to Dr. Bingham, professor of medicine and director of the Johns Hopkins Arthritis Center in Baltimore.
To date, only limited data from case series are available on rheumatic IRAEs. There are no prospective patient registries logging accurate data on the incidence of these rheumatic adverse events among cancer patients treated with immune checkpoint inhibitors (ICIs). These IRAEs, which lie at the intersection of rheumatology and oncology, are of special interest to Dr. Bingham – he and his coinvestigators have published five articles on the topic over the course of a single year.
In a wide-ranging talk at the symposium, he touched on the phenotypic spectrum of rheumatologic IRAEs, his conviction that they are greatly underdiagnosed, why physicians can expect to encounter them much more frequently, rheumatologic IRAE treatment issues, and the risks of prescribing ICIs in patients with known preexisting rheumatologic disease.
Rheumatologic IRAE presentations
Inflammatory arthritis is the most common form of rheumatologic IRAE, followed by sicca syndrome. At the Johns Hopkins Arthritis Center, Dr. Bingham and his coworkers have 25 well-characterized patients with inflammatory arthritis resulting from an ICI, only 1 of whom is HLA-B27-positive.
“Also, just one is autoantibody-positive, even though they all look for all the world as though they have rheumatoid arthritis,” the rheumatologist observed.
This ICI-induced inflammatory arthritis initially presents most commonly in the midsize and large joints – knees, ankles, elbows – then expands to include small joints such as the wrists, proximal interphalangeal joints, and the metacarpophalangeal joints.
Notably, the Hopkins group also has three patients with classic reactive arthritis marked by conjunctivitis, urethritis, arthritis, and dactylitis.
“I don’t know about you, but, in our general rheumatology practice, we see maybe one case of reactive arthritis in several years, so this is something that has struck us as really quite interesting,” said Dr. Bingham, who is also director of research in the division of rheumatology at Johns Hopkins.
The arthritis center is also managing a group of patients with ICI-induced sicca syndrome, which is uniformly extremely severe and treatment resistant, as well as a couple of patients with myositis IRAE, one with polymyalgia rheumatica, and two with crystal disease that is highly inflammatory in nature, difficult to treat, and includes an inflammatory polyarthritis component not typical in patients with crystal arthritis.
Why physicians will see more rheumatologic IRAEs
ICIs have dramatically transformed the treatment of selected advanced-stage cancers. For example, whereas patients with metastatic melanoma historically had a 2-year survival rate of 5%, combination therapy with the ICIs ipilimumab (Yervoy) and nivolumab (Opdivo) resulted in a 60% rate of partial or complete remission in a landmark clinical trial.
The basis of cancer immunotherapy is the discovery that, in order for cancer cells to thrive, they emit blocking signals that downregulate the native ability of T cells to recognize and kill them. This is true for both solid tumors and hematologic malignancies. The ICIs inhibit these blocking signals, which include cytotoxic T-lymphocyte–associated protein 4 (CTLA4), programmed death-1 (PD-1), and programmed death ligand-1 (PDL-1), thereby freeing up the T cells for tumor fighting.
Because of the nonspecific mechanism of this T-cell activation, however, ICIs have, as their main toxicities, T-cell–mediated autoimmune inflammatory tissue damage, which gets lumped under the umbrella term IRAEs. It can affect almost every organ system. Skin rashes are the most common, colitis second. Other commonly encountered IRAEs include thyroiditis, hypophysitis, hepatitis, peripheral neuropathy, and pneumonitis.
In addition to the four currently approved ICIs – ipilimumab, nivolumab, pembrolizumab (Keytruda), and atezolizumab (Tecentriq) – investigational ICIs targeting CTLA4, PD-1, and/or PDL-1 are in development. Plus, new ICIs targeting other blocking signals, including lymphocyte activation gene-3, CD137, and T-cell immunoglobulin and mucin domain-3, are now in clinical trials.
Clinical trials aimed at expanding the indications of existing ICIs and using ICIs in earlier-stage cancers in an effort to improve rates of lasting remission are also underway.
All told, probably at least 400 clinical trials of ICIs are ongoing worldwide, the rheumatologist estimated.
“More people will be exposed to these drugs, and we’ll see more and more of these rheumatologic IRAEs,” Dr. Bingham predicted.
