Immuno-oncology

Adverse events limited the dose intensity or schedule of chemotherapy when added to nivolumab in patients with treatment-naive advanced gastric cancer, according to results from a small, phase 2 trial.

Fully 95% of patients delayed or reduced the dose of chemotherapy because of adverse events. Serious (grade 3 or higher) treatment-related adverse events affected 15% of patients and 13% of patients stopped treatment because of adverse events, said Narikazu Boku, MD, PhD, of National Cancer Center Hospital in Tokyo, together with his associates. The findings were published in Annals of Oncology.

Nivolumab (Opdivo) is not approved for treating gastric cancer in the United States but is approved as third-line or later therapy in several other countries. In the phase 2 ATTRACTION-4 trial, 39 patients with previously untreated, unresectable, advanced, or recurrent gastric or gastroesophageal junction cancer received nivolumab (360 mg intravenously every 3 weeks), plus either S-1 (40 mg/m² orally twice daily for 14 days followed by 7 days off) or capecitabine (1000 mg/m² orally twice daily for 14 days followed by 7 days off), plus oxaliplatin (130 mg/m² intravenously on day 1 every 3 weeks).

For the regimen containing S-1, the most common serious adverse events requiring delays or reductions in chemotherapy were thrombocytopenia (57%), neutropenia (48%), and nausea (19%), followed by diarrhea, vomiting, abdominal pain, peripheral sensory neuropathy, and fatigue (14% each). For the regimen containing capecitabine, the most common of these adverse events were neutropenia (44%), decreased appetite (28%), and palmar-plantar erythrodysesthesia syndrome (22%), followed by nausea, vomiting, diarrhea, and peripheral sensory neuropathy (17% each). There were no treatment-related deaths.

Efficacy endpoints were secondary and limited by small sample size. Nonetheless, regardless of which of the two chemotherapy regimens patients received, about two-thirds had a complete or partial treatment response, which is “numerically higher” than that reported for either chemotherapy regimen alone, the researchers wrote. After a median follow-up of 13.2 months, median overall survival was not reached, while median progression-free survival was 9.7 months for the S-1-based regimen and 10.6 months for the capecitabine-based regimen. Antitumor response appeared to be unrelated to programmed death–ligand 1 status.

Based on the findings, both nivolumab-chemotherapy regimens have “manageable safety profile and clinically relevant antitumor profile,” Dr. Boku and his coinvestigators stated. The second part of ATTRACTION-4 has recruited a larger group of patients and should shed more light on efficacy.

Ono Pharmaceutical and Bristol-Myers Squibb funded the work. Dr. Boku reported financial ties to both companies and to AstraZeneca and Chugai Pharmaceutical.

SOURCE: Boku N et al. Ann Oncol. 2018 Dec 19. doi: 10.1093/annonc/mdy540.

Adverse events limited the dose intensity or schedule of chemotherapy when added to nivolumab in patients with treatment-naive advanced gastric cancer, according to results from a small, phase 2 trial.

Fully 95% of patients delayed or reduced the dose of chemotherapy because of adverse events. Serious (grade 3 or higher) treatment-related adverse events affected 15% of patients and 13% of patients stopped treatment because of adverse events, said Narikazu Boku, MD, PhD, of National Cancer Center Hospital in Tokyo, together with his associates. The findings were published in Annals of Oncology.

Nivolumab (Opdivo) is not approved for treating gastric cancer in the United States but is approved as third-line or later therapy in several other countries. In the phase 2 ATTRACTION-4 trial, 39 patients with previously untreated, unresectable, advanced, or recurrent gastric or gastroesophageal junction cancer received nivolumab (360 mg intravenously every 3 weeks), plus either S-1 (40 mg/m² orally twice daily for 14 days followed by 7 days off) or capecitabine (1000 mg/m² orally twice daily for 14 days followed by 7 days off), plus oxaliplatin (130 mg/m² intravenously on day 1 every 3 weeks).

For the regimen containing S-1, the most common serious adverse events requiring delays or reductions in chemotherapy were thrombocytopenia (57%), neutropenia (48%), and nausea (19%), followed by diarrhea, vomiting, abdominal pain, peripheral sensory neuropathy, and fatigue (14% each). For the regimen containing capecitabine, the most common of these adverse events were neutropenia (44%), decreased appetite (28%), and palmar-plantar erythrodysesthesia syndrome (22%), followed by nausea, vomiting, diarrhea, and peripheral sensory neuropathy (17% each). There were no treatment-related deaths.

Efficacy endpoints were secondary and limited by small sample size. Nonetheless, regardless of which of the two chemotherapy regimens patients received, about two-thirds had a complete or partial treatment response, which is “numerically higher” than that reported for either chemotherapy regimen alone, the researchers wrote. After a median follow-up of 13.2 months, median overall survival was not reached, while median progression-free survival was 9.7 months for the S-1-based regimen and 10.6 months for the capecitabine-based regimen. Antitumor response appeared to be unrelated to programmed death–ligand 1 status.

Based on the findings, both nivolumab-chemotherapy regimens have “manageable safety profile and clinically relevant antitumor profile,” Dr. Boku and his coinvestigators stated. The second part of ATTRACTION-4 has recruited a larger group of patients and should shed more light on efficacy.

Ono Pharmaceutical and Bristol-Myers Squibb funded the work. Dr. Boku reported financial ties to both companies and to AstraZeneca and Chugai Pharmaceutical.

SOURCE: Boku N et al. Ann Oncol. 2018 Dec 19. doi: 10.1093/annonc/mdy540.

Adverse events limited the dose intensity or schedule of chemotherapy when added to nivolumab in patients with treatment-naive advanced gastric cancer, according to results from a small, phase 2 trial.

Fully 95% of patients delayed or reduced the dose of chemotherapy because of adverse events. Serious (grade 3 or higher) treatment-related adverse events affected 15% of patients and 13% of patients stopped treatment because of adverse events, said Narikazu Boku, MD, PhD, of National Cancer Center Hospital in Tokyo, together with his associates. The findings were published in Annals of Oncology.

Nivolumab (Opdivo) is not approved for treating gastric cancer in the United States but is approved as third-line or later therapy in several other countries. In the phase 2 ATTRACTION-4 trial, 39 patients with previously untreated, unresectable, advanced, or recurrent gastric or gastroesophageal junction cancer received nivolumab (360 mg intravenously every 3 weeks), plus either S-1 (40 mg/m² orally twice daily for 14 days followed by 7 days off) or capecitabine (1000 mg/m² orally twice daily for 14 days followed by 7 days off), plus oxaliplatin (130 mg/m² intravenously on day 1 every 3 weeks).

For the regimen containing S-1, the most common serious adverse events requiring delays or reductions in chemotherapy were thrombocytopenia (57%), neutropenia (48%), and nausea (19%), followed by diarrhea, vomiting, abdominal pain, peripheral sensory neuropathy, and fatigue (14% each). For the regimen containing capecitabine, the most common of these adverse events were neutropenia (44%), decreased appetite (28%), and palmar-plantar erythrodysesthesia syndrome (22%), followed by nausea, vomiting, diarrhea, and peripheral sensory neuropathy (17% each). There were no treatment-related deaths.

Efficacy endpoints were secondary and limited by small sample size. Nonetheless, regardless of which of the two chemotherapy regimens patients received, about two-thirds had a complete or partial treatment response, which is “numerically higher” than that reported for either chemotherapy regimen alone, the researchers wrote. After a median follow-up of 13.2 months, median overall survival was not reached, while median progression-free survival was 9.7 months for the S-1-based regimen and 10.6 months for the capecitabine-based regimen. Antitumor response appeared to be unrelated to programmed death–ligand 1 status.

Based on the findings, both nivolumab-chemotherapy regimens have “manageable safety profile and clinically relevant antitumor profile,” Dr. Boku and his coinvestigators stated. The second part of ATTRACTION-4 has recruited a larger group of patients and should shed more light on efficacy.

Ono Pharmaceutical and Bristol-Myers Squibb funded the work. Dr. Boku reported financial ties to both companies and to AstraZeneca and Chugai Pharmaceutical.

SOURCE: Boku N et al. Ann Oncol. 2018 Dec 19. doi: 10.1093/annonc/mdy540.

Men and women with cancer may derive a similar survival benefit from immune checkpoint inhibitor therapy, results of a recent meta-analysis suggest.

Both men and women had an overall survival benefit from immunotherapy versus standard of care therapy, with no significant difference between the sexes, according to authors of this meta-analysis, which included 23 randomized clinical trials comprising nearly 14,000 patients.

The findings, reported in JAMA Oncology, contrast with those of another recent analysis, which suggested that men had a greater advantage of receiving immunotherapy versus standard of care than women did.

“We found no evidence that sex should be considered when deciding whether to offer immunotherapy to patients with advanced cancers,” said Christopher J.D. Wallis, MD, PhD, of the University of Toronto, and his coauthors said in their report.

The present meta-analysis was based on a “more contemporary and comprehensive” literature search strategy than the earlier one, according to Dr. Wallis and his coinvestigators.

Specifically, they considered immunotherapy agents not included in the previous analysis, added seven new studies published since the previous analysis, and excluded three trials that compared immunotherapy agents, rather than comparing immunotherapy with standard of care, they explained in their report.

Their resulting meta-analysis included a total of 9,322 men and 4,399 women, most of whom were in their 70s. Overall, they found that immune checkpoint inhibitor therapy offered a statistically significant overall survival advantage versus standard systemic therapy, with a hazard ratio of 0.75 (95% confidence interval, 0.70-0.81; P less than .001).

That overall survival advantage was found for both men, with a hazard ratio of 0.75 (95% CI, 0.69-0.81; P less than .001) and women, at 0.77 (95% CI, 0.67-0.88; P = .002), investigators further reported. There was no statistically significant difference in overall survival advantage between men and women, both overall (P = 0.60) and in subgroup analyses that accounted for tumor type, line of treatment, and prevalence of women in the study.

The previous meta-analysis, published in the Lancet, found an overall survival hazard ratio of 0.72 for men receiving checkpoint inhibitors and 0.86 for women receiving checkpoint inhibitors (P = .0019), prompting those investigators to conclude that the magnitude of benefit was sex-dependent and that different immunotherapeutic approaches may be needed for men versus women.

