Immuno-oncology

CHICAGO – Adjuvant pembrolizumab for resected high-risk melanoma slowed the rate of recurrence or death by 43% compared with placebo in a phase 3 trial of 1,519 patients.

After 15 months of follow-up, 12-month rates of recurrence-free survival (RFS) were 75% for pembrolizumab and 61% for placebo (hazard ratio, 0.57; P less than .001), Alexander M.M. Eggermont, MD, PhD, reported at the annual meeting of the American Association for Cancer Research.

By 18 months, the RFS difference between the arms had widened even more (71% versus 53%), Dr. Eggermont and his associates said at the meeting. The report was published simultaneously in the New England Journal of Medicine.

Adjuvant pembrolizumab was effective irrespective of PD-L1 tumor expression status. In a subgroup of more than 800 patients with PD-L1-positive tumors, 12-month RFS rates were 77% for pembrolizumab and 63% for placebo (HR, 0.54; 95% CI, 0.42 to 0.69; P less than .001). Among 116 patients who were PD-L1-negative, these rates were 72% and 52%, respectively (HR, 0.47; P = .01).

Treatment produced no new safety signals, said Dr. Eggermont of Gustave Roussy Cancer Campus Grand Paris and University Paris-Saclay, Villejuif, France. Grade 3 or higher toxicities affected 15% of pembrolizumab patients. Myositis caused one pembrolizumab-related death.

The findings bolster data suggesting that adjuvant therapy can stop or delay recurrence in resected high-risk melanoma. Previously, adjuvant ipilimumab was approved after significantly extending RFS and overall survival in the placebo-controlled European Organization for Research and Treatment of Cancer 18071 trial. More recently, adjuvant dabrafenib plus trametinib reduced the risk of recurrence compared with placebo in completely resected stage III melanoma with BRAF mutations (COMBI-AD), and adjuvant nivolumab significantly improved RFS and was less toxic than was ipilimumab in patients with advanced resected BRAF-mutated and BRAF-wild-type melanomas (CheckMate 238).

SOURCE: Eggermont AMM et al. AACR Annual Meeting Abstract CT001.

CHICAGO – Adjuvant pembrolizumab for resected high-risk melanoma slowed the rate of recurrence or death by 43% compared with placebo in a phase 3 trial of 1,519 patients.

After 15 months of follow-up, 12-month rates of recurrence-free survival (RFS) were 75% for pembrolizumab and 61% for placebo (hazard ratio, 0.57; P less than .001), Alexander M.M. Eggermont, MD, PhD, reported at the annual meeting of the American Association for Cancer Research.

By 18 months, the RFS difference between the arms had widened even more (71% versus 53%), Dr. Eggermont and his associates said at the meeting. The report was published simultaneously in the New England Journal of Medicine.

Adjuvant pembrolizumab was effective irrespective of PD-L1 tumor expression status. In a subgroup of more than 800 patients with PD-L1-positive tumors, 12-month RFS rates were 77% for pembrolizumab and 63% for placebo (HR, 0.54; 95% CI, 0.42 to 0.69; P less than .001). Among 116 patients who were PD-L1-negative, these rates were 72% and 52%, respectively (HR, 0.47; P = .01).

Treatment produced no new safety signals, said Dr. Eggermont of Gustave Roussy Cancer Campus Grand Paris and University Paris-Saclay, Villejuif, France. Grade 3 or higher toxicities affected 15% of pembrolizumab patients. Myositis caused one pembrolizumab-related death.

The findings bolster data suggesting that adjuvant therapy can stop or delay recurrence in resected high-risk melanoma. Previously, adjuvant ipilimumab was approved after significantly extending RFS and overall survival in the placebo-controlled European Organization for Research and Treatment of Cancer 18071 trial. More recently, adjuvant dabrafenib plus trametinib reduced the risk of recurrence compared with placebo in completely resected stage III melanoma with BRAF mutations (COMBI-AD), and adjuvant nivolumab significantly improved RFS and was less toxic than was ipilimumab in patients with advanced resected BRAF-mutated and BRAF-wild-type melanomas (CheckMate 238).

SOURCE: Eggermont AMM et al. AACR Annual Meeting Abstract CT001.

CHICAGO – Adjuvant pembrolizumab for resected high-risk melanoma slowed the rate of recurrence or death by 43% compared with placebo in a phase 3 trial of 1,519 patients.

After 15 months of follow-up, 12-month rates of recurrence-free survival (RFS) were 75% for pembrolizumab and 61% for placebo (hazard ratio, 0.57; P less than .001), Alexander M.M. Eggermont, MD, PhD, reported at the annual meeting of the American Association for Cancer Research.

By 18 months, the RFS difference between the arms had widened even more (71% versus 53%), Dr. Eggermont and his associates said at the meeting. The report was published simultaneously in the New England Journal of Medicine.

Adjuvant pembrolizumab was effective irrespective of PD-L1 tumor expression status. In a subgroup of more than 800 patients with PD-L1-positive tumors, 12-month RFS rates were 77% for pembrolizumab and 63% for placebo (HR, 0.54; 95% CI, 0.42 to 0.69; P less than .001). Among 116 patients who were PD-L1-negative, these rates were 72% and 52%, respectively (HR, 0.47; P = .01).

Treatment produced no new safety signals, said Dr. Eggermont of Gustave Roussy Cancer Campus Grand Paris and University Paris-Saclay, Villejuif, France. Grade 3 or higher toxicities affected 15% of pembrolizumab patients. Myositis caused one pembrolizumab-related death.

The findings bolster data suggesting that adjuvant therapy can stop or delay recurrence in resected high-risk melanoma. Previously, adjuvant ipilimumab was approved after significantly extending RFS and overall survival in the placebo-controlled European Organization for Research and Treatment of Cancer 18071 trial. More recently, adjuvant dabrafenib plus trametinib reduced the risk of recurrence compared with placebo in completely resected stage III melanoma with BRAF mutations (COMBI-AD), and adjuvant nivolumab significantly improved RFS and was less toxic than was ipilimumab in patients with advanced resected BRAF-mutated and BRAF-wild-type melanomas (CheckMate 238).