Rheumatologic IRAEs are seriously underdiagnosed
Back in the pre-ICI days, Dr. Bingham was coauthor of a major study which concluded that clinical trialists in oncology consistently downgrade the severity of rheumatologic adverse events, often by 1 or 2 grades (J Rheumatol. 2007 Jun;34[6]:1401-14).
Unpublished details of ICI clinical trials in melanoma that he obtained from Bristol-Myers Squibb suggest that the true rate of rheumatologic IRAEs is about 20%, or roughly double that reported in the studies. That’s because the adverse events–grading system used in oncology undercalls the severity of arthritis and autoimmune disorders.
Indeed, the National Cancer Institute’s Common Terminology Criteria for Adverse Events, used in oncology clinical trials, is confusing on the topic of musculoskeletal and connective tissue disorders as treatment-emergent adverse events, according to Dr. Bingham. He noted that an oncologist can code a swollen joint in three different ways – joint effusion, arthritis, or arthralgia – and it takes disabling interference with self-care in activities of daily living for that swollen joint to rise to the level of a Grade 3 adverse event. From a rheumatology trialist’s perspective, that would be a Grade 4 disability.
Plus, neither the product labeling nor the patient information guides for the approved immunotherapy drugs mention the importance of monitoring for rheumatologic IRAEs or their management.
“There is poor awareness of musculoskeletal and rheumatic IRAEs in the general oncology community,” Dr. Bingham asserted. “But, if you talk with any oncology nurses who work in a clinical trial, they will tell you they’re seeing these events with significant frequency and severity.”
Treatment and response
It’s critical to gain control of rheumatologic IRAEs quickly so that patients can get on with their cancer immunotherapy. Dr. Bingham uses intra-articular steroid injections for patients with oligoarthritis and high-dose oral prednisone for polyarticular disease. He starts methotrexate and/or leflunomide early because the conventional disease-modifying antirheumatic drugs have roughly a 2-month delay in onset of action. He has had several patients who are unable to taper steroids despite background methotrexate.
In the most severely affected patients, he has turned to biologic agents in consultation with their oncologists. Tumor necrosis factor (TNF) inhibitors are the ones he and other rheumatologists have used most often.
“Notably, we have not been able to taper down very well. We have patients who are out more than 2 years now who still require their TNF inhibitor to treat their inflammatory arthritis, and these are patients on conventional disease–modifying antirheumatic drugs as well. As soon as it’s tapered, the arthritis begins to come back,” according to Dr. Bingham.
In marked contrast, colitis as an IRAE typically clears in response to just one or two doses of a TNF inhibitor.
One audience member related that she’d encountered a roadblock in trying to get authorization for a TNF inhibitor for a patient with a rheumatologic IRAE secondary to ICI treatment for metastatic melanoma because the labeling states these agents are relatively contraindicated in melanoma patients. Dr. Bingham offered a tip: Collaborate with the patient’s oncologist.
“In most cases, oncologists can get infliximab for these patients and administer it in their infusion centers. They are able to get things authorized with very little trouble,” he said.
Besides, most of these patients with severe inflammatory arthritis meet conventional criteria for TNF inhibitor therapy, based on their number of infected joints and elevated acute phase reactants for longer than 6 weeks, Dr. Bingham noted.
“We’ve had some very interesting conversations with patients. It’s impressive to see the impact arthritis can have on people. A lot of patients have said, ‘I don’t care if I die. Get me functional right now.’ That’s pretty profound. Quality of life is still very important for people, even when dealing with life-threatening diseases,” he observed.
Oncologists are actually eager for their patients to get on steroid-sparing therapy because of concern that high doses of steroids may reduce the efficacy of cancer immunotherapy. That’s not an issue with the TNF inhibitors, the rheumatologist continued.
Turning to the utility of other classes of biologic agents, Dr. Bingham advised avoiding abatacept (Orencia) because its mechanism of action is likely to cause interference with the cancer immunotherapy. Rituximab (Rituxan) takes too long to act. Anakinra (Kineret), tofacitinib (Xeljanz), and tocilizumab (Actemra), on the other hand, are agents he is interested in using as alternatives to TNF inhibitors, although he hasn’t done so yet.
Use of ICIs in patients with preexisting autoimmune disease
The experience here is entirely anecdotal, since such patients have been excluded from ICI clinical trials, but the available evidence suggests physicians should be prepared for higher rheumatologic IRAE rates in this setting. Investigators at Vanderbilt University reported that 8 of 30 cancer patients with known preexisting autoimmune disease experienced flares of that disease when treated with ipilimumab, and 10 developed a new IRAE (Therap Adv Gastroenterol. 2016 Jul;9[4]:457-62).