“The present meta-analysis provides a more specific assessment of the research question while including a greater number of immunotherapy agents and an updated search,” Dr. Wallis and his coauthors said in a discussion of their more recent findings.

Dr. Wallis reported no disclosures related to the study. Study coauthors provided disclosures related to Merck, AstraZeneca, Bristol-Myers Squibb, Illumina, Tempus, Novartis, Eli Lilly, Fate, Incyte, MedImmune, Pfizer, Roche/Genentech, Xcovery, Fate Therapeutics, Genocea, and Iovance.
 

SOURCE: Wallis CJD et al. JAMA Oncol. 2019 Jan 3. doi:10.1001/jamaoncol.2018.5904.

Men and women with cancer may derive a similar survival benefit from immune checkpoint inhibitor therapy, results of a recent meta-analysis suggest.

Both men and women had an overall survival benefit from immunotherapy versus standard of care therapy, with no significant difference between the sexes, according to authors of this meta-analysis, which included 23 randomized clinical trials comprising nearly 14,000 patients.

The findings, reported in JAMA Oncology, contrast with those of another recent analysis, which suggested that men had a greater advantage of receiving immunotherapy versus standard of care than women did.

“We found no evidence that sex should be considered when deciding whether to offer immunotherapy to patients with advanced cancers,” said Christopher J.D. Wallis, MD, PhD, of the University of Toronto, and his coauthors said in their report.

The present meta-analysis was based on a “more contemporary and comprehensive” literature search strategy than the earlier one, according to Dr. Wallis and his coinvestigators.

Specifically, they considered immunotherapy agents not included in the previous analysis, added seven new studies published since the previous analysis, and excluded three trials that compared immunotherapy agents, rather than comparing immunotherapy with standard of care, they explained in their report.

Their resulting meta-analysis included a total of 9,322 men and 4,399 women, most of whom were in their 70s. Overall, they found that immune checkpoint inhibitor therapy offered a statistically significant overall survival advantage versus standard systemic therapy, with a hazard ratio of 0.75 (95% confidence interval, 0.70-0.81; P less than .001).

That overall survival advantage was found for both men, with a hazard ratio of 0.75 (95% CI, 0.69-0.81; P less than .001) and women, at 0.77 (95% CI, 0.67-0.88; P = .002), investigators further reported. There was no statistically significant difference in overall survival advantage between men and women, both overall (P = 0.60) and in subgroup analyses that accounted for tumor type, line of treatment, and prevalence of women in the study.

The previous meta-analysis, published in the Lancet, found an overall survival hazard ratio of 0.72 for men receiving checkpoint inhibitors and 0.86 for women receiving checkpoint inhibitors (P = .0019), prompting those investigators to conclude that the magnitude of benefit was sex-dependent and that different immunotherapeutic approaches may be needed for men versus women.

“The present meta-analysis provides a more specific assessment of the research question while including a greater number of immunotherapy agents and an updated search,” Dr. Wallis and his coauthors said in a discussion of their more recent findings.

Dr. Wallis reported no disclosures related to the study. Study coauthors provided disclosures related to Merck, AstraZeneca, Bristol-Myers Squibb, Illumina, Tempus, Novartis, Eli Lilly, Fate, Incyte, MedImmune, Pfizer, Roche/Genentech, Xcovery, Fate Therapeutics, Genocea, and Iovance.
 

SOURCE: Wallis CJD et al. JAMA Oncol. 2019 Jan 3. doi:10.1001/jamaoncol.2018.5904.

Men and women with cancer may derive a similar survival benefit from immune checkpoint inhibitor therapy, results of a recent meta-analysis suggest.

Both men and women had an overall survival benefit from immunotherapy versus standard of care therapy, with no significant difference between the sexes, according to authors of this meta-analysis, which included 23 randomized clinical trials comprising nearly 14,000 patients.

The findings, reported in JAMA Oncology, contrast with those of another recent analysis, which suggested that men had a greater advantage of receiving immunotherapy versus standard of care than women did.

“We found no evidence that sex should be considered when deciding whether to offer immunotherapy to patients with advanced cancers,” said Christopher J.D. Wallis, MD, PhD, of the University of Toronto, and his coauthors said in their report.

The present meta-analysis was based on a “more contemporary and comprehensive” literature search strategy than the earlier one, according to Dr. Wallis and his coinvestigators.

Specifically, they considered immunotherapy agents not included in the previous analysis, added seven new studies published since the previous analysis, and excluded three trials that compared immunotherapy agents, rather than comparing immunotherapy with standard of care, they explained in their report.

Their resulting meta-analysis included a total of 9,322 men and 4,399 women, most of whom were in their 70s. Overall, they found that immune checkpoint inhibitor therapy offered a statistically significant overall survival advantage versus standard systemic therapy, with a hazard ratio of 0.75 (95% confidence interval, 0.70-0.81; P less than .001).

That overall survival advantage was found for both men, with a hazard ratio of 0.75 (95% CI, 0.69-0.81; P less than .001) and women, at 0.77 (95% CI, 0.67-0.88; P = .002), investigators further reported. There was no statistically significant difference in overall survival advantage between men and women, both overall (P = 0.60) and in subgroup analyses that accounted for tumor type, line of treatment, and prevalence of women in the study.

The previous meta-analysis, published in the Lancet, found an overall survival hazard ratio of 0.72 for men receiving checkpoint inhibitors and 0.86 for women receiving checkpoint inhibitors (P = .0019), prompting those investigators to conclude that the magnitude of benefit was sex-dependent and that different immunotherapeutic approaches may be needed for men versus women.

“The present meta-analysis provides a more specific assessment of the research question while including a greater number of immunotherapy agents and an updated search,” Dr. Wallis and his coauthors said in a discussion of their more recent findings.

Dr. Wallis reported no disclosures related to the study. Study coauthors provided disclosures related to Merck, AstraZeneca, Bristol-Myers Squibb, Illumina, Tempus, Novartis, Eli Lilly, Fate, Incyte, MedImmune, Pfizer, Roche/Genentech, Xcovery, Fate Therapeutics, Genocea, and Iovance.
 

SOURCE: Wallis CJD et al. JAMA Oncol. 2019 Jan 3. doi:10.1001/jamaoncol.2018.5904.

SAN DIEGO – A second-generation CD19-specific “armored” chimeric antigen receptor (CAR) T-cell construct was associated with high complete remission rates in diffuse large B-cell lymphoma (DLBCL) and indolent non-Hodgkin lymphoma (NHL) in a phase 1 trial.

Neil Osterweil/ MDedge News

The CAR T construct – labeled 1928z-41BBL – also induced “encouraging” complete remission rates in patients with chronic lymphocytic leukemia (CLL) with Richter’s transformation, reported Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center (MSKCC), New York, and his colleagues.

“Interestingly and encouragingly, severe [cytokine release syndrome] was not seen and grade 3 neurotoxicity was observed in less than 10%, with no grade 4 neurotoxicity, so there appears to be a favorable side effect profile,” Dr. Park said at the annual meeting of the American Society of Hematology.

Just as armored cars are designed to protect their valuable contents from people with bad intent, armored CAR T cells are engineered to protect the modified T-cells from a hostile tumor microenvironment and simultaneously recruit non-modified T cells to the target to produce a more robust immune response against malignant cells.

MSKCC investigators had previously shown that in contrast to other CAR T-cell constructs, the 1928z-41BBL configuration, which consists of two signaling domains (CD28 and CD3zeta) and the 4-1BB ligand, hit the sweet spot between tumor-killing function and T-cell persistence (Cancer Cell. 2015 Oct 12;28[4]:415-28).

In the current study, they enrolled 35 adults with relapsed or refractory CD19-positive hematologic malignancies, 29 of whom eventually underwent CAR T-cell infusions. The treated population comprised 14 patients with CLL (4 of whom had Richter’s transformation), 9 with DLBCL, 5 with indolent NHL, and 1 with acute lymphoblastic leukemia.

The patients with CLL had received a median of 5.5 prior lines of therapy, including ibrutinib (Imbruvica) and venetoclax (Venclexta).

There were 15 complete remissions (CR), with CR rates of 78% in DLBCL, 20% in CLL, 67% in CLL with Richter’s transformation, 60% in patients with indolent NHL, as well as CR in the single patient with ALL.

There were eight partial remissions. One patient with CLL had stable disease, and four patients had disease progression (one patient each with DLBCL, CLL, CLL with Richter’s, and indolent NHL).

Dr. Park noted that T cells are being detected in peripheral blood more than 6 months after T-cell infusion.

There were no cases of severe cytokine release syndrome, defined as requiring vasopressors and/or mechanical ventilation for hypoxia, and just three cases of grade 3 neurotoxicity. There were no cases of grade 4 neurotoxicity, no deaths related to neurotoxicity, and no cases of cerebral edema – a serious complication that has been seen in earlier CAR T-cell studies.

Split or multiple infusions of CAR T cells or incorporation of the technique into earlier lines of therapy might generate higher response rates, Dr. Park said.

The study was supported by Juno Therapeutics. Dr. Park reported consulting for and research funding from Juno, and financial relationships with other companies.
 

SOURCE: Park JH et al. ASH 2018, Abstract 224.

SAN DIEGO – A second-generation CD19-specific “armored” chimeric antigen receptor (CAR) T-cell construct was associated with high complete remission rates in diffuse large B-cell lymphoma (DLBCL) and indolent non-Hodgkin lymphoma (NHL) in a phase 1 trial.

Neil Osterweil/ MDedge News

The CAR T construct – labeled 1928z-41BBL – also induced “encouraging” complete remission rates in patients with chronic lymphocytic leukemia (CLL) with Richter’s transformation, reported Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center (MSKCC), New York, and his colleagues.

“Interestingly and encouragingly, severe [cytokine release syndrome] was not seen and grade 3 neurotoxicity was observed in less than 10%, with no grade 4 neurotoxicity, so there appears to be a favorable side effect profile,” Dr. Park said at the annual meeting of the American Society of Hematology.