SOURCE: Eggermont AMM et al. AACR Annual Meeting Abstract CT001.

After treatment with blinatumomab, most patients with minimal residual disease–positive acute lymphoblastic leukemia (ALL) achieved complete MRD response, according to results of a single-arm phase 2 study.

Achieving complete MRD response was associated with significantly longer relapse-free and overall survival in the patients, who were already in hematologic complete remission, researchers reported in the journal Blood.

“Our results suggest that targeted treatment in early stages of MRD is a viable therapeutic strategy for patients with B-cell precursor ALL and that it should also be evaluated in other hematologic malignancies,” Nicola Gökbuget, MD, University Hospital, Frankfurt, Germany, and her coauthors wrote.

This is the first international multicenter study to specifically enroll MRD-positive ALL patients and evaluate them for an MRD-based primary outcome in a cohort of MRD-positive ALL patients, according to the authors.

Preemptively treating low but measurable disease in ALL in remission, instead of waiting for overt relapse, is a strategy that may prolong overall survival, Dr. Gökbuget and her colleagues said in describing the rationale for their study. While there is no standard therapy yet for ALL patients with detectable MRD after intensive chemotherapy, hematopoietic stem cell transplantation (HSCT) is recommended, based on data that it may improve outcomes in patients with persistent MRD. However, other studies suggest detectable MRD before HSCT is associated with higher relapse rates, and many patients relapse while waiting for HSCT, the researchers noted.

To test an MRD-directed treatment strategy, Dr. Gökbuget and colleagues at 46 centers in Europe and Russia conducted an open-label, single-arm, phase 2 study including 116 patients with B-cell precursor ALL in hematologic complete remission. Patients in the study received up to four cycles of blinatumomab, a bispecific, T cell–engager antibody construct that enables T cells to recognize and eliminate CD19-positive cells.

Of 113 evaluable patients, 88 (78%) achieved complete MRD response after one cycle, the primary end point of the study. Relapse-free survival at 18 months was estimated at 54% and median overall survival was 36.5 months in the subset of 110 patients with Philadelphia chromosome–negative ALL in hematologic remission.

SOURCE: Gökbuget N et al. Blood. 2018 Apr 5;131(14):1522-31.

After treatment with blinatumomab, most patients with minimal residual disease–positive acute lymphoblastic leukemia (ALL) achieved complete MRD response, according to results of a single-arm phase 2 study.

Achieving complete MRD response was associated with significantly longer relapse-free and overall survival in the patients, who were already in hematologic complete remission, researchers reported in the journal Blood.

“Our results suggest that targeted treatment in early stages of MRD is a viable therapeutic strategy for patients with B-cell precursor ALL and that it should also be evaluated in other hematologic malignancies,” Nicola Gökbuget, MD, University Hospital, Frankfurt, Germany, and her coauthors wrote.

This is the first international multicenter study to specifically enroll MRD-positive ALL patients and evaluate them for an MRD-based primary outcome in a cohort of MRD-positive ALL patients, according to the authors.

Preemptively treating low but measurable disease in ALL in remission, instead of waiting for overt relapse, is a strategy that may prolong overall survival, Dr. Gökbuget and her colleagues said in describing the rationale for their study. While there is no standard therapy yet for ALL patients with detectable MRD after intensive chemotherapy, hematopoietic stem cell transplantation (HSCT) is recommended, based on data that it may improve outcomes in patients with persistent MRD. However, other studies suggest detectable MRD before HSCT is associated with higher relapse rates, and many patients relapse while waiting for HSCT, the researchers noted.

To test an MRD-directed treatment strategy, Dr. Gökbuget and colleagues at 46 centers in Europe and Russia conducted an open-label, single-arm, phase 2 study including 116 patients with B-cell precursor ALL in hematologic complete remission. Patients in the study received up to four cycles of blinatumomab, a bispecific, T cell–engager antibody construct that enables T cells to recognize and eliminate CD19-positive cells.

Of 113 evaluable patients, 88 (78%) achieved complete MRD response after one cycle, the primary end point of the study. Relapse-free survival at 18 months was estimated at 54% and median overall survival was 36.5 months in the subset of 110 patients with Philadelphia chromosome–negative ALL in hematologic remission.

SOURCE: Gökbuget N et al. Blood. 2018 Apr 5;131(14):1522-31.

After treatment with blinatumomab, most patients with minimal residual disease–positive acute lymphoblastic leukemia (ALL) achieved complete MRD response, according to results of a single-arm phase 2 study.

Achieving complete MRD response was associated with significantly longer relapse-free and overall survival in the patients, who were already in hematologic complete remission, researchers reported in the journal Blood.

“Our results suggest that targeted treatment in early stages of MRD is a viable therapeutic strategy for patients with B-cell precursor ALL and that it should also be evaluated in other hematologic malignancies,” Nicola Gökbuget, MD, University Hospital, Frankfurt, Germany, and her coauthors wrote.

This is the first international multicenter study to specifically enroll MRD-positive ALL patients and evaluate them for an MRD-based primary outcome in a cohort of MRD-positive ALL patients, according to the authors.

Preemptively treating low but measurable disease in ALL in remission, instead of waiting for overt relapse, is a strategy that may prolong overall survival, Dr. Gökbuget and her colleagues said in describing the rationale for their study. While there is no standard therapy yet for ALL patients with detectable MRD after intensive chemotherapy, hematopoietic stem cell transplantation (HSCT) is recommended, based on data that it may improve outcomes in patients with persistent MRD. However, other studies suggest detectable MRD before HSCT is associated with higher relapse rates, and many patients relapse while waiting for HSCT, the researchers noted.