The Hopkins group has three patients with preexisting rheumatoid arthritis and two with preexisting scleroderma who have received ICIs. All three rheumatoid arthritis patients flared. Rheumatologists are trying to manage these flares so the patients can continue on their ICI. One of the scleroderma patients experienced no change in that disease while on an ICI, while the other showed a definite improvement in scleroderma symptoms.
“I think the jury’s still out in terms of what you do about ICI therapy in patients with preexisting autoimmunity. The data would say that there’s maybe a 50-50 chance of the autoimmune disease becoming worse, but, if patients have an otherwise fatal cancer, I think it’s probably worth the chance,” Dr. Bingham said.
Anecdotal reports suggest that more severe IRAEs may be a favorable prognostic sign in terms of cancer eradication, but a lot more patient experience will be needed in order to be sure, the rheumatologist said.
Dr. Bingham reported serving as a consultant to Bristol-Myers Squibb.
SNOWMASS, COLO. – Physicians can expect to encounter more and more patients with inflammatory arthritis and other rheumatic adverse events induced by immune checkpoint inhibitors as a result of anticipated exponential growth in the use of these drugs to treat an expanding list of cancers, Clifton O. Bingham III, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
These cancer immunotherapy–induced rheumatic diseases may superficially look like the classic forms of familiar autoimmune diseases, but they have highly atypical features that will affect treatment decisions.
“What we’ve seen consistently is that the normal doses of prednisone we would use to treat an inflammatory arthritis are really ineffective in most of these patients. We’ve had to use super doses – up to 120 mg/day – for initial control, and then 7.5-40 mg daily for maintenance of response,” according to Dr. Bingham, professor of medicine and director of the Johns Hopkins Arthritis Center in Baltimore.
To date, only limited data from case series are available on rheumatic IRAEs. There are no prospective patient registries logging accurate data on the incidence of these rheumatic adverse events among cancer patients treated with immune checkpoint inhibitors (ICIs). These IRAEs, which lie at the intersection of rheumatology and oncology, are of special interest to Dr. Bingham – he and his coinvestigators have published five articles on the topic over the course of a single year.
In a wide-ranging talk at the symposium, he touched on the phenotypic spectrum of rheumatologic IRAEs, his conviction that they are greatly underdiagnosed, why physicians can expect to encounter them much more frequently, rheumatologic IRAE treatment issues, and the risks of prescribing ICIs in patients with known preexisting rheumatologic disease.
Rheumatologic IRAE presentations
Inflammatory arthritis is the most common form of rheumatologic IRAE, followed by sicca syndrome. At the Johns Hopkins Arthritis Center, Dr. Bingham and his coworkers have 25 well-characterized patients with inflammatory arthritis resulting from an ICI, only 1 of whom is HLA-B27-positive.
“Also, just one is autoantibody-positive, even though they all look for all the world as though they have rheumatoid arthritis,” the rheumatologist observed.
This ICI-induced inflammatory arthritis initially presents most commonly in the midsize and large joints – knees, ankles, elbows – then expands to include small joints such as the wrists, proximal interphalangeal joints, and the metacarpophalangeal joints.
Notably, the Hopkins group also has three patients with classic reactive arthritis marked by conjunctivitis, urethritis, arthritis, and dactylitis.
“I don’t know about you, but, in our general rheumatology practice, we see maybe one case of reactive arthritis in several years, so this is something that has struck us as really quite interesting,” said Dr. Bingham, who is also director of research in the division of rheumatology at Johns Hopkins.
The arthritis center is also managing a group of patients with ICI-induced sicca syndrome, which is uniformly extremely severe and treatment resistant, as well as a couple of patients with myositis IRAE, one with polymyalgia rheumatica, and two with crystal disease that is highly inflammatory in nature, difficult to treat, and includes an inflammatory polyarthritis component not typical in patients with crystal arthritis.
Why physicians will see more rheumatologic IRAEs
ICIs have dramatically transformed the treatment of selected advanced-stage cancers. For example, whereas patients with metastatic melanoma historically had a 2-year survival rate of 5%, combination therapy with the ICIs ipilimumab (Yervoy) and nivolumab (Opdivo) resulted in a 60% rate of partial or complete remission in a landmark clinical trial.