Just as armored cars are designed to protect their valuable contents from people with bad intent, armored CAR T cells are engineered to protect the modified T-cells from a hostile tumor microenvironment and simultaneously recruit non-modified T cells to the target to produce a more robust immune response against malignant cells.

MSKCC investigators had previously shown that in contrast to other CAR T-cell constructs, the 1928z-41BBL configuration, which consists of two signaling domains (CD28 and CD3zeta) and the 4-1BB ligand, hit the sweet spot between tumor-killing function and T-cell persistence (Cancer Cell. 2015 Oct 12;28[4]:415-28).

In the current study, they enrolled 35 adults with relapsed or refractory CD19-positive hematologic malignancies, 29 of whom eventually underwent CAR T-cell infusions. The treated population comprised 14 patients with CLL (4 of whom had Richter’s transformation), 9 with DLBCL, 5 with indolent NHL, and 1 with acute lymphoblastic leukemia.

The patients with CLL had received a median of 5.5 prior lines of therapy, including ibrutinib (Imbruvica) and venetoclax (Venclexta).

There were 15 complete remissions (CR), with CR rates of 78% in DLBCL, 20% in CLL, 67% in CLL with Richter’s transformation, 60% in patients with indolent NHL, as well as CR in the single patient with ALL.

There were eight partial remissions. One patient with CLL had stable disease, and four patients had disease progression (one patient each with DLBCL, CLL, CLL with Richter’s, and indolent NHL).

Dr. Park noted that T cells are being detected in peripheral blood more than 6 months after T-cell infusion.

There were no cases of severe cytokine release syndrome, defined as requiring vasopressors and/or mechanical ventilation for hypoxia, and just three cases of grade 3 neurotoxicity. There were no cases of grade 4 neurotoxicity, no deaths related to neurotoxicity, and no cases of cerebral edema – a serious complication that has been seen in earlier CAR T-cell studies.

Split or multiple infusions of CAR T cells or incorporation of the technique into earlier lines of therapy might generate higher response rates, Dr. Park said.

The study was supported by Juno Therapeutics. Dr. Park reported consulting for and research funding from Juno, and financial relationships with other companies.
 

SOURCE: Park JH et al. ASH 2018, Abstract 224.

SAN DIEGO – A second-generation CD19-specific “armored” chimeric antigen receptor (CAR) T-cell construct was associated with high complete remission rates in diffuse large B-cell lymphoma (DLBCL) and indolent non-Hodgkin lymphoma (NHL) in a phase 1 trial.

Neil Osterweil/ MDedge News

The CAR T construct – labeled 1928z-41BBL – also induced “encouraging” complete remission rates in patients with chronic lymphocytic leukemia (CLL) with Richter’s transformation, reported Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center (MSKCC), New York, and his colleagues.

“Interestingly and encouragingly, severe [cytokine release syndrome] was not seen and grade 3 neurotoxicity was observed in less than 10%, with no grade 4 neurotoxicity, so there appears to be a favorable side effect profile,” Dr. Park said at the annual meeting of the American Society of Hematology.

Just as armored cars are designed to protect their valuable contents from people with bad intent, armored CAR T cells are engineered to protect the modified T-cells from a hostile tumor microenvironment and simultaneously recruit non-modified T cells to the target to produce a more robust immune response against malignant cells.

MSKCC investigators had previously shown that in contrast to other CAR T-cell constructs, the 1928z-41BBL configuration, which consists of two signaling domains (CD28 and CD3zeta) and the 4-1BB ligand, hit the sweet spot between tumor-killing function and T-cell persistence (Cancer Cell. 2015 Oct 12;28[4]:415-28).

In the current study, they enrolled 35 adults with relapsed or refractory CD19-positive hematologic malignancies, 29 of whom eventually underwent CAR T-cell infusions. The treated population comprised 14 patients with CLL (4 of whom had Richter’s transformation), 9 with DLBCL, 5 with indolent NHL, and 1 with acute lymphoblastic leukemia.

The patients with CLL had received a median of 5.5 prior lines of therapy, including ibrutinib (Imbruvica) and venetoclax (Venclexta).

There were 15 complete remissions (CR), with CR rates of 78% in DLBCL, 20% in CLL, 67% in CLL with Richter’s transformation, 60% in patients with indolent NHL, as well as CR in the single patient with ALL.

There were eight partial remissions. One patient with CLL had stable disease, and four patients had disease progression (one patient each with DLBCL, CLL, CLL with Richter’s, and indolent NHL).

Dr. Park noted that T cells are being detected in peripheral blood more than 6 months after T-cell infusion.

There were no cases of severe cytokine release syndrome, defined as requiring vasopressors and/or mechanical ventilation for hypoxia, and just three cases of grade 3 neurotoxicity. There were no cases of grade 4 neurotoxicity, no deaths related to neurotoxicity, and no cases of cerebral edema – a serious complication that has been seen in earlier CAR T-cell studies.

Split or multiple infusions of CAR T cells or incorporation of the technique into earlier lines of therapy might generate higher response rates, Dr. Park said.

The study was supported by Juno Therapeutics. Dr. Park reported consulting for and research funding from Juno, and financial relationships with other companies.
 

SOURCE: Park JH et al. ASH 2018, Abstract 224.

A significant number of patients who receive only a placebo in a clinical trial of cancer immunotherapy still experience grade three or grade four adverse events, research suggests.

Writing in JAMA Network Open, researchers reported the outcomes of a systematic review and meta-analysis of 10 randomized, double-blind, placebo-controlled, phase 3 trials of targeted therapy or immunotherapy drugs for cancer, in which patients in the placebo group were treated only with placebo and no other anticancer drugs.

Among the 4,873 patients who were randomized to placebo, a mean of 85.1% experienced some sort of placebo adverse event. The overall incidence of grade 3-4 placebo adverse events was 18% but was as high as 25% in two trials – one in renal cell carcinoma and one in melanoma – and as low as 11% in one trial.

Hypertension was the most frequent grade 3-4 adverse event among patients on placebo, experienced by a mean of 2.8% of patients, followed by fatigue (1%) and diarrhea (0.8%).

Neither route of administration nor cancer type made a significant difference in terms of the rate of placebo adverse events. No deaths attributed to the placebo were reported, but the mean rate of discontinuation due to placebo adverse events was 3.9%, and was higher than 5% for four trials.

The median duration of placebo administration ranged from 10 to 15 months for all but one study, and the authors noted that the longer the placebo exposure, the higher the proportion of grade 3-4 adverse events.

The investigators – Matías Rodrigo Chacón, MD, and his colleagues in the research department at the Argentine Association of Clinical Oncology – said that studies with a lower incidence of grade 3-4 adverse events in the treatment arm also had a lower incidence of grade 3-4 placebo adverse events, while the higher incidences of placebo adverse events were seen in studies that also had a higher incidence of treatment-related adverse events.

They suggested that “contextual factors,” such as the information given during the informed consent process, could contribute to negative expectations of adverse events.

“To illustrate this point, in an RCT [randomized controlled trial] of aspirin as a treatment for unstable angina, a higher incidence of gastrointestinal irritation was reported in centers that specified its potential occurrence in the informed consent compared with research units that did not include that risk,” they wrote.

They also suggested that patients may experience anxiety associated with the uncertainty about whether they had received active treatment or placebo, and this could also affect their distress levels.

No conflicts of interest were declared.

SOURCE: Chacón M et al. JAMA Network Open. 2018 Dec 7. doi: 10.1001/jamanetworkopen.2018.5617.

A significant number of patients who receive only a placebo in a clinical trial of cancer immunotherapy still experience grade three or grade four adverse events, research suggests.

Writing in JAMA Network Open, researchers reported the outcomes of a systematic review and meta-analysis of 10 randomized, double-blind, placebo-controlled, phase 3 trials of targeted therapy or immunotherapy drugs for cancer, in which patients in the placebo group were treated only with placebo and no other anticancer drugs.

Among the 4,873 patients who were randomized to placebo, a mean of 85.1% experienced some sort of placebo adverse event. The overall incidence of grade 3-4 placebo adverse events was 18% but was as high as 25% in two trials – one in renal cell carcinoma and one in melanoma – and as low as 11% in one trial.

Hypertension was the most frequent grade 3-4 adverse event among patients on placebo, experienced by a mean of 2.8% of patients, followed by fatigue (1%) and diarrhea (0.8%).

Neither route of administration nor cancer type made a significant difference in terms of the rate of placebo adverse events. No deaths attributed to the placebo were reported, but the mean rate of discontinuation due to placebo adverse events was 3.9%, and was higher than 5% for four trials.

The median duration of placebo administration ranged from 10 to 15 months for all but one study, and the authors noted that the longer the placebo exposure, the higher the proportion of grade 3-4 adverse events.

The investigators – Matías Rodrigo Chacón, MD, and his colleagues in the research department at the Argentine Association of Clinical Oncology – said that studies with a lower incidence of grade 3-4 adverse events in the treatment arm also had a lower incidence of grade 3-4 placebo adverse events, while the higher incidences of placebo adverse events were seen in studies that also had a higher incidence of treatment-related adverse events.

They suggested that “contextual factors,” such as the information given during the informed consent process, could contribute to negative expectations of adverse events.

“To illustrate this point, in an RCT [randomized controlled trial] of aspirin as a treatment for unstable angina, a higher incidence of gastrointestinal irritation was reported in centers that specified its potential occurrence in the informed consent compared with research units that did not include that risk,” they wrote.

They also suggested that patients may experience anxiety associated with the uncertainty about whether they had received active treatment or placebo, and this could also affect their distress levels.

No conflicts of interest were declared.

SOURCE: Chacón M et al. JAMA Network Open. 2018 Dec 7. doi: 10.1001/jamanetworkopen.2018.5617.

A significant number of patients who receive only a placebo in a clinical trial of cancer immunotherapy still experience grade three or grade four adverse events, research suggests.

Writing in JAMA Network Open, researchers reported the outcomes of a systematic review and meta-analysis of 10 randomized, double-blind, placebo-controlled, phase 3 trials of targeted therapy or immunotherapy drugs for cancer, in which patients in the placebo group were treated only with placebo and no other anticancer drugs.