To test an MRD-directed treatment strategy, Dr. Gökbuget and colleagues at 46 centers in Europe and Russia conducted an open-label, single-arm, phase 2 study including 116 patients with B-cell precursor ALL in hematologic complete remission. Patients in the study received up to four cycles of blinatumomab, a bispecific, T cell–engager antibody construct that enables T cells to recognize and eliminate CD19-positive cells.

Of 113 evaluable patients, 88 (78%) achieved complete MRD response after one cycle, the primary end point of the study. Relapse-free survival at 18 months was estimated at 54% and median overall survival was 36.5 months in the subset of 110 patients with Philadelphia chromosome–negative ALL in hematologic remission.

SOURCE: Gökbuget N et al. Blood. 2018 Apr 5;131(14):1522-31.

CHICAGO – Surgical resection is an effective treatment in selected patients with advanced melanoma treated with checkpoint blockade immunotherapy, according to a study of an institutional database at Memorial Sloan Kettering Cancer Center in New York presented at the Society of Surgical Oncology Annual Cancer Symposium.

“In the era of improved systemic therapy, checkpoint blockade for metastatic melanoma and the ability to surgically resect all disease after treatment is associated with an estimated survival of 75%, better than what’s been previously reported,” said Danielle M. Bello, MD, of Memorial Sloan Kettering.

The study analyzed a cohort of 237 patients who had unresectable stage III and IV melanoma and were treated with checkpoint blockade, including CTLA-4, programmed cell death protein 1 (PD-1), and programmed death-ligand 1 inhibitors, and then had surgical resection during 2003-2017.

Dr. Bello noted two previous studies that had reported encouraging outcomes in advanced melanoma. The first highlighted the role for surgery in stage IV melanoma. In that phase 3 clinical trial, patients had resection of up to five sites of metastatic disease and were then randomized to one of two treatment arms: bacillus Calmette-Guérin and allogeneic whole-cell vaccine (Canvaxin) or bacillus Calmette-Guérin and placebo. While this trial found no difference in overall survival between groups, it did report a 5-year overall survival exceeding 40% in both treatment arms, which highlighted that Stage IV patients who underwent resection of all their disease had survival outcomes superior to outcomes previously reported (Ann Surg Onc. 2017 Dec;24[13]:3991-4000). The second trial, the recent Checkmate 067 trial, emphasized the role of effective systemic checkpoint blockade in advanced stage III and IV melanoma. It reported that patients treated with combined nivolumab/ipilimumab therapy had not reached median overall survival at minimum 36 months of follow-up (N Engl J Med. 2017 Oct 5;377[14]:1345-56).

“We know that checkpoint inhibitor therapy has revolutionized the landscape of unresectable stage III and IV melanoma,” Dr. Bello said. However, despite encouraging trial readouts of overall survival, progression-free survival is a different story. “We know that the median progression-free survival even in our best combination therapy is 11.5 months, meaning that 50% of patients will go on to progress in a year and many will go on to surgical resection of their disease and do quite well,” she said.

Dr. Bello and her coauthors set out to describe outcomes of a “highly selective group” of patients who had surgical resection after checkpoint inhibitor therapy. “The majority of patients in our study had a cutaneous primary melanoma,” she said. Median age was 63 years, and 88% had stage IV disease. Regarding checkpoint blockade regimen, 62% received anti–CTLA-4, and 29% received combination anti–PD-1 and anti–CLTA-4 either sequentially or concomitantly prior to resection.

The median time from the start of immunotherapy to the first operation was 7 months. Forty-six percent had no further postoperative treatment after resection. In those, who did require further treatment, the majority received anti–PD-1 followed by targeted BRAF/MEK therapy, she said.

The analysis stratified patients into the following three categories based on radiological response to immunotherapy:

• Overall response to checkpoint blockade and the index lesion was either smaller since initiation of therapy or stabilized (12; 5.1%). Half of this group had a pathological complete response.
• Isolated site of progressive disease with residual stable disease elsewhere or as the only site of progressive disease (106; 44.7%).
• Multiple sites of progressive and palliative operations (119; 50.2%).

Median overall survival was 21 months in the entire study cohort with a median follow-up of 23 months, Dr. Bello said. “Those resected to no evidence of disease (NED) – 87 patients – had an estimated 5-year overall survival of 75%.” The NED group did not reach median OS.

The analysis also stratified overall survival by response to immunotherapy. “Patients with responding or stable disease had an estimated 90% 5-year overall survival,” Dr. Bellow said. “Those with one isolated progressive lesion that was resected had a 60% 5-year overall survival.” A more detailed analysis of the latter group found that those who had a resection to NED had an improved overall survival of 75% at 5 years. Resected patients who had residual remaining disease had a 30% 5-year overall survival.

“Further follow-up is needed to assess the durability and contributions of surgery, and further studies are underway to identify biomarkers associated with improved survival after immunotherapy and surgery,” Dr. Bello said.

SOURCE: Bello DM et al. SSO 2018, Abstract 5.

CHICAGO – Surgical resection is an effective treatment in selected patients with advanced melanoma treated with checkpoint blockade immunotherapy, according to a study of an institutional database at Memorial Sloan Kettering Cancer Center in New York presented at the Society of Surgical Oncology Annual Cancer Symposium.

“In the era of improved systemic therapy, checkpoint blockade for metastatic melanoma and the ability to surgically resect all disease after treatment is associated with an estimated survival of 75%, better than what’s been previously reported,” said Danielle M. Bello, MD, of Memorial Sloan Kettering.

The study analyzed a cohort of 237 patients who had unresectable stage III and IV melanoma and were treated with checkpoint blockade, including CTLA-4, programmed cell death protein 1 (PD-1), and programmed death-ligand 1 inhibitors, and then had surgical resection during 2003-2017.