The basis of cancer immunotherapy is the discovery that, in order for cancer cells to thrive, they emit blocking signals that downregulate the native ability of T cells to recognize and kill them. This is true for both solid tumors and hematologic malignancies. The ICIs inhibit these blocking signals, which include cytotoxic T-lymphocyte–associated protein 4 (CTLA4), programmed death-1 (PD-1), and programmed death ligand-1 (PDL-1), thereby freeing up the T cells for tumor fighting.
Because of the nonspecific mechanism of this T-cell activation, however, ICIs have, as their main toxicities, T-cell–mediated autoimmune inflammatory tissue damage, which gets lumped under the umbrella term IRAEs. It can affect almost every organ system. Skin rashes are the most common, colitis second. Other commonly encountered IRAEs include thyroiditis, hypophysitis, hepatitis, peripheral neuropathy, and pneumonitis.
In addition to the four currently approved ICIs – ipilimumab, nivolumab, pembrolizumab (Keytruda), and atezolizumab (Tecentriq) – investigational ICIs targeting CTLA4, PD-1, and/or PDL-1 are in development. Plus, new ICIs targeting other blocking signals, including lymphocyte activation gene-3, CD137, and T-cell immunoglobulin and mucin domain-3, are now in clinical trials.
Clinical trials aimed at expanding the indications of existing ICIs and using ICIs in earlier-stage cancers in an effort to improve rates of lasting remission are also underway.
All told, probably at least 400 clinical trials of ICIs are ongoing worldwide, the rheumatologist estimated.
“More people will be exposed to these drugs, and we’ll see more and more of these rheumatologic IRAEs,” Dr. Bingham predicted.
Rheumatologic IRAEs are seriously underdiagnosed
Back in the pre-ICI days, Dr. Bingham was coauthor of a major study which concluded that clinical trialists in oncology consistently downgrade the severity of rheumatologic adverse events, often by 1 or 2 grades (J Rheumatol. 2007 Jun;34[6]:1401-14).
Unpublished details of ICI clinical trials in melanoma that he obtained from Bristol-Myers Squibb suggest that the true rate of rheumatologic IRAEs is about 20%, or roughly double that reported in the studies. That’s because the adverse events–grading system used in oncology undercalls the severity of arthritis and autoimmune disorders.
Indeed, the National Cancer Institute’s Common Terminology Criteria for Adverse Events, used in oncology clinical trials, is confusing on the topic of musculoskeletal and connective tissue disorders as treatment-emergent adverse events, according to Dr. Bingham. He noted that an oncologist can code a swollen joint in three different ways – joint effusion, arthritis, or arthralgia – and it takes disabling interference with self-care in activities of daily living for that swollen joint to rise to the level of a Grade 3 adverse event. From a rheumatology trialist’s perspective, that would be a Grade 4 disability.
Plus, neither the product labeling nor the patient information guides for the approved immunotherapy drugs mention the importance of monitoring for rheumatologic IRAEs or their management.
“There is poor awareness of musculoskeletal and rheumatic IRAEs in the general oncology community,” Dr. Bingham asserted. “But, if you talk with any oncology nurses who work in a clinical trial, they will tell you they’re seeing these events with significant frequency and severity.”
Treatment and response
It’s critical to gain control of rheumatologic IRAEs quickly so that patients can get on with their cancer immunotherapy. Dr. Bingham uses intra-articular steroid injections for patients with oligoarthritis and high-dose oral prednisone for polyarticular disease. He starts methotrexate and/or leflunomide early because the conventional disease-modifying antirheumatic drugs have roughly a 2-month delay in onset of action. He has had several patients who are unable to taper steroids despite background methotrexate.
In the most severely affected patients, he has turned to biologic agents in consultation with their oncologists. Tumor necrosis factor (TNF) inhibitors are the ones he and other rheumatologists have used most often.
“Notably, we have not been able to taper down very well. We have patients who are out more than 2 years now who still require their TNF inhibitor to treat their inflammatory arthritis, and these are patients on conventional disease–modifying antirheumatic drugs as well. As soon as it’s tapered, the arthritis begins to come back,” according to Dr. Bingham.
In marked contrast, colitis as an IRAE typically clears in response to just one or two doses of a TNF inhibitor.