Among the 4,873 patients who were randomized to placebo, a mean of 85.1% experienced some sort of placebo adverse event. The overall incidence of grade 3-4 placebo adverse events was 18% but was as high as 25% in two trials – one in renal cell carcinoma and one in melanoma – and as low as 11% in one trial.

Hypertension was the most frequent grade 3-4 adverse event among patients on placebo, experienced by a mean of 2.8% of patients, followed by fatigue (1%) and diarrhea (0.8%).

Neither route of administration nor cancer type made a significant difference in terms of the rate of placebo adverse events. No deaths attributed to the placebo were reported, but the mean rate of discontinuation due to placebo adverse events was 3.9%, and was higher than 5% for four trials.

The median duration of placebo administration ranged from 10 to 15 months for all but one study, and the authors noted that the longer the placebo exposure, the higher the proportion of grade 3-4 adverse events.

The investigators – Matías Rodrigo Chacón, MD, and his colleagues in the research department at the Argentine Association of Clinical Oncology – said that studies with a lower incidence of grade 3-4 adverse events in the treatment arm also had a lower incidence of grade 3-4 placebo adverse events, while the higher incidences of placebo adverse events were seen in studies that also had a higher incidence of treatment-related adverse events.

They suggested that “contextual factors,” such as the information given during the informed consent process, could contribute to negative expectations of adverse events.

“To illustrate this point, in an RCT [randomized controlled trial] of aspirin as a treatment for unstable angina, a higher incidence of gastrointestinal irritation was reported in centers that specified its potential occurrence in the informed consent compared with research units that did not include that risk,” they wrote.

They also suggested that patients may experience anxiety associated with the uncertainty about whether they had received active treatment or placebo, and this could also affect their distress levels.

No conflicts of interest were declared.

SOURCE: Chacón M et al. JAMA Network Open. 2018 Dec 7. doi: 10.1001/jamanetworkopen.2018.5617.

SAN ANTONIO – Programmed death-ligand 1 (PD-L1) expression on tumor-infiltrating immune cells is the best predictor of response to atezolizumab + nab-paclitaxel in patients with untreated metastatic triple-negative breast cancer, according to exploratory efficacy analyses of data from the phase 3 IMpassion130 trial.

The analyses of data for the 902 patients randomized to receive the PD-L1 inhibitor atezolizumab (Tecentriq) plus nanoparticle albumin-bound (nab)–paclitaxel or placebo plus nab-palcitaxel for the study also showed consistency between local and central estrogen-receptor, progesterone-receptor, and human epidermal growth factor–receptor 2 testing, Leisha A. Emens, MD, reported at the San Antonio Breast Cancer Symposium.

“IMpassion130 is the first phase 3 study to demonstrate a benefit from [atezolizumab + nab-paclitaxel] in metastatic triple-negative breast cancer (mTNBC),” said Dr. Emens, professor of medicine in hematology/oncology, coleader of the Hillman Cancer Immunology and Immunotherapy Program, and director of translational immunotherapy for the Women’s Cancer Research Center at the University of Pittsburgh Medical Center.

She explained that progression-free survival (PFS) was significantly better in PD-L1–positive mTNBC patients treated with the atezolizumab + nab-paclitaxel, than in those who received placebo + nab-paclitaxel (hazard ratios in the intent-to-treat population, 0.8 and 0.62, respectively).

At the first interim overall survival analysis, a clinically meaningful improvement in OS was seen in PD-L1–positive patients in the treatment group (HR, 0.62; median OS improvement from 15.5 months with placebo to 25 months), she added.

In exploratory analyses, Dr. Emens and her colleagues sought to evaluate whether preexisting immune biology is associated with clinical benefit from atezolizumab + nab-paclitaxel, as has been demonstrated in studies of other agents that target the PD-1 pathway in other cancer types of cancer. They also assessed BRCA 1/2 mutation status as a biomarker for response.

“In patients enrolled on the IMpassion130 trial we found that PD-L1 in triple-negative breast cancer was expressed primarily on tumor-infiltrating immune cells,” she said. “In contrast to this, we found a very low rate of PD-L1 expression specifically on tumor cells across the patient population.”

Looking at both of those biomarkers together showed that a majority of patients with expression of PD-L1 on tumor cells were included in the PD-L1 immune cell–positive population, with only 2% having PD-L1 expression exclusively on their tumor cells.

Data previously reported at the European Society for Medical Oncology and published in the New England Journal of Medicine showed a PFS benefit, as well as a clinically meaningful improvement in OS of nearly 10 months, specifically in patients with PD-L1 immune cell–positive lesions treated with atezolizumab + nab-paclitaxel, she noted.

“In data presented for the first time today you can see that PD-L1–negative patients derive no overall survival benefit as there was no treatment effect with this therapy combination,” she said.

A trend was seen toward an association between immune cell positivity and poor prognosis, but this was not statistically significant, she said.

“Taken together, these data definitively show that PD-L1 immune cell positivity is predictive of both progression-free and overall survival benefit with atezolizumab + nab-paclitaxel,” she said.

She and her colleagues also looked at the level of PD-L1 expression in immune cells to assess whether there is a threshold that might be required.

“As long as there was a PD-L1 expression level of 1% or more in the immune cells, there was a significant progression-free and overall survival benefit for patients treated with atezolizumab + nab-paclitaxel. This suggests that this expression of over 1% will represent a threshold for identifying those patients who are likely to benefit from this combination,” she said.

Further assessment by CD8 T-cell status showed that patients who had CD8-positive T cells but who were PD-L1 immune cell negative had no benefit from atezolizumab + nab-paclitaxel, whereas those who were positive for both CD8 and PD-L1 expression on their immune cells derived significant PFS and OS benefit (HR, 0.89 and 0.77, respectively).

“So patients with CD8-positive tumors derive clinical benefit only if their tumors are also PD-L1-positive,” she said.

Similarly, no clinical benefit was seen in patients with stromal tumor-infiltrating lymphocyte (TIL)–positive tumors but who were PD-L1-negative, whereas those with stromal TIL-positive PD-L1–positive tumors derived significant PFS and OS benefit (HRs, 0.99 and 1.53, respectively), and this was also seen in the 15% of evaluable patients who had BRCA mutations.

“In patients who were BRCA mutated, but who were PD-L1 immune cell negative, there was no association of progression-free survival or an overall survival benefit [with atezolizumab + nab-paclitaxel]. In contrast, in patients who were BRCA mutated but PD-L1 immune cell positive ... there was an association with progression-free survival and a trend toward overall survival,” she said, noting that while the BRCA mutation findings are limited by small numbers, “they do show that mutations in BRCA and PD-L1 expression in immune cells are independent biomarkers; patients with BRCA1 or 2 mutations derive clinical benefit only if their tumors are also PD-L1 positive.”

“In this phase 3 IMpassion130 study, PD-L1 expression on immune cells is a predictive biomarker for selecting patients who benefit clinically during first-line treatment with atezolizumab + nab-paclitaxel for metastatic triple-negative breast cancer,” she concluded, adding that “patients with newly diagnosed metastatic and unresectable locally advanced triple-negative breast cancer should be routinely tested for their PD-L1 immune cell status to determine if they might benefit from the combination of atezolizumab + nab-paclitaxel.

IMpassion130 was sponsored by Hoffman-La Roche. Dr. Emens reported receiving royalties and consulting fees from several companies. She has contracts with Roche/Genentech, Corvus, AstraZeneca, and EMD Serono, and ownership in Molecuvax. She receives other support from DSMB and Syndax, and has received grants from Aduro Biotech, Merck, Maxcyte, and the Breast Cancer Research Foundation. She also reported serving as a member of the Food and Drug Administration Advisory Committee on Tissue, Cell, and Gene Therapies, and is a member of the board of directors for the Society of Immunotherapy for Cancer.

SOURCE: Emens L et al. SABCS 2018, Abstract GS1-04.

SAN ANTONIO – Programmed death-ligand 1 (PD-L1) expression on tumor-infiltrating immune cells is the best predictor of response to atezolizumab + nab-paclitaxel in patients with untreated metastatic triple-negative breast cancer, according to exploratory efficacy analyses of data from the phase 3 IMpassion130 trial.

The analyses of data for the 902 patients randomized to receive the PD-L1 inhibitor atezolizumab (Tecentriq) plus nanoparticle albumin-bound (nab)–paclitaxel or placebo plus nab-palcitaxel for the study also showed consistency between local and central estrogen-receptor, progesterone-receptor, and human epidermal growth factor–receptor 2 testing, Leisha A. Emens, MD, reported at the San Antonio Breast Cancer Symposium.

“IMpassion130 is the first phase 3 study to demonstrate a benefit from [atezolizumab + nab-paclitaxel] in metastatic triple-negative breast cancer (mTNBC),” said Dr. Emens, professor of medicine in hematology/oncology, coleader of the Hillman Cancer Immunology and Immunotherapy Program, and director of translational immunotherapy for the Women’s Cancer Research Center at the University of Pittsburgh Medical Center.

She explained that progression-free survival (PFS) was significantly better in PD-L1–positive mTNBC patients treated with the atezolizumab + nab-paclitaxel, than in those who received placebo + nab-paclitaxel (hazard ratios in the intent-to-treat population, 0.8 and 0.62, respectively).

At the first interim overall survival analysis, a clinically meaningful improvement in OS was seen in PD-L1–positive patients in the treatment group (HR, 0.62; median OS improvement from 15.5 months with placebo to 25 months), she added.

In exploratory analyses, Dr. Emens and her colleagues sought to evaluate whether preexisting immune biology is associated with clinical benefit from atezolizumab + nab-paclitaxel, as has been demonstrated in studies of other agents that target the PD-1 pathway in other cancer types of cancer. They also assessed BRCA 1/2 mutation status as a biomarker for response.

“In patients enrolled on the IMpassion130 trial we found that PD-L1 in triple-negative breast cancer was expressed primarily on tumor-infiltrating immune cells,” she said. “In contrast to this, we found a very low rate of PD-L1 expression specifically on tumor cells across the patient population.”

Looking at both of those biomarkers together showed that a majority of patients with expression of PD-L1 on tumor cells were included in the PD-L1 immune cell–positive population, with only 2% having PD-L1 expression exclusively on their tumor cells.