Dr. Bello noted two previous studies that had reported encouraging outcomes in advanced melanoma. The first highlighted the role for surgery in stage IV melanoma. In that phase 3 clinical trial, patients had resection of up to five sites of metastatic disease and were then randomized to one of two treatment arms: bacillus Calmette-Guérin and allogeneic whole-cell vaccine (Canvaxin) or bacillus Calmette-Guérin and placebo. While this trial found no difference in overall survival between groups, it did report a 5-year overall survival exceeding 40% in both treatment arms, which highlighted that Stage IV patients who underwent resection of all their disease had survival outcomes superior to outcomes previously reported (Ann Surg Onc. 2017 Dec;24[13]:3991-4000). The second trial, the recent Checkmate 067 trial, emphasized the role of effective systemic checkpoint blockade in advanced stage III and IV melanoma. It reported that patients treated with combined nivolumab/ipilimumab therapy had not reached median overall survival at minimum 36 months of follow-up (N Engl J Med. 2017 Oct 5;377[14]:1345-56).

“We know that checkpoint inhibitor therapy has revolutionized the landscape of unresectable stage III and IV melanoma,” Dr. Bello said. However, despite encouraging trial readouts of overall survival, progression-free survival is a different story. “We know that the median progression-free survival even in our best combination therapy is 11.5 months, meaning that 50% of patients will go on to progress in a year and many will go on to surgical resection of their disease and do quite well,” she said.

Dr. Bello and her coauthors set out to describe outcomes of a “highly selective group” of patients who had surgical resection after checkpoint inhibitor therapy. “The majority of patients in our study had a cutaneous primary melanoma,” she said. Median age was 63 years, and 88% had stage IV disease. Regarding checkpoint blockade regimen, 62% received anti–CTLA-4, and 29% received combination anti–PD-1 and anti–CLTA-4 either sequentially or concomitantly prior to resection.

The median time from the start of immunotherapy to the first operation was 7 months. Forty-six percent had no further postoperative treatment after resection. In those, who did require further treatment, the majority received anti–PD-1 followed by targeted BRAF/MEK therapy, she said.

The analysis stratified patients into the following three categories based on radiological response to immunotherapy:

• Overall response to checkpoint blockade and the index lesion was either smaller since initiation of therapy or stabilized (12; 5.1%). Half of this group had a pathological complete response.
• Isolated site of progressive disease with residual stable disease elsewhere or as the only site of progressive disease (106; 44.7%).
• Multiple sites of progressive and palliative operations (119; 50.2%).

Median overall survival was 21 months in the entire study cohort with a median follow-up of 23 months, Dr. Bello said. “Those resected to no evidence of disease (NED) – 87 patients – had an estimated 5-year overall survival of 75%.” The NED group did not reach median OS.

The analysis also stratified overall survival by response to immunotherapy. “Patients with responding or stable disease had an estimated 90% 5-year overall survival,” Dr. Bellow said. “Those with one isolated progressive lesion that was resected had a 60% 5-year overall survival.” A more detailed analysis of the latter group found that those who had a resection to NED had an improved overall survival of 75% at 5 years. Resected patients who had residual remaining disease had a 30% 5-year overall survival.

“Further follow-up is needed to assess the durability and contributions of surgery, and further studies are underway to identify biomarkers associated with improved survival after immunotherapy and surgery,” Dr. Bello said.

SOURCE: Bello DM et al. SSO 2018, Abstract 5.

CHICAGO – Surgical resection is an effective treatment in selected patients with advanced melanoma treated with checkpoint blockade immunotherapy, according to a study of an institutional database at Memorial Sloan Kettering Cancer Center in New York presented at the Society of Surgical Oncology Annual Cancer Symposium.

“In the era of improved systemic therapy, checkpoint blockade for metastatic melanoma and the ability to surgically resect all disease after treatment is associated with an estimated survival of 75%, better than what’s been previously reported,” said Danielle M. Bello, MD, of Memorial Sloan Kettering.

The study analyzed a cohort of 237 patients who had unresectable stage III and IV melanoma and were treated with checkpoint blockade, including CTLA-4, programmed cell death protein 1 (PD-1), and programmed death-ligand 1 inhibitors, and then had surgical resection during 2003-2017.

Dr. Bello noted two previous studies that had reported encouraging outcomes in advanced melanoma. The first highlighted the role for surgery in stage IV melanoma. In that phase 3 clinical trial, patients had resection of up to five sites of metastatic disease and were then randomized to one of two treatment arms: bacillus Calmette-Guérin and allogeneic whole-cell vaccine (Canvaxin) or bacillus Calmette-Guérin and placebo. While this trial found no difference in overall survival between groups, it did report a 5-year overall survival exceeding 40% in both treatment arms, which highlighted that Stage IV patients who underwent resection of all their disease had survival outcomes superior to outcomes previously reported (Ann Surg Onc. 2017 Dec;24[13]:3991-4000). The second trial, the recent Checkmate 067 trial, emphasized the role of effective systemic checkpoint blockade in advanced stage III and IV melanoma. It reported that patients treated with combined nivolumab/ipilimumab therapy had not reached median overall survival at minimum 36 months of follow-up (N Engl J Med. 2017 Oct 5;377[14]:1345-56).

“We know that checkpoint inhibitor therapy has revolutionized the landscape of unresectable stage III and IV melanoma,” Dr. Bello said. However, despite encouraging trial readouts of overall survival, progression-free survival is a different story. “We know that the median progression-free survival even in our best combination therapy is 11.5 months, meaning that 50% of patients will go on to progress in a year and many will go on to surgical resection of their disease and do quite well,” she said.

Dr. Bello and her coauthors set out to describe outcomes of a “highly selective group” of patients who had surgical resection after checkpoint inhibitor therapy. “The majority of patients in our study had a cutaneous primary melanoma,” she said. Median age was 63 years, and 88% had stage IV disease. Regarding checkpoint blockade regimen, 62% received anti–CTLA-4, and 29% received combination anti–PD-1 and anti–CLTA-4 either sequentially or concomitantly prior to resection.