One audience member related that she’d encountered a roadblock in trying to get authorization for a TNF inhibitor for a patient with a rheumatologic IRAE secondary to ICI treatment for metastatic melanoma because the labeling states these agents are relatively contraindicated in melanoma patients. Dr. Bingham offered a tip: Collaborate with the patient’s oncologist.
“In most cases, oncologists can get infliximab for these patients and administer it in their infusion centers. They are able to get things authorized with very little trouble,” he said.
Besides, most of these patients with severe inflammatory arthritis meet conventional criteria for TNF inhibitor therapy, based on their number of infected joints and elevated acute phase reactants for longer than 6 weeks, Dr. Bingham noted.
“We’ve had some very interesting conversations with patients. It’s impressive to see the impact arthritis can have on people. A lot of patients have said, ‘I don’t care if I die. Get me functional right now.’ That’s pretty profound. Quality of life is still very important for people, even when dealing with life-threatening diseases,” he observed.
Oncologists are actually eager for their patients to get on steroid-sparing therapy because of concern that high doses of steroids may reduce the efficacy of cancer immunotherapy. That’s not an issue with the TNF inhibitors, the rheumatologist continued.
Turning to the utility of other classes of biologic agents, Dr. Bingham advised avoiding abatacept (Orencia) because its mechanism of action is likely to cause interference with the cancer immunotherapy. Rituximab (Rituxan) takes too long to act. Anakinra (Kineret), tofacitinib (Xeljanz), and tocilizumab (Actemra), on the other hand, are agents he is interested in using as alternatives to TNF inhibitors, although he hasn’t done so yet.
Use of ICIs in patients with preexisting autoimmune disease
The experience here is entirely anecdotal, since such patients have been excluded from ICI clinical trials, but the available evidence suggests physicians should be prepared for higher rheumatologic IRAE rates in this setting. Investigators at Vanderbilt University reported that 8 of 30 cancer patients with known preexisting autoimmune disease experienced flares of that disease when treated with ipilimumab, and 10 developed a new IRAE (Therap Adv Gastroenterol. 2016 Jul;9[4]:457-62).
The Hopkins group has three patients with preexisting rheumatoid arthritis and two with preexisting scleroderma who have received ICIs. All three rheumatoid arthritis patients flared. Rheumatologists are trying to manage these flares so the patients can continue on their ICI. One of the scleroderma patients experienced no change in that disease while on an ICI, while the other showed a definite improvement in scleroderma symptoms.
“I think the jury’s still out in terms of what you do about ICI therapy in patients with preexisting autoimmunity. The data would say that there’s maybe a 50-50 chance of the autoimmune disease becoming worse, but, if patients have an otherwise fatal cancer, I think it’s probably worth the chance,” Dr. Bingham said.
Anecdotal reports suggest that more severe IRAEs may be a favorable prognostic sign in terms of cancer eradication, but a lot more patient experience will be needed in order to be sure, the rheumatologist said.
Dr. Bingham reported serving as a consultant to Bristol-Myers Squibb.
SNOWMASS, COLO. – Physicians can expect to encounter more and more patients with inflammatory arthritis and other rheumatic adverse events induced by immune checkpoint inhibitors as a result of anticipated exponential growth in the use of these drugs to treat an expanding list of cancers, Clifton O. Bingham III, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
These cancer immunotherapy–induced rheumatic diseases may superficially look like the classic forms of familiar autoimmune diseases, but they have highly atypical features that will affect treatment decisions.
“What we’ve seen consistently is that the normal doses of prednisone we would use to treat an inflammatory arthritis are really ineffective in most of these patients. We’ve had to use super doses – up to 120 mg/day – for initial control, and then 7.5-40 mg daily for maintenance of response,” according to Dr. Bingham, professor of medicine and director of the Johns Hopkins Arthritis Center in Baltimore.
To date, only limited data from case series are available on rheumatic IRAEs. There are no prospective patient registries logging accurate data on the incidence of these rheumatic adverse events among cancer patients treated with immune checkpoint inhibitors (ICIs). These IRAEs, which lie at the intersection of rheumatology and oncology, are of special interest to Dr. Bingham – he and his coinvestigators have published five articles on the topic over the course of a single year.
In a wide-ranging talk at the symposium, he touched on the phenotypic spectrum of rheumatologic IRAEs, his conviction that they are greatly underdiagnosed, why physicians can expect to encounter them much more frequently, rheumatologic IRAE treatment issues, and the risks of prescribing ICIs in patients with known preexisting rheumatologic disease.