Data previously reported at the European Society for Medical Oncology and published in the New England Journal of Medicine showed a PFS benefit, as well as a clinically meaningful improvement in OS of nearly 10 months, specifically in patients with PD-L1 immune cell–positive lesions treated with atezolizumab + nab-paclitaxel, she noted.

“In data presented for the first time today you can see that PD-L1–negative patients derive no overall survival benefit as there was no treatment effect with this therapy combination,” she said.

A trend was seen toward an association between immune cell positivity and poor prognosis, but this was not statistically significant, she said.

“Taken together, these data definitively show that PD-L1 immune cell positivity is predictive of both progression-free and overall survival benefit with atezolizumab + nab-paclitaxel,” she said.

She and her colleagues also looked at the level of PD-L1 expression in immune cells to assess whether there is a threshold that might be required.

“As long as there was a PD-L1 expression level of 1% or more in the immune cells, there was a significant progression-free and overall survival benefit for patients treated with atezolizumab + nab-paclitaxel. This suggests that this expression of over 1% will represent a threshold for identifying those patients who are likely to benefit from this combination,” she said.

Further assessment by CD8 T-cell status showed that patients who had CD8-positive T cells but who were PD-L1 immune cell negative had no benefit from atezolizumab + nab-paclitaxel, whereas those who were positive for both CD8 and PD-L1 expression on their immune cells derived significant PFS and OS benefit (HR, 0.89 and 0.77, respectively).

“So patients with CD8-positive tumors derive clinical benefit only if their tumors are also PD-L1-positive,” she said.

Similarly, no clinical benefit was seen in patients with stromal tumor-infiltrating lymphocyte (TIL)–positive tumors but who were PD-L1-negative, whereas those with stromal TIL-positive PD-L1–positive tumors derived significant PFS and OS benefit (HRs, 0.99 and 1.53, respectively), and this was also seen in the 15% of evaluable patients who had BRCA mutations.

“In patients who were BRCA mutated, but who were PD-L1 immune cell negative, there was no association of progression-free survival or an overall survival benefit [with atezolizumab + nab-paclitaxel]. In contrast, in patients who were BRCA mutated but PD-L1 immune cell positive ... there was an association with progression-free survival and a trend toward overall survival,” she said, noting that while the BRCA mutation findings are limited by small numbers, “they do show that mutations in BRCA and PD-L1 expression in immune cells are independent biomarkers; patients with BRCA1 or 2 mutations derive clinical benefit only if their tumors are also PD-L1 positive.”

“In this phase 3 IMpassion130 study, PD-L1 expression on immune cells is a predictive biomarker for selecting patients who benefit clinically during first-line treatment with atezolizumab + nab-paclitaxel for metastatic triple-negative breast cancer,” she concluded, adding that “patients with newly diagnosed metastatic and unresectable locally advanced triple-negative breast cancer should be routinely tested for their PD-L1 immune cell status to determine if they might benefit from the combination of atezolizumab + nab-paclitaxel.

IMpassion130 was sponsored by Hoffman-La Roche. Dr. Emens reported receiving royalties and consulting fees from several companies. She has contracts with Roche/Genentech, Corvus, AstraZeneca, and EMD Serono, and ownership in Molecuvax. She receives other support from DSMB and Syndax, and has received grants from Aduro Biotech, Merck, Maxcyte, and the Breast Cancer Research Foundation. She also reported serving as a member of the Food and Drug Administration Advisory Committee on Tissue, Cell, and Gene Therapies, and is a member of the board of directors for the Society of Immunotherapy for Cancer.

SOURCE: Emens L et al. SABCS 2018, Abstract GS1-04.

SAN ANTONIO – Programmed death-ligand 1 (PD-L1) expression on tumor-infiltrating immune cells is the best predictor of response to atezolizumab + nab-paclitaxel in patients with untreated metastatic triple-negative breast cancer, according to exploratory efficacy analyses of data from the phase 3 IMpassion130 trial.

The analyses of data for the 902 patients randomized to receive the PD-L1 inhibitor atezolizumab (Tecentriq) plus nanoparticle albumin-bound (nab)–paclitaxel or placebo plus nab-palcitaxel for the study also showed consistency between local and central estrogen-receptor, progesterone-receptor, and human epidermal growth factor–receptor 2 testing, Leisha A. Emens, MD, reported at the San Antonio Breast Cancer Symposium.

“IMpassion130 is the first phase 3 study to demonstrate a benefit from [atezolizumab + nab-paclitaxel] in metastatic triple-negative breast cancer (mTNBC),” said Dr. Emens, professor of medicine in hematology/oncology, coleader of the Hillman Cancer Immunology and Immunotherapy Program, and director of translational immunotherapy for the Women’s Cancer Research Center at the University of Pittsburgh Medical Center.

She explained that progression-free survival (PFS) was significantly better in PD-L1–positive mTNBC patients treated with the atezolizumab + nab-paclitaxel, than in those who received placebo + nab-paclitaxel (hazard ratios in the intent-to-treat population, 0.8 and 0.62, respectively).

At the first interim overall survival analysis, a clinically meaningful improvement in OS was seen in PD-L1–positive patients in the treatment group (HR, 0.62; median OS improvement from 15.5 months with placebo to 25 months), she added.

In exploratory analyses, Dr. Emens and her colleagues sought to evaluate whether preexisting immune biology is associated with clinical benefit from atezolizumab + nab-paclitaxel, as has been demonstrated in studies of other agents that target the PD-1 pathway in other cancer types of cancer. They also assessed BRCA 1/2 mutation status as a biomarker for response.

“In patients enrolled on the IMpassion130 trial we found that PD-L1 in triple-negative breast cancer was expressed primarily on tumor-infiltrating immune cells,” she said. “In contrast to this, we found a very low rate of PD-L1 expression specifically on tumor cells across the patient population.”

Looking at both of those biomarkers together showed that a majority of patients with expression of PD-L1 on tumor cells were included in the PD-L1 immune cell–positive population, with only 2% having PD-L1 expression exclusively on their tumor cells.

Data previously reported at the European Society for Medical Oncology and published in the New England Journal of Medicine showed a PFS benefit, as well as a clinically meaningful improvement in OS of nearly 10 months, specifically in patients with PD-L1 immune cell–positive lesions treated with atezolizumab + nab-paclitaxel, she noted.

“In data presented for the first time today you can see that PD-L1–negative patients derive no overall survival benefit as there was no treatment effect with this therapy combination,” she said.

A trend was seen toward an association between immune cell positivity and poor prognosis, but this was not statistically significant, she said.

“Taken together, these data definitively show that PD-L1 immune cell positivity is predictive of both progression-free and overall survival benefit with atezolizumab + nab-paclitaxel,” she said.

She and her colleagues also looked at the level of PD-L1 expression in immune cells to assess whether there is a threshold that might be required.

“As long as there was a PD-L1 expression level of 1% or more in the immune cells, there was a significant progression-free and overall survival benefit for patients treated with atezolizumab + nab-paclitaxel. This suggests that this expression of over 1% will represent a threshold for identifying those patients who are likely to benefit from this combination,” she said.

Further assessment by CD8 T-cell status showed that patients who had CD8-positive T cells but who were PD-L1 immune cell negative had no benefit from atezolizumab + nab-paclitaxel, whereas those who were positive for both CD8 and PD-L1 expression on their immune cells derived significant PFS and OS benefit (HR, 0.89 and 0.77, respectively).

“So patients with CD8-positive tumors derive clinical benefit only if their tumors are also PD-L1-positive,” she said.

Similarly, no clinical benefit was seen in patients with stromal tumor-infiltrating lymphocyte (TIL)–positive tumors but who were PD-L1-negative, whereas those with stromal TIL-positive PD-L1–positive tumors derived significant PFS and OS benefit (HRs, 0.99 and 1.53, respectively), and this was also seen in the 15% of evaluable patients who had BRCA mutations.

“In patients who were BRCA mutated, but who were PD-L1 immune cell negative, there was no association of progression-free survival or an overall survival benefit [with atezolizumab + nab-paclitaxel]. In contrast, in patients who were BRCA mutated but PD-L1 immune cell positive ... there was an association with progression-free survival and a trend toward overall survival,” she said, noting that while the BRCA mutation findings are limited by small numbers, “they do show that mutations in BRCA and PD-L1 expression in immune cells are independent biomarkers; patients with BRCA1 or 2 mutations derive clinical benefit only if their tumors are also PD-L1 positive.”

“In this phase 3 IMpassion130 study, PD-L1 expression on immune cells is a predictive biomarker for selecting patients who benefit clinically during first-line treatment with atezolizumab + nab-paclitaxel for metastatic triple-negative breast cancer,” she concluded, adding that “patients with newly diagnosed metastatic and unresectable locally advanced triple-negative breast cancer should be routinely tested for their PD-L1 immune cell status to determine if they might benefit from the combination of atezolizumab + nab-paclitaxel.

IMpassion130 was sponsored by Hoffman-La Roche. Dr. Emens reported receiving royalties and consulting fees from several companies. She has contracts with Roche/Genentech, Corvus, AstraZeneca, and EMD Serono, and ownership in Molecuvax. She receives other support from DSMB and Syndax, and has received grants from Aduro Biotech, Merck, Maxcyte, and the Breast Cancer Research Foundation. She also reported serving as a member of the Food and Drug Administration Advisory Committee on Tissue, Cell, and Gene Therapies, and is a member of the board of directors for the Society of Immunotherapy for Cancer.

SOURCE: Emens L et al. SABCS 2018, Abstract GS1-04.

Older patients with ccRCC may respond better than younger patients to phosphoinositide 3-kinase (PI3K) or checkpoint inhibition because of age-related changes in gene expression, according to investigators.

This possibility was raised by in silico results from a broader study of gene expression patterns in clear cell renal carcinoma (ccRCC) and normal kidney tissues, reported lead author, Lara Feulner, MD, of the department of human genetics at McGill University and Genome Quebec Innovation Centre in Montreal.

“Several factors could contribute to the interindividual diversity among cancer patients,” the investigators wrote in a report published in Urologic Oncology.