The median time from the start of immunotherapy to the first operation was 7 months. Forty-six percent had no further postoperative treatment after resection. In those, who did require further treatment, the majority received anti–PD-1 followed by targeted BRAF/MEK therapy, she said.

The analysis stratified patients into the following three categories based on radiological response to immunotherapy:

• Overall response to checkpoint blockade and the index lesion was either smaller since initiation of therapy or stabilized (12; 5.1%). Half of this group had a pathological complete response.
• Isolated site of progressive disease with residual stable disease elsewhere or as the only site of progressive disease (106; 44.7%).
• Multiple sites of progressive and palliative operations (119; 50.2%).

Median overall survival was 21 months in the entire study cohort with a median follow-up of 23 months, Dr. Bello said. “Those resected to no evidence of disease (NED) – 87 patients – had an estimated 5-year overall survival of 75%.” The NED group did not reach median OS.

The analysis also stratified overall survival by response to immunotherapy. “Patients with responding or stable disease had an estimated 90% 5-year overall survival,” Dr. Bellow said. “Those with one isolated progressive lesion that was resected had a 60% 5-year overall survival.” A more detailed analysis of the latter group found that those who had a resection to NED had an improved overall survival of 75% at 5 years. Resected patients who had residual remaining disease had a 30% 5-year overall survival.

“Further follow-up is needed to assess the durability and contributions of surgery, and further studies are underway to identify biomarkers associated with improved survival after immunotherapy and surgery,” Dr. Bello said.

SOURCE: Bello DM et al. SSO 2018, Abstract 5.

ORLANDO – Checkpoint blockade is associated with reduced toxicity when compared with antiangiogenic therapies for the treatment of advanced non–small-cell lung cancer, a systematic review and meta-analysis suggests.

In 16,810 patients from 37 trials included in the analysis, first-line treatment with nivolumab or pembrolizumab, compared with first-line sorafenib plus platinum doublets, for example, was associated with less combined direct and indirect toxicity (odds ratios, 0.08 and 0.12, respectively), Chin-Chuan Hung, MD, and her colleagues reported in a poster at the annual conference of the National Comprehensive Cancer Network.

For subsequent therapy, nivolumab showed lower risk than most antiangiogenic therapies, particularly combination ramucirumab and docetaxel (OR, 0.06), said Dr. Hung of China Medical University Hospital in Taichung, Taiwan.

The findings are notable because tolerability is an essential selection criterion for patients with advanced stage disease, and while checkpoint inhibitors – including nivolumab, pembrolizumab, and atezolizumab – and antiangiogenic agents – including bevacizumab, ramucirumab, and nintedanib – have become the treatments of choice, direct comparisons with respect to tolerability are lacking, she noted.

The investigators performed a systematic review using Bayesian-model network meta-analysis of studies conducted through July 2017 comparing first-line and subsequent regimens containing chemotherapy, antiangiogenic therapy, and/or immune checkpoint inhibitors. Chemotherapy agents studied included cisplatin, carboplatin, oxaliplatin, gemcitabine, paclitaxel, docetaxel, and pemetrexed; antiangiogenic agents included bevacizumab, aflibercept, ramucirumab, nintedanib, axitinib, sorafenib, vandetanib, and sunitinib; and immune checkpoint inhibitors included ipilimumab, pembrolizumab, nivolumab, and atezolizumab.

Direct and indirect data for all grade 3-5 adverse events were combined using random-effects network meta-analysis.

“The results indicated that [checkpoint] inhibitors can be preferred choices for less toxicity to treat advanced stage NSCLC compared with antiangiogenic therapies in first-line and subsequent settings,” Dr. Hung and her associates concluded.

This study was supported by the China Medical University Beigang Hospital.

[email protected]

SOURCE: Hsu C et al. NCCN poster 13

ORLANDO – Checkpoint blockade is associated with reduced toxicity when compared with antiangiogenic therapies for the treatment of advanced non–small-cell lung cancer, a systematic review and meta-analysis suggests.

In 16,810 patients from 37 trials included in the analysis, first-line treatment with nivolumab or pembrolizumab, compared with first-line sorafenib plus platinum doublets, for example, was associated with less combined direct and indirect toxicity (odds ratios, 0.08 and 0.12, respectively), Chin-Chuan Hung, MD, and her colleagues reported in a poster at the annual conference of the National Comprehensive Cancer Network.

For subsequent therapy, nivolumab showed lower risk than most antiangiogenic therapies, particularly combination ramucirumab and docetaxel (OR, 0.06), said Dr. Hung of China Medical University Hospital in Taichung, Taiwan.

The findings are notable because tolerability is an essential selection criterion for patients with advanced stage disease, and while checkpoint inhibitors – including nivolumab, pembrolizumab, and atezolizumab – and antiangiogenic agents – including bevacizumab, ramucirumab, and nintedanib – have become the treatments of choice, direct comparisons with respect to tolerability are lacking, she noted.

The investigators performed a systematic review using Bayesian-model network meta-analysis of studies conducted through July 2017 comparing first-line and subsequent regimens containing chemotherapy, antiangiogenic therapy, and/or immune checkpoint inhibitors. Chemotherapy agents studied included cisplatin, carboplatin, oxaliplatin, gemcitabine, paclitaxel, docetaxel, and pemetrexed; antiangiogenic agents included bevacizumab, aflibercept, ramucirumab, nintedanib, axitinib, sorafenib, vandetanib, and sunitinib; and immune checkpoint inhibitors included ipilimumab, pembrolizumab, nivolumab, and atezolizumab.

Direct and indirect data for all grade 3-5 adverse events were combined using random-effects network meta-analysis.

“The results indicated that [checkpoint] inhibitors can be preferred choices for less toxicity to treat advanced stage NSCLC compared with antiangiogenic therapies in first-line and subsequent settings,” Dr. Hung and her associates concluded.