Rheumatologic IRAE presentations
Inflammatory arthritis is the most common form of rheumatologic IRAE, followed by sicca syndrome. At the Johns Hopkins Arthritis Center, Dr. Bingham and his coworkers have 25 well-characterized patients with inflammatory arthritis resulting from an ICI, only 1 of whom is HLA-B27-positive.
“Also, just one is autoantibody-positive, even though they all look for all the world as though they have rheumatoid arthritis,” the rheumatologist observed.
This ICI-induced inflammatory arthritis initially presents most commonly in the midsize and large joints – knees, ankles, elbows – then expands to include small joints such as the wrists, proximal interphalangeal joints, and the metacarpophalangeal joints.
Notably, the Hopkins group also has three patients with classic reactive arthritis marked by conjunctivitis, urethritis, arthritis, and dactylitis.
“I don’t know about you, but, in our general rheumatology practice, we see maybe one case of reactive arthritis in several years, so this is something that has struck us as really quite interesting,” said Dr. Bingham, who is also director of research in the division of rheumatology at Johns Hopkins.
The arthritis center is also managing a group of patients with ICI-induced sicca syndrome, which is uniformly extremely severe and treatment resistant, as well as a couple of patients with myositis IRAE, one with polymyalgia rheumatica, and two with crystal disease that is highly inflammatory in nature, difficult to treat, and includes an inflammatory polyarthritis component not typical in patients with crystal arthritis.
Why physicians will see more rheumatologic IRAEs
ICIs have dramatically transformed the treatment of selected advanced-stage cancers. For example, whereas patients with metastatic melanoma historically had a 2-year survival rate of 5%, combination therapy with the ICIs ipilimumab (Yervoy) and nivolumab (Opdivo) resulted in a 60% rate of partial or complete remission in a landmark clinical trial.
The basis of cancer immunotherapy is the discovery that, in order for cancer cells to thrive, they emit blocking signals that downregulate the native ability of T cells to recognize and kill them. This is true for both solid tumors and hematologic malignancies. The ICIs inhibit these blocking signals, which include cytotoxic T-lymphocyte–associated protein 4 (CTLA4), programmed death-1 (PD-1), and programmed death ligand-1 (PDL-1), thereby freeing up the T cells for tumor fighting.
Because of the nonspecific mechanism of this T-cell activation, however, ICIs have, as their main toxicities, T-cell–mediated autoimmune inflammatory tissue damage, which gets lumped under the umbrella term IRAEs. It can affect almost every organ system. Skin rashes are the most common, colitis second. Other commonly encountered IRAEs include thyroiditis, hypophysitis, hepatitis, peripheral neuropathy, and pneumonitis.
In addition to the four currently approved ICIs – ipilimumab, nivolumab, pembrolizumab (Keytruda), and atezolizumab (Tecentriq) – investigational ICIs targeting CTLA4, PD-1, and/or PDL-1 are in development. Plus, new ICIs targeting other blocking signals, including lymphocyte activation gene-3, CD137, and T-cell immunoglobulin and mucin domain-3, are now in clinical trials.
Clinical trials aimed at expanding the indications of existing ICIs and using ICIs in earlier-stage cancers in an effort to improve rates of lasting remission are also underway.
All told, probably at least 400 clinical trials of ICIs are ongoing worldwide, the rheumatologist estimated.
“More people will be exposed to these drugs, and we’ll see more and more of these rheumatologic IRAEs,” Dr. Bingham predicted.
Rheumatologic IRAEs are seriously underdiagnosed
Back in the pre-ICI days, Dr. Bingham was coauthor of a major study which concluded that clinical trialists in oncology consistently downgrade the severity of rheumatologic adverse events, often by 1 or 2 grades (J Rheumatol. 2007 Jun;34[6]:1401-14).
Unpublished details of ICI clinical trials in melanoma that he obtained from Bristol-Myers Squibb suggest that the true rate of rheumatologic IRAEs is about 20%, or roughly double that reported in the studies. That’s because the adverse events–grading system used in oncology undercalls the severity of arthritis and autoimmune disorders.