“Their disease course could be affected not only by cell-intrinsic factors, but also by age-related changes impacting the vasculature, immune system and stroma. Little is known in this regard about ccRCC, a disease which affects adults across a wide age spectrum. Whether and how aging and comorbidities such as atherosclerosis may affect the biology and therapy of ccRCC has scarcely been considered,” they wrote.

The investigators explored this territory by analyzing datasets from The Cancer Genome Atlas (TCGA) and the Cancer Genomics of the Kidney (CAGEKID) program of the International Cancer Genome Consortium. Using regression, pathway enrichment, and connectivity mapping analyses, they were able to determine associations between age and gene expression, cellular processes, and drug treatment responses, respectively.

The investigators reported that age-related gene expression patterns occurred commonly in both normal and tumor tissues. Associations were reproducible between TCGA and CAGEKID datasets for both classes of tissue (tumor samples, R equal to 0.416, P less than 2.2 x 10-16; normal samples, R equal to 0.403, P less than 2.2 x 10-16). Out of the top 1,000 age-associated genes in tumor samples from each dataset, 383 were commonly downregulated with age and 294 were commonly upregulated with age in both datasets (P less than 2.2 x 10-16).

Among cellular pathways, the investigators found opposite age-relationship patterns. For example, normal tissues upregulated extracellular matrix and cell adhesion pathways with age, whereas tumor tissues downregulated the same pathways. Similar patterns of opposition were found in metabolism and oxidation pathways. Other age-related patterns were noted in some immune pathways, such as upregulation of toll-like receptor and tumor necrosis factor 2 noncanonical NF-kappa-B signaling in tumors, which became more common with age. A closer look showed that upregulation of tumor necrosis factor signaling was more common in female patients, who also downregulated Notch pathways more often than men.

Analysis of treatment responses showed possible relationships with age-dependent gene expression and immunotherapy. Specifically, of 532 genes tied to programmed cell death protein 1 (PD-1) resistance, 69 were among the 383 genes downregulated in older patients with ccRCC (P less than 2.2 x 10-16; 4.05 fold-enrichment), suggesting that older patients may respond better to anti-PD-1 therapy than younger patients. Similarly, connectivity map analysis showed that age-dependent gene expression may improve candidacy of older ccRCC patients for PI3K inhibition.

“We now have evidence that there are notable differences in tumor-associated pathway regulation between younger and older ccRCC patients, which may be therapeutically actionable,” the authors concluded.

The study was funded by the Cancer Research Society operation grant, a Canadian Cancer Society Research Institute Innovation-to-Impact grant, and a Canadian Institutes of Health Research Foundation grant. The authors reported no conflicts of interest.

SOURCE: Feulner et al. Urol Onc. 2018 Nov 23. doi: 10.1016/j.urolonc.2018.11.006.

Older patients with ccRCC may respond better than younger patients to phosphoinositide 3-kinase (PI3K) or checkpoint inhibition because of age-related changes in gene expression, according to investigators.

This possibility was raised by in silico results from a broader study of gene expression patterns in clear cell renal carcinoma (ccRCC) and normal kidney tissues, reported lead author, Lara Feulner, MD, of the department of human genetics at McGill University and Genome Quebec Innovation Centre in Montreal.

“Several factors could contribute to the interindividual diversity among cancer patients,” the investigators wrote in a report published in Urologic Oncology.

“Their disease course could be affected not only by cell-intrinsic factors, but also by age-related changes impacting the vasculature, immune system and stroma. Little is known in this regard about ccRCC, a disease which affects adults across a wide age spectrum. Whether and how aging and comorbidities such as atherosclerosis may affect the biology and therapy of ccRCC has scarcely been considered,” they wrote.

The investigators explored this territory by analyzing datasets from The Cancer Genome Atlas (TCGA) and the Cancer Genomics of the Kidney (CAGEKID) program of the International Cancer Genome Consortium. Using regression, pathway enrichment, and connectivity mapping analyses, they were able to determine associations between age and gene expression, cellular processes, and drug treatment responses, respectively.

The investigators reported that age-related gene expression patterns occurred commonly in both normal and tumor tissues. Associations were reproducible between TCGA and CAGEKID datasets for both classes of tissue (tumor samples, R equal to 0.416, P less than 2.2 x 10-16; normal samples, R equal to 0.403, P less than 2.2 x 10-16). Out of the top 1,000 age-associated genes in tumor samples from each dataset, 383 were commonly downregulated with age and 294 were commonly upregulated with age in both datasets (P less than 2.2 x 10-16).

Among cellular pathways, the investigators found opposite age-relationship patterns. For example, normal tissues upregulated extracellular matrix and cell adhesion pathways with age, whereas tumor tissues downregulated the same pathways. Similar patterns of opposition were found in metabolism and oxidation pathways. Other age-related patterns were noted in some immune pathways, such as upregulation of toll-like receptor and tumor necrosis factor 2 noncanonical NF-kappa-B signaling in tumors, which became more common with age. A closer look showed that upregulation of tumor necrosis factor signaling was more common in female patients, who also downregulated Notch pathways more often than men.

Analysis of treatment responses showed possible relationships with age-dependent gene expression and immunotherapy. Specifically, of 532 genes tied to programmed cell death protein 1 (PD-1) resistance, 69 were among the 383 genes downregulated in older patients with ccRCC (P less than 2.2 x 10-16; 4.05 fold-enrichment), suggesting that older patients may respond better to anti-PD-1 therapy than younger patients. Similarly, connectivity map analysis showed that age-dependent gene expression may improve candidacy of older ccRCC patients for PI3K inhibition.

“We now have evidence that there are notable differences in tumor-associated pathway regulation between younger and older ccRCC patients, which may be therapeutically actionable,” the authors concluded.

The study was funded by the Cancer Research Society operation grant, a Canadian Cancer Society Research Institute Innovation-to-Impact grant, and a Canadian Institutes of Health Research Foundation grant. The authors reported no conflicts of interest.

SOURCE: Feulner et al. Urol Onc. 2018 Nov 23. doi: 10.1016/j.urolonc.2018.11.006.

Older patients with ccRCC may respond better than younger patients to phosphoinositide 3-kinase (PI3K) or checkpoint inhibition because of age-related changes in gene expression, according to investigators.

This possibility was raised by in silico results from a broader study of gene expression patterns in clear cell renal carcinoma (ccRCC) and normal kidney tissues, reported lead author, Lara Feulner, MD, of the department of human genetics at McGill University and Genome Quebec Innovation Centre in Montreal.

“Several factors could contribute to the interindividual diversity among cancer patients,” the investigators wrote in a report published in Urologic Oncology.

“Their disease course could be affected not only by cell-intrinsic factors, but also by age-related changes impacting the vasculature, immune system and stroma. Little is known in this regard about ccRCC, a disease which affects adults across a wide age spectrum. Whether and how aging and comorbidities such as atherosclerosis may affect the biology and therapy of ccRCC has scarcely been considered,” they wrote.

The investigators explored this territory by analyzing datasets from The Cancer Genome Atlas (TCGA) and the Cancer Genomics of the Kidney (CAGEKID) program of the International Cancer Genome Consortium. Using regression, pathway enrichment, and connectivity mapping analyses, they were able to determine associations between age and gene expression, cellular processes, and drug treatment responses, respectively.

The investigators reported that age-related gene expression patterns occurred commonly in both normal and tumor tissues. Associations were reproducible between TCGA and CAGEKID datasets for both classes of tissue (tumor samples, R equal to 0.416, P less than 2.2 x 10-16; normal samples, R equal to 0.403, P less than 2.2 x 10-16). Out of the top 1,000 age-associated genes in tumor samples from each dataset, 383 were commonly downregulated with age and 294 were commonly upregulated with age in both datasets (P less than 2.2 x 10-16).

Among cellular pathways, the investigators found opposite age-relationship patterns. For example, normal tissues upregulated extracellular matrix and cell adhesion pathways with age, whereas tumor tissues downregulated the same pathways. Similar patterns of opposition were found in metabolism and oxidation pathways. Other age-related patterns were noted in some immune pathways, such as upregulation of toll-like receptor and tumor necrosis factor 2 noncanonical NF-kappa-B signaling in tumors, which became more common with age. A closer look showed that upregulation of tumor necrosis factor signaling was more common in female patients, who also downregulated Notch pathways more often than men.

Analysis of treatment responses showed possible relationships with age-dependent gene expression and immunotherapy. Specifically, of 532 genes tied to programmed cell death protein 1 (PD-1) resistance, 69 were among the 383 genes downregulated in older patients with ccRCC (P less than 2.2 x 10-16; 4.05 fold-enrichment), suggesting that older patients may respond better to anti-PD-1 therapy than younger patients. Similarly, connectivity map analysis showed that age-dependent gene expression may improve candidacy of older ccRCC patients for PI3K inhibition.

“We now have evidence that there are notable differences in tumor-associated pathway regulation between younger and older ccRCC patients, which may be therapeutically actionable,” the authors concluded.

The study was funded by the Cancer Research Society operation grant, a Canadian Cancer Society Research Institute Innovation-to-Impact grant, and a Canadian Institutes of Health Research Foundation grant. The authors reported no conflicts of interest.

SOURCE: Feulner et al. Urol Onc. 2018 Nov 23. doi: 10.1016/j.urolonc.2018.11.006.

SAN DIEGO – Two-thirds of adults with relapsed or refractory diffuse large B-cell lymphoma who had early responses to chimeric antigen receptor T-cell (CAR T) therapy with tisagenlecleucel (Kymriah) remain in remission with no evidence of minimal residual disease, according to an updated analysis of the JULIET trial.

In the single-arm, open-label trial, the overall response rate after 19 months of follow-up was 54%, including 40% complete remissions and 14% partial remissions. The median duration of response had not been reached at the time of data cutoff, and the median overall survival had not been reached for patients with a complete remission. Overall survival in this heavily pretreated population as a whole (all patients who received CAR T-cell infusions) was 11.1 months.

Adverse events were similar to those previously reported and were manageable, according to investigator Richard Thomas Maziarz, MD, from the Oregon Health & Science Knight Cancer Institute in Portland.