This study was supported by the China Medical University Beigang Hospital.

[email protected]

SOURCE: Hsu C et al. NCCN poster 13

ORLANDO – Checkpoint blockade is associated with reduced toxicity when compared with antiangiogenic therapies for the treatment of advanced non–small-cell lung cancer, a systematic review and meta-analysis suggests.

In 16,810 patients from 37 trials included in the analysis, first-line treatment with nivolumab or pembrolizumab, compared with first-line sorafenib plus platinum doublets, for example, was associated with less combined direct and indirect toxicity (odds ratios, 0.08 and 0.12, respectively), Chin-Chuan Hung, MD, and her colleagues reported in a poster at the annual conference of the National Comprehensive Cancer Network.

For subsequent therapy, nivolumab showed lower risk than most antiangiogenic therapies, particularly combination ramucirumab and docetaxel (OR, 0.06), said Dr. Hung of China Medical University Hospital in Taichung, Taiwan.

The findings are notable because tolerability is an essential selection criterion for patients with advanced stage disease, and while checkpoint inhibitors – including nivolumab, pembrolizumab, and atezolizumab – and antiangiogenic agents – including bevacizumab, ramucirumab, and nintedanib – have become the treatments of choice, direct comparisons with respect to tolerability are lacking, she noted.

The investigators performed a systematic review using Bayesian-model network meta-analysis of studies conducted through July 2017 comparing first-line and subsequent regimens containing chemotherapy, antiangiogenic therapy, and/or immune checkpoint inhibitors. Chemotherapy agents studied included cisplatin, carboplatin, oxaliplatin, gemcitabine, paclitaxel, docetaxel, and pemetrexed; antiangiogenic agents included bevacizumab, aflibercept, ramucirumab, nintedanib, axitinib, sorafenib, vandetanib, and sunitinib; and immune checkpoint inhibitors included ipilimumab, pembrolizumab, nivolumab, and atezolizumab.

Direct and indirect data for all grade 3-5 adverse events were combined using random-effects network meta-analysis.

“The results indicated that [checkpoint] inhibitors can be preferred choices for less toxicity to treat advanced stage NSCLC compared with antiangiogenic therapies in first-line and subsequent settings,” Dr. Hung and her associates concluded.

This study was supported by the China Medical University Beigang Hospital.

[email protected]

SOURCE: Hsu C et al. NCCN poster 13

Some patients with previously treated advanced non-small cell lung cancer (NSCLC), a malignancy with a historically dim prognosis, survived at least 5 years after receiving the immune checkpoint inhibitor nivolumab (Opdivo) in an early phase 1 trial.

For 129 patients with NSCLC treated with nivolumab in the CA209-003 trial, the estimated 5 year overall survival (OS) was 16%. Twelve patients who did not receive any subsequent therapy following completion of nivolumab were alive with no evidence of disease at the 5-year follow-up mark, reported Scott Gettinger, MD, of the Yale Cancer Center in New Haven, Connecticut, and colleagues.

“Considering the historically low 5-year survival rate for patients with metastatic lung cancer, the estimated 5-year OS rate of 16% from the time of nivolumab treatment initiation observed in this cohort of heavily pretreated patients with advanced NSCLC constitutes a milestone in the advancement of lung cancer treatment,” they wrote in the Journal of Clinical Oncology. In the NSCLC cohort of the phase 1 dose-escalation and expansion study, 129 patients with heavily pretreated advanced NSCLC received nivolumab in doses of 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. The investigators previously reportedthat after a median follow-up of 39 weeks, the median overall survival across all three dose groups was 9.9 months. For 37 patients treated at the 3 mg/kg dose chosen for further development, the median 1-, 2-, and 3-year OS rates were 56%, 42%, and 27%, respectively.

In the current study, they followed the patients out to a minimum of 58.25 months. The median OS was 9.9 months, and the estimated 5-year OS rate, as noted before, was 16%. The 5-year OS rates for patients with squamous histology cancers was 16%, and the rate for patients with nonsquamous histology was 15%.

In all, 16 patients survived at least 5 years, with the longest follow-up out to 88.6 months. Two of the patients died before the database lock in November 2016, one from disease progression, and one from chronic obstructive pulmonary disease.

Among 10 long-term survivors who had quantifiable expression of the programmed death-1 ligand 1 (PD-L1), seven had at least 1% PD-L1 expression at baseline.

Of the 16 5-year survivors, 12 (75%) had a partial response to nivolumab according to RECIST (Response Evaluation Criteria in Solid Tumors), version 1. Two others had stable disease, and two had disease progression at the best response.

In all, nine of the 5-year survivors had completed the maximum 96 weeks of nivolumab, four had discontinued due to adverse events, and three had stopped because of disease progression.

“The findings from CA209-003 indicate some patients can derive long-term benefit from nivolumab treatment that is limited to 2 years; however, the question of optimal treatment duration remains to be formally addressed in a prospective controlled trial,” Dr. Gettinger and associates wrote.

The study was supported by Bristol-Myers Squibb and Ono Pharmaceuticals. Dr. Gettinger and multiple co-authors reported consulting/advisory roles and research funding with BMS and other relationships with multiple companies. Several co-authors are BMS employees.

SOURCE: : Getting S et al. J Clin Oncol. 2018 Mar 23 doi: 10.1200/JCO.2017.77.0412 .




 

Some patients with previously treated advanced non-small cell lung cancer (NSCLC), a malignancy with a historically dim prognosis, survived at least 5 years after receiving the immune checkpoint inhibitor nivolumab (Opdivo) in an early phase 1 trial.

For 129 patients with NSCLC treated with nivolumab in the CA209-003 trial, the estimated 5 year overall survival (OS) was 16%. Twelve patients who did not receive any subsequent therapy following completion of nivolumab were alive with no evidence of disease at the 5-year follow-up mark, reported Scott Gettinger, MD, of the Yale Cancer Center in New Haven, Connecticut, and colleagues.