Indeed, the National Cancer Institute’s Common Terminology Criteria for Adverse Events, used in oncology clinical trials, is confusing on the topic of musculoskeletal and connective tissue disorders as treatment-emergent adverse events, according to Dr. Bingham. He noted that an oncologist can code a swollen joint in three different ways – joint effusion, arthritis, or arthralgia – and it takes disabling interference with self-care in activities of daily living for that swollen joint to rise to the level of a Grade 3 adverse event. From a rheumatology trialist’s perspective, that would be a Grade 4 disability.
Plus, neither the product labeling nor the patient information guides for the approved immunotherapy drugs mention the importance of monitoring for rheumatologic IRAEs or their management.
“There is poor awareness of musculoskeletal and rheumatic IRAEs in the general oncology community,” Dr. Bingham asserted. “But, if you talk with any oncology nurses who work in a clinical trial, they will tell you they’re seeing these events with significant frequency and severity.”
Treatment and response
It’s critical to gain control of rheumatologic IRAEs quickly so that patients can get on with their cancer immunotherapy. Dr. Bingham uses intra-articular steroid injections for patients with oligoarthritis and high-dose oral prednisone for polyarticular disease. He starts methotrexate and/or leflunomide early because the conventional disease-modifying antirheumatic drugs have roughly a 2-month delay in onset of action. He has had several patients who are unable to taper steroids despite background methotrexate.
In the most severely affected patients, he has turned to biologic agents in consultation with their oncologists. Tumor necrosis factor (TNF) inhibitors are the ones he and other rheumatologists have used most often.
“Notably, we have not been able to taper down very well. We have patients who are out more than 2 years now who still require their TNF inhibitor to treat their inflammatory arthritis, and these are patients on conventional disease–modifying antirheumatic drugs as well. As soon as it’s tapered, the arthritis begins to come back,” according to Dr. Bingham.
In marked contrast, colitis as an IRAE typically clears in response to just one or two doses of a TNF inhibitor.
One audience member related that she’d encountered a roadblock in trying to get authorization for a TNF inhibitor for a patient with a rheumatologic IRAE secondary to ICI treatment for metastatic melanoma because the labeling states these agents are relatively contraindicated in melanoma patients. Dr. Bingham offered a tip: Collaborate with the patient’s oncologist.
“In most cases, oncologists can get infliximab for these patients and administer it in their infusion centers. They are able to get things authorized with very little trouble,” he said.
Besides, most of these patients with severe inflammatory arthritis meet conventional criteria for TNF inhibitor therapy, based on their number of infected joints and elevated acute phase reactants for longer than 6 weeks, Dr. Bingham noted.
“We’ve had some very interesting conversations with patients. It’s impressive to see the impact arthritis can have on people. A lot of patients have said, ‘I don’t care if I die. Get me functional right now.’ That’s pretty profound. Quality of life is still very important for people, even when dealing with life-threatening diseases,” he observed.
Oncologists are actually eager for their patients to get on steroid-sparing therapy because of concern that high doses of steroids may reduce the efficacy of cancer immunotherapy. That’s not an issue with the TNF inhibitors, the rheumatologist continued.
Turning to the utility of other classes of biologic agents, Dr. Bingham advised avoiding abatacept (Orencia) because its mechanism of action is likely to cause interference with the cancer immunotherapy. Rituximab (Rituxan) takes too long to act. Anakinra (Kineret), tofacitinib (Xeljanz), and tocilizumab (Actemra), on the other hand, are agents he is interested in using as alternatives to TNF inhibitors, although he hasn’t done so yet.
Use of ICIs in patients with preexisting autoimmune disease
The experience here is entirely anecdotal, since such patients have been excluded from ICI clinical trials, but the available evidence suggests physicians should be prepared for higher rheumatologic IRAE rates in this setting. Investigators at Vanderbilt University reported that 8 of 30 cancer patients with known preexisting autoimmune disease experienced flares of that disease when treated with ipilimumab, and 10 developed a new IRAE (Therap Adv Gastroenterol. 2016 Jul;9[4]:457-62).
The Hopkins group has three patients with preexisting rheumatoid arthritis and two with preexisting scleroderma who have received ICIs. All three rheumatoid arthritis patients flared. Rheumatologists are trying to manage these flares so the patients can continue on their ICI. One of the scleroderma patients experienced no change in that disease while on an ICI, while the other showed a definite improvement in scleroderma symptoms.
“I think the jury’s still out in terms of what you do about ICI therapy in patients with preexisting autoimmunity. The data would say that there’s maybe a 50-50 chance of the autoimmune disease becoming worse, but, if patients have an otherwise fatal cancer, I think it’s probably worth the chance,” Dr. Bingham said.