In this video interview at the annual meeting of the American Society of Hematology, Dr. Maziarz discusses the promising results using CAR T cells in this difficult to treat population.

SAN DIEGO – Two-thirds of adults with relapsed or refractory diffuse large B-cell lymphoma who had early responses to chimeric antigen receptor T-cell (CAR T) therapy with tisagenlecleucel (Kymriah) remain in remission with no evidence of minimal residual disease, according to an updated analysis of the JULIET trial.

In the single-arm, open-label trial, the overall response rate after 19 months of follow-up was 54%, including 40% complete remissions and 14% partial remissions. The median duration of response had not been reached at the time of data cutoff, and the median overall survival had not been reached for patients with a complete remission. Overall survival in this heavily pretreated population as a whole (all patients who received CAR T-cell infusions) was 11.1 months.

Adverse events were similar to those previously reported and were manageable, according to investigator Richard Thomas Maziarz, MD, from the Oregon Health & Science Knight Cancer Institute in Portland.

In this video interview at the annual meeting of the American Society of Hematology, Dr. Maziarz discusses the promising results using CAR T cells in this difficult to treat population.

SAN DIEGO – Two-thirds of adults with relapsed or refractory diffuse large B-cell lymphoma who had early responses to chimeric antigen receptor T-cell (CAR T) therapy with tisagenlecleucel (Kymriah) remain in remission with no evidence of minimal residual disease, according to an updated analysis of the JULIET trial.

In the single-arm, open-label trial, the overall response rate after 19 months of follow-up was 54%, including 40% complete remissions and 14% partial remissions. The median duration of response had not been reached at the time of data cutoff, and the median overall survival had not been reached for patients with a complete remission. Overall survival in this heavily pretreated population as a whole (all patients who received CAR T-cell infusions) was 11.1 months.

Adverse events were similar to those previously reported and were manageable, according to investigator Richard Thomas Maziarz, MD, from the Oregon Health & Science Knight Cancer Institute in Portland.

In this video interview at the annual meeting of the American Society of Hematology, Dr. Maziarz discusses the promising results using CAR T cells in this difficult to treat population.

SAN DIEGO – Diversity of the gut microbiome, sampled either before or after an allogeneic hematopoietic cell transplant (HCT), is predictive of overall survival.

A multinational study of intestinal microbiota in the United States, Europe, and Japan showed that in all four geographic regions patients scheduled for HCT had about a 100% lower median diversity of intestinal bacteria, compared with healthy volunteers, and that enterococcal species predominated in the transplant candidates, reported Jonathan U. Peled, MD, PhD, from the bone marrow transplantation service at Memorial Sloan Kettering Cancer Center in New York.

The investigators also found that intestinal microbial diversity was significantly associated with overall survival following an HCT.

In a video interview at the annual meeting of the American Society of Hematology, Dr. Peled elaborated on the study findings and described potential pre- and posttransplant interventions that could improve results and increase survival following HCT.

Dr. Peled reported current or prior relationships with Seres Therapeutics, the Parker Institute for Cancer Immunotherapy, and Merck/Society for Immunotherapy of Cancer.

SAN DIEGO – Diversity of the gut microbiome, sampled either before or after an allogeneic hematopoietic cell transplant (HCT), is predictive of overall survival.

A multinational study of intestinal microbiota in the United States, Europe, and Japan showed that in all four geographic regions patients scheduled for HCT had about a 100% lower median diversity of intestinal bacteria, compared with healthy volunteers, and that enterococcal species predominated in the transplant candidates, reported Jonathan U. Peled, MD, PhD, from the bone marrow transplantation service at Memorial Sloan Kettering Cancer Center in New York.

The investigators also found that intestinal microbial diversity was significantly associated with overall survival following an HCT.

In a video interview at the annual meeting of the American Society of Hematology, Dr. Peled elaborated on the study findings and described potential pre- and posttransplant interventions that could improve results and increase survival following HCT.

Dr. Peled reported current or prior relationships with Seres Therapeutics, the Parker Institute for Cancer Immunotherapy, and Merck/Society for Immunotherapy of Cancer.

SAN DIEGO – Diversity of the gut microbiome, sampled either before or after an allogeneic hematopoietic cell transplant (HCT), is predictive of overall survival.

A multinational study of intestinal microbiota in the United States, Europe, and Japan showed that in all four geographic regions patients scheduled for HCT had about a 100% lower median diversity of intestinal bacteria, compared with healthy volunteers, and that enterococcal species predominated in the transplant candidates, reported Jonathan U. Peled, MD, PhD, from the bone marrow transplantation service at Memorial Sloan Kettering Cancer Center in New York.

The investigators also found that intestinal microbial diversity was significantly associated with overall survival following an HCT.

In a video interview at the annual meeting of the American Society of Hematology, Dr. Peled elaborated on the study findings and described potential pre- and posttransplant interventions that could improve results and increase survival following HCT.

Dr. Peled reported current or prior relationships with Seres Therapeutics, the Parker Institute for Cancer Immunotherapy, and Merck/Society for Immunotherapy of Cancer.

WASHINGTON – Positron emission tomography (PET) using the CD8-tracer ⁸⁹Zr-IAB22M2C was safe and provided detailed whole-body information on the biodistribution of CD8 T-cells in advanced solid tumors and reference tissue in an open-label, phase 1, first-in-human study.

The findings demonstrate the ability of the tracer–an anti-CD8 zirconium-labeled minibody–to noninvasively detect CD8 distribution in patients with metastatic solid tumors, potentially providing more information – and more quickly – than is possible with a single biopsy, Michael S. Gordon, MD, reported during a late-breaking abstract session at the annual meeting of the Society for Immunotherapy of Cancer.

During a dose escalation period (stage 1) of the study, six patients received 3 mCi of ⁸⁹Zr-IAB22M2C once intravenously followed by serial PET scans over a period of 5-7 days. The patients received increasing protein doses of 0.2 through 10 mg to establish safety and determine a “recommended protein dose and scanning parameters for subsequent trials,” explained Dr. Gordon of HonorHealth Research Institute, Scottsdale, Ariz.

Stage 1 was followed by a dose expansion period (stage 2) in which an additional nine subjects were scanned to better delineate the recommended phase 2 study dose, he said.

All patients were monitored for drug-related adverse events and evaluated with blood chemistry, hematology, cytokine assay, and anti-drug antibodies. Biodistribution, radiodosimetry and semi-quantitative evaluation of CD8-tracer uptake were performed in all patients.

“We saw rapid clearance with excretion through the hepatobiliary mechanism, uptake in T-cell rich tissues, and no uptake in background normal tissues – so no uptake in muscle, heart, brain, or lungs,” he said, adding that “tumor uptake was variable and was clearly seen in 10 out of 15 patients.

“The protein dose that was considered to have favorable biodistribution was the range between 0.5 and 1.5, and based upon the analysis, the most favorable imaging time point ... was deemed to be 24 hours,” he said, noting that changes could be seen in as early as 6 hours.

SOURCE: Gordon M et al., SITC 2018: Abstract LB49.

WASHINGTON – Positron emission tomography (PET) using the CD8-tracer ⁸⁹Zr-IAB22M2C was safe and provided detailed whole-body information on the biodistribution of CD8 T-cells in advanced solid tumors and reference tissue in an open-label, phase 1, first-in-human study.

The findings demonstrate the ability of the tracer–an anti-CD8 zirconium-labeled minibody–to noninvasively detect CD8 distribution in patients with metastatic solid tumors, potentially providing more information – and more quickly – than is possible with a single biopsy, Michael S. Gordon, MD, reported during a late-breaking abstract session at the annual meeting of the Society for Immunotherapy of Cancer.

During a dose escalation period (stage 1) of the study, six patients received 3 mCi of ⁸⁹Zr-IAB22M2C once intravenously followed by serial PET scans over a period of 5-7 days. The patients received increasing protein doses of 0.2 through 10 mg to establish safety and determine a “recommended protein dose and scanning parameters for subsequent trials,” explained Dr. Gordon of HonorHealth Research Institute, Scottsdale, Ariz.

Stage 1 was followed by a dose expansion period (stage 2) in which an additional nine subjects were scanned to better delineate the recommended phase 2 study dose, he said.

All patients were monitored for drug-related adverse events and evaluated with blood chemistry, hematology, cytokine assay, and anti-drug antibodies. Biodistribution, radiodosimetry and semi-quantitative evaluation of CD8-tracer uptake were performed in all patients.

“We saw rapid clearance with excretion through the hepatobiliary mechanism, uptake in T-cell rich tissues, and no uptake in background normal tissues – so no uptake in muscle, heart, brain, or lungs,” he said, adding that “tumor uptake was variable and was clearly seen in 10 out of 15 patients.

“The protein dose that was considered to have favorable biodistribution was the range between 0.5 and 1.5, and based upon the analysis, the most favorable imaging time point ... was deemed to be 24 hours,” he said, noting that changes could be seen in as early as 6 hours.

SOURCE: Gordon M et al., SITC 2018: Abstract LB49.

WASHINGTON – Positron emission tomography (PET) using the CD8-tracer ⁸⁹Zr-IAB22M2C was safe and provided detailed whole-body information on the biodistribution of CD8 T-cells in advanced solid tumors and reference tissue in an open-label, phase 1, first-in-human study.

The findings demonstrate the ability of the tracer–an anti-CD8 zirconium-labeled minibody–to noninvasively detect CD8 distribution in patients with metastatic solid tumors, potentially providing more information – and more quickly – than is possible with a single biopsy, Michael S. Gordon, MD, reported during a late-breaking abstract session at the annual meeting of the Society for Immunotherapy of Cancer.

During a dose escalation period (stage 1) of the study, six patients received 3 mCi of ⁸⁹Zr-IAB22M2C once intravenously followed by serial PET scans over a period of 5-7 days. The patients received increasing protein doses of 0.2 through 10 mg to establish safety and determine a “recommended protein dose and scanning parameters for subsequent trials,” explained Dr. Gordon of HonorHealth Research Institute, Scottsdale, Ariz.

Stage 1 was followed by a dose expansion period (stage 2) in which an additional nine subjects were scanned to better delineate the recommended phase 2 study dose, he said.