“Considering the historically low 5-year survival rate for patients with metastatic lung cancer, the estimated 5-year OS rate of 16% from the time of nivolumab treatment initiation observed in this cohort of heavily pretreated patients with advanced NSCLC constitutes a milestone in the advancement of lung cancer treatment,” they wrote in the Journal of Clinical Oncology. In the NSCLC cohort of the phase 1 dose-escalation and expansion study, 129 patients with heavily pretreated advanced NSCLC received nivolumab in doses of 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. The investigators previously reportedthat after a median follow-up of 39 weeks, the median overall survival across all three dose groups was 9.9 months. For 37 patients treated at the 3 mg/kg dose chosen for further development, the median 1-, 2-, and 3-year OS rates were 56%, 42%, and 27%, respectively.

In the current study, they followed the patients out to a minimum of 58.25 months. The median OS was 9.9 months, and the estimated 5-year OS rate, as noted before, was 16%. The 5-year OS rates for patients with squamous histology cancers was 16%, and the rate for patients with nonsquamous histology was 15%.

In all, 16 patients survived at least 5 years, with the longest follow-up out to 88.6 months. Two of the patients died before the database lock in November 2016, one from disease progression, and one from chronic obstructive pulmonary disease.

Among 10 long-term survivors who had quantifiable expression of the programmed death-1 ligand 1 (PD-L1), seven had at least 1% PD-L1 expression at baseline.

Of the 16 5-year survivors, 12 (75%) had a partial response to nivolumab according to RECIST (Response Evaluation Criteria in Solid Tumors), version 1. Two others had stable disease, and two had disease progression at the best response.

In all, nine of the 5-year survivors had completed the maximum 96 weeks of nivolumab, four had discontinued due to adverse events, and three had stopped because of disease progression.

“The findings from CA209-003 indicate some patients can derive long-term benefit from nivolumab treatment that is limited to 2 years; however, the question of optimal treatment duration remains to be formally addressed in a prospective controlled trial,” Dr. Gettinger and associates wrote.

The study was supported by Bristol-Myers Squibb and Ono Pharmaceuticals. Dr. Gettinger and multiple co-authors reported consulting/advisory roles and research funding with BMS and other relationships with multiple companies. Several co-authors are BMS employees.

SOURCE: : Getting S et al. J Clin Oncol. 2018 Mar 23 doi: 10.1200/JCO.2017.77.0412 .




 

Some patients with previously treated advanced non-small cell lung cancer (NSCLC), a malignancy with a historically dim prognosis, survived at least 5 years after receiving the immune checkpoint inhibitor nivolumab (Opdivo) in an early phase 1 trial.

For 129 patients with NSCLC treated with nivolumab in the CA209-003 trial, the estimated 5 year overall survival (OS) was 16%. Twelve patients who did not receive any subsequent therapy following completion of nivolumab were alive with no evidence of disease at the 5-year follow-up mark, reported Scott Gettinger, MD, of the Yale Cancer Center in New Haven, Connecticut, and colleagues.

“Considering the historically low 5-year survival rate for patients with metastatic lung cancer, the estimated 5-year OS rate of 16% from the time of nivolumab treatment initiation observed in this cohort of heavily pretreated patients with advanced NSCLC constitutes a milestone in the advancement of lung cancer treatment,” they wrote in the Journal of Clinical Oncology. In the NSCLC cohort of the phase 1 dose-escalation and expansion study, 129 patients with heavily pretreated advanced NSCLC received nivolumab in doses of 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. The investigators previously reportedthat after a median follow-up of 39 weeks, the median overall survival across all three dose groups was 9.9 months. For 37 patients treated at the 3 mg/kg dose chosen for further development, the median 1-, 2-, and 3-year OS rates were 56%, 42%, and 27%, respectively.

In the current study, they followed the patients out to a minimum of 58.25 months. The median OS was 9.9 months, and the estimated 5-year OS rate, as noted before, was 16%. The 5-year OS rates for patients with squamous histology cancers was 16%, and the rate for patients with nonsquamous histology was 15%.

In all, 16 patients survived at least 5 years, with the longest follow-up out to 88.6 months. Two of the patients died before the database lock in November 2016, one from disease progression, and one from chronic obstructive pulmonary disease.

Among 10 long-term survivors who had quantifiable expression of the programmed death-1 ligand 1 (PD-L1), seven had at least 1% PD-L1 expression at baseline.

Of the 16 5-year survivors, 12 (75%) had a partial response to nivolumab according to RECIST (Response Evaluation Criteria in Solid Tumors), version 1. Two others had stable disease, and two had disease progression at the best response.

In all, nine of the 5-year survivors had completed the maximum 96 weeks of nivolumab, four had discontinued due to adverse events, and three had stopped because of disease progression.

“The findings from CA209-003 indicate some patients can derive long-term benefit from nivolumab treatment that is limited to 2 years; however, the question of optimal treatment duration remains to be formally addressed in a prospective controlled trial,” Dr. Gettinger and associates wrote.

The study was supported by Bristol-Myers Squibb and Ono Pharmaceuticals. Dr. Gettinger and multiple co-authors reported consulting/advisory roles and research funding with BMS and other relationships with multiple companies. Several co-authors are BMS employees.

SOURCE: : Getting S et al. J Clin Oncol. 2018 Mar 23 doi: 10.1200/JCO.2017.77.0412 .




 

ORLANDO – The novel combination of entinostat and nivolumab with or without ipilimumab showed encouraging safety, tolerability, and antitumor activity in early results from an ongoing phase 1 trial of patients with advanced breast cancer.

Of 30 patients who were enrolled and treated in the dose-escalation phase of the study as of Feb. 24, 2018, 20 had evaluable responses, and of those, 3 had a partial response for an overall response rate of 15%. An additional 12 had stable disease, and 5 had disease progression, Roisin M. Connolly, MD, reported in a poster at the annual conference of the National Comprehensive Cancer Network.