Anecdotal reports suggest that more severe IRAEs may be a favorable prognostic sign in terms of cancer eradication, but a lot more patient experience will be needed in order to be sure, the rheumatologist said.
Dr. Bingham reported serving as a consultant to Bristol-Myers Squibb.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
VIDEO: It’s too early to give up on immunotherapy for breast cancer
MIAMI BEACH – The remarkable progress seen with immune checkpoint inhibitors in metastatic melanoma, non–small-cell lung cancer, and other tumors has yet to be replicated in breast cancer, but it’s early days yet, and breast cancer researchers need more time before the ultimate clinical benefits of immunotherapy in breast cancer can be ascertained, said Adam M. Brufsky, MD, PhD, of the University of Pittsburgh.
Early studies with inhibitors of programmed death-1 (PD-1) and its ligand PD-L1 in patients with advanced triple-negative breast cancer have yielded only minimal response rates to date, but it it’s far too early to give up on the concept, Dr. Brufsky cautioned at the annual Miami Breast Cancer Conference, held by Physicians’ Education Resource.
In a video interview, he discussed the challenges of treating breast cancers, which may be less immunogenic and have a lower tumor mutational burden than other malignancies that respond more readily to PD-1 inhibition. Several large, phase III clinical trials of checkpoint inhibitors combined with cytotoxic chemotherapy are underway, he said, and those eventual findings may shed light on the optimal approach to using immunotherapy to treat patients with refractory metastatic breast cancers.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Brufsky disclosed consulting with Novartis, Eisai, Celgene, Lilly, Pfizer, Agendia, Genomic Health, NanoString Technologies and Biotheranostics.
MIAMI BEACH – The remarkable progress seen with immune checkpoint inhibitors in metastatic melanoma, non–small-cell lung cancer, and other tumors has yet to be replicated in breast cancer, but it’s early days yet, and breast cancer researchers need more time before the ultimate clinical benefits of immunotherapy in breast cancer can be ascertained, said Adam M. Brufsky, MD, PhD, of the University of Pittsburgh.
Early studies with inhibitors of programmed death-1 (PD-1) and its ligand PD-L1 in patients with advanced triple-negative breast cancer have yielded only minimal response rates to date, but it it’s far too early to give up on the concept, Dr. Brufsky cautioned at the annual Miami Breast Cancer Conference, held by Physicians’ Education Resource.
In a video interview, he discussed the challenges of treating breast cancers, which may be less immunogenic and have a lower tumor mutational burden than other malignancies that respond more readily to PD-1 inhibition. Several large, phase III clinical trials of checkpoint inhibitors combined with cytotoxic chemotherapy are underway, he said, and those eventual findings may shed light on the optimal approach to using immunotherapy to treat patients with refractory metastatic breast cancers.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Brufsky disclosed consulting with Novartis, Eisai, Celgene, Lilly, Pfizer, Agendia, Genomic Health, NanoString Technologies and Biotheranostics.
MIAMI BEACH – The remarkable progress seen with immune checkpoint inhibitors in metastatic melanoma, non–small-cell lung cancer, and other tumors has yet to be replicated in breast cancer, but it’s early days yet, and breast cancer researchers need more time before the ultimate clinical benefits of immunotherapy in breast cancer can be ascertained, said Adam M. Brufsky, MD, PhD, of the University of Pittsburgh.
Early studies with inhibitors of programmed death-1 (PD-1) and its ligand PD-L1 in patients with advanced triple-negative breast cancer have yielded only minimal response rates to date, but it it’s far too early to give up on the concept, Dr. Brufsky cautioned at the annual Miami Breast Cancer Conference, held by Physicians’ Education Resource.
In a video interview, he discussed the challenges of treating breast cancers, which may be less immunogenic and have a lower tumor mutational burden than other malignancies that respond more readily to PD-1 inhibition. Several large, phase III clinical trials of checkpoint inhibitors combined with cytotoxic chemotherapy are underway, he said, and those eventual findings may shed light on the optimal approach to using immunotherapy to treat patients with refractory metastatic breast cancers.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Brufsky disclosed consulting with Novartis, Eisai, Celgene, Lilly, Pfizer, Agendia, Genomic Health, NanoString Technologies and Biotheranostics.
AT MBCC