All patients were monitored for drug-related adverse events and evaluated with blood chemistry, hematology, cytokine assay, and anti-drug antibodies. Biodistribution, radiodosimetry and semi-quantitative evaluation of CD8-tracer uptake were performed in all patients.

“We saw rapid clearance with excretion through the hepatobiliary mechanism, uptake in T-cell rich tissues, and no uptake in background normal tissues – so no uptake in muscle, heart, brain, or lungs,” he said, adding that “tumor uptake was variable and was clearly seen in 10 out of 15 patients.

“The protein dose that was considered to have favorable biodistribution was the range between 0.5 and 1.5, and based upon the analysis, the most favorable imaging time point ... was deemed to be 24 hours,” he said, noting that changes could be seen in as early as 6 hours.

SOURCE: Gordon M et al., SITC 2018: Abstract LB49.

WASHINGTON – Combination lenvatinib and pembrolizumab shows promising clinical activity and a manageable safety profile in previously treated patients with confirmed, measurable, metastatic non–small cell lung cancer (NSCLC), according to interim findings from a phase 1b/2 study.

Sharon Worcester/MDedge News

Of note, the 21 patients enrolled in the multicenter, open-label study as of March 2018 were not preselected for programmed death-ligand 1 (PD-L1) tumor expression status, Marcia S. Brose, MD, reported at the annual meeting of the Society for the Immunotherapy of Cancer.

They were treated with 20 mg of oral lenvatinib daily and 200 mg of intravenous pembrolizumab every 3 weeks, and the overall response rate at 24 weeks – the primary endpoint of the study – was 33.3%, said Dr. Brose of Abramson Cancer Center of the University of Pennsylvania, Philadelphia.

One patient had a complete response, six had a partial response, 10 had stable disease, two progressed on treatment, and the outcome in two was unknown or not evaluable, for an overall clinical benefit rate of 66%, she said, adding that the median duration of response was 10.9 months and median progression-free survival (PFS) was 5.9 months.

All patients had good performance status (ECOG score of 0-1), and nine (43%) were PD-L1–positive as defined by a tumor proportion score of at least 1%, five (24%) were PD-L1-negative, and seven (33%) were not tested for PD-L1 status. Three (14%) were treatment naive, while seven (33%), 10 (48%), and one (5%) had received one, two, or three or more prior lines of systemic therapy, respectively. No prior nivolumab or pembrolizumab treatment was allowed.

“At least one of the patients who was PD-L1–negative remained on study after 40 weeks and still continuing to respond, and ... the PD-L1–positive patients were also doing well,” Dr. Brose said.

Tumor assessments were performed by study investigators using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).

Grade 3 or greater treatment-related adverse events occurred in 10 patients (48%), and mainly included hypertension, fatigue, and diarrhea, but only four were considered serious treatment-related adverse events. Nineteen patients had treatment adjustments because of adverse events, four discontinued treatment due to adverse events, and one patient died from a pulmonary hemorrhage that was thought to possibly be treatment related, Dr. Brose said.

“The toxicity is really what you would have expected from either of these drugs on their own; it didn’t seem like there was anything that happened in synergy from the two that was unexpected,” she noted.

Lenvatinib is a multikinase inhibitor of vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor receptors (FGFR) 1-4, platelet-derived growth factor receptor (PDGFR) alpha, and the RET and c-KIT proto-oncogenes. Pembrolizumab is an anti–PD-1 antibody approved as a monotherapy for previously treated patients with metastatic PD-L1–positive NSCLC, and it has been shown to be associated with an overall response rate of 18%, she explained.

The current results are from the NSCLC cohort of an ongoing trial of lenvatinib plus pembrolizumab in patients with solid tumors.

“Further investigation of this study drug combination in patients is warranted, but we will have to think carefully about what point in the treatment paradigm these patients should be treated in order to maximize the benefit from this combination therapy,” she concluded.

Dr. Brose has received consulting fees, research grants, and honorarium from Eisai.

SOURCE: Brose M et al. SITC 2018, Abstract P392.

WASHINGTON – Combination lenvatinib and pembrolizumab shows promising clinical activity and a manageable safety profile in previously treated patients with confirmed, measurable, metastatic non–small cell lung cancer (NSCLC), according to interim findings from a phase 1b/2 study.

Sharon Worcester/MDedge News

Of note, the 21 patients enrolled in the multicenter, open-label study as of March 2018 were not preselected for programmed death-ligand 1 (PD-L1) tumor expression status, Marcia S. Brose, MD, reported at the annual meeting of the Society for the Immunotherapy of Cancer.

They were treated with 20 mg of oral lenvatinib daily and 200 mg of intravenous pembrolizumab every 3 weeks, and the overall response rate at 24 weeks – the primary endpoint of the study – was 33.3%, said Dr. Brose of Abramson Cancer Center of the University of Pennsylvania, Philadelphia.

One patient had a complete response, six had a partial response, 10 had stable disease, two progressed on treatment, and the outcome in two was unknown or not evaluable, for an overall clinical benefit rate of 66%, she said, adding that the median duration of response was 10.9 months and median progression-free survival (PFS) was 5.9 months.

All patients had good performance status (ECOG score of 0-1), and nine (43%) were PD-L1–positive as defined by a tumor proportion score of at least 1%, five (24%) were PD-L1-negative, and seven (33%) were not tested for PD-L1 status. Three (14%) were treatment naive, while seven (33%), 10 (48%), and one (5%) had received one, two, or three or more prior lines of systemic therapy, respectively. No prior nivolumab or pembrolizumab treatment was allowed.

“At least one of the patients who was PD-L1–negative remained on study after 40 weeks and still continuing to respond, and ... the PD-L1–positive patients were also doing well,” Dr. Brose said.

Tumor assessments were performed by study investigators using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).

Grade 3 or greater treatment-related adverse events occurred in 10 patients (48%), and mainly included hypertension, fatigue, and diarrhea, but only four were considered serious treatment-related adverse events. Nineteen patients had treatment adjustments because of adverse events, four discontinued treatment due to adverse events, and one patient died from a pulmonary hemorrhage that was thought to possibly be treatment related, Dr. Brose said.

“The toxicity is really what you would have expected from either of these drugs on their own; it didn’t seem like there was anything that happened in synergy from the two that was unexpected,” she noted.

Lenvatinib is a multikinase inhibitor of vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor receptors (FGFR) 1-4, platelet-derived growth factor receptor (PDGFR) alpha, and the RET and c-KIT proto-oncogenes. Pembrolizumab is an anti–PD-1 antibody approved as a monotherapy for previously treated patients with metastatic PD-L1–positive NSCLC, and it has been shown to be associated with an overall response rate of 18%, she explained.

The current results are from the NSCLC cohort of an ongoing trial of lenvatinib plus pembrolizumab in patients with solid tumors.

“Further investigation of this study drug combination in patients is warranted, but we will have to think carefully about what point in the treatment paradigm these patients should be treated in order to maximize the benefit from this combination therapy,” she concluded.

Dr. Brose has received consulting fees, research grants, and honorarium from Eisai.

SOURCE: Brose M et al. SITC 2018, Abstract P392.

WASHINGTON – Combination lenvatinib and pembrolizumab shows promising clinical activity and a manageable safety profile in previously treated patients with confirmed, measurable, metastatic non–small cell lung cancer (NSCLC), according to interim findings from a phase 1b/2 study.

Sharon Worcester/MDedge News

Of note, the 21 patients enrolled in the multicenter, open-label study as of March 2018 were not preselected for programmed death-ligand 1 (PD-L1) tumor expression status, Marcia S. Brose, MD, reported at the annual meeting of the Society for the Immunotherapy of Cancer.

They were treated with 20 mg of oral lenvatinib daily and 200 mg of intravenous pembrolizumab every 3 weeks, and the overall response rate at 24 weeks – the primary endpoint of the study – was 33.3%, said Dr. Brose of Abramson Cancer Center of the University of Pennsylvania, Philadelphia.

One patient had a complete response, six had a partial response, 10 had stable disease, two progressed on treatment, and the outcome in two was unknown or not evaluable, for an overall clinical benefit rate of 66%, she said, adding that the median duration of response was 10.9 months and median progression-free survival (PFS) was 5.9 months.

All patients had good performance status (ECOG score of 0-1), and nine (43%) were PD-L1–positive as defined by a tumor proportion score of at least 1%, five (24%) were PD-L1-negative, and seven (33%) were not tested for PD-L1 status. Three (14%) were treatment naive, while seven (33%), 10 (48%), and one (5%) had received one, two, or three or more prior lines of systemic therapy, respectively. No prior nivolumab or pembrolizumab treatment was allowed.

“At least one of the patients who was PD-L1–negative remained on study after 40 weeks and still continuing to respond, and ... the PD-L1–positive patients were also doing well,” Dr. Brose said.

Tumor assessments were performed by study investigators using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).

Grade 3 or greater treatment-related adverse events occurred in 10 patients (48%), and mainly included hypertension, fatigue, and diarrhea, but only four were considered serious treatment-related adverse events. Nineteen patients had treatment adjustments because of adverse events, four discontinued treatment due to adverse events, and one patient died from a pulmonary hemorrhage that was thought to possibly be treatment related, Dr. Brose said.

“The toxicity is really what you would have expected from either of these drugs on their own; it didn’t seem like there was anything that happened in synergy from the two that was unexpected,” she noted.

Lenvatinib is a multikinase inhibitor of vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor receptors (FGFR) 1-4, platelet-derived growth factor receptor (PDGFR) alpha, and the RET and c-KIT proto-oncogenes. Pembrolizumab is an anti–PD-1 antibody approved as a monotherapy for previously treated patients with metastatic PD-L1–positive NSCLC, and it has been shown to be associated with an overall response rate of 18%, she explained.

The current results are from the NSCLC cohort of an ongoing trial of lenvatinib plus pembrolizumab in patients with solid tumors.

“Further investigation of this study drug combination in patients is warranted, but we will have to think carefully about what point in the treatment paradigm these patients should be treated in order to maximize the benefit from this combination therapy,” she concluded.

Dr. Brose has received consulting fees, research grants, and honorarium from Eisai.

SOURCE: Brose M et al. SITC 2018, Abstract P392.