Sharon Worcester/MDedge News

“The rationale for the study was based on preclinical work suggesting that epigenetic modifiers might be able to enhance the efficacy of immune therapies, and this would be particularly important for ‘colder’ tumor types like breast cancer that might not have the same sort of responses that we see in other tumor types,” Dr. Connolly explained in an interview. “The lab work suggested, for example, that the [histone deacetylase] inhibitor entinostat might affect myeloid-derived suppressor and regulatory T cells that might prevent cytotoxic T cells from fighting the cancer.”

There may be other mechanisms for this activity as well, she noted.

The run-in period with entinostat alone allowed collection of pre- and posttreatment biopsies to examine the effects on the tissues, such as whether treatment affects T cells, myeloid-derived suppressor cells, or their pathways, she said.

“We’re seeing [the] same types of toxicities seen with combination immune-oncology strategies, and we’re seeing some tumor responses that are of interest. Now we will delve into the tissue biopsies and blood samples we’ve collected to explore the mechanisms in more detail. In the near future we will open our breast cancer expansion cohort to look in more detail at what these drugs might be doing in breast cancer,” she added.

Specifically, she and her colleagues are evaluating the effects of treatment on immune-related biomarkers, measuring tumor-specific mutations and mutant neoantigens recognized by patient T cells in tumor biopsies, evaluating changes in the frequency of T cells recognizing tumor-specific mutant neoantigens in peripheral blood lymphocytes pre- and posttherapy, and looking at epigenetic changes pre- and posttherapy.

These preliminary findings suggest that the combination of entinostat and nivolumab with or without ipilimumab is safe and tolerable, with expected rates of immune-related adverse events, Dr. Connolly said, noting that the recommended phase 2 dose to be used in the dose expansion phase of the study has yet to be determined.

The findings, should they be confirmed as the trial progresses, could have important implications because immune checkpoint inhibitors, which work best in patients with immunogenic cancers that naturally attract T-cell infiltration into their tumor microenvironment, have limited single-agent activity in tumors, such as breast cancer, that are not believed to be immunogenic, she reported. Such cancers have thus far had only modest responses to single-agent immune checkpoint inhibition in advanced triple-negative and HER2+ breast cancer, with overall response rates of 5%-20%.

However, women who do respond to immune checkpoint inhibition tend to have durable and sustainable responses, she said, explaining that suboptimal immune responsiveness is likely a result of a lack of tumor antigen expression and/or recognition, as well as multiple suppressive signals in the tumor microenvironment.

Should the novel strategy tested in this study for converting breast cancers into immune responsive tumors facilitate improved response to immune checkpoint agents, it has the potential to significantly extend survival in breast cancer patients, she concluded.

This study was funded by grants from the National Institutes of Health, Bloomberg Kimmel Institute for Immunotherapy, NCCN, and the Mary Kay Foundation, as well as a V Foundation award. Dr. Connolly reported having no disclosures

[email protected]

SOURCE: Connolly RM et al. NCCN, Poster 3.

ORLANDO – The novel combination of entinostat and nivolumab with or without ipilimumab showed encouraging safety, tolerability, and antitumor activity in early results from an ongoing phase 1 trial of patients with advanced breast cancer.

Of 30 patients who were enrolled and treated in the dose-escalation phase of the study as of Feb. 24, 2018, 20 had evaluable responses, and of those, 3 had a partial response for an overall response rate of 15%. An additional 12 had stable disease, and 5 had disease progression, Roisin M. Connolly, MD, reported in a poster at the annual conference of the National Comprehensive Cancer Network.

Sharon Worcester/MDedge News

“The rationale for the study was based on preclinical work suggesting that epigenetic modifiers might be able to enhance the efficacy of immune therapies, and this would be particularly important for ‘colder’ tumor types like breast cancer that might not have the same sort of responses that we see in other tumor types,” Dr. Connolly explained in an interview. “The lab work suggested, for example, that the [histone deacetylase] inhibitor entinostat might affect myeloid-derived suppressor and regulatory T cells that might prevent cytotoxic T cells from fighting the cancer.”

There may be other mechanisms for this activity as well, she noted.

The run-in period with entinostat alone allowed collection of pre- and posttreatment biopsies to examine the effects on the tissues, such as whether treatment affects T cells, myeloid-derived suppressor cells, or their pathways, she said.

“We’re seeing [the] same types of toxicities seen with combination immune-oncology strategies, and we’re seeing some tumor responses that are of interest. Now we will delve into the tissue biopsies and blood samples we’ve collected to explore the mechanisms in more detail. In the near future we will open our breast cancer expansion cohort to look in more detail at what these drugs might be doing in breast cancer,” she added.

Specifically, she and her colleagues are evaluating the effects of treatment on immune-related biomarkers, measuring tumor-specific mutations and mutant neoantigens recognized by patient T cells in tumor biopsies, evaluating changes in the frequency of T cells recognizing tumor-specific mutant neoantigens in peripheral blood lymphocytes pre- and posttherapy, and looking at epigenetic changes pre- and posttherapy.

These preliminary findings suggest that the combination of entinostat and nivolumab with or without ipilimumab is safe and tolerable, with expected rates of immune-related adverse events, Dr. Connolly said, noting that the recommended phase 2 dose to be used in the dose expansion phase of the study has yet to be determined.

The findings, should they be confirmed as the trial progresses, could have important implications because immune checkpoint inhibitors, which work best in patients with immunogenic cancers that naturally attract T-cell infiltration into their tumor microenvironment, have limited single-agent activity in tumors, such as breast cancer, that are not believed to be immunogenic, she reported. Such cancers have thus far had only modest responses to single-agent immune checkpoint inhibition in advanced triple-negative and HER2+ breast cancer, with overall response rates of 5%-20%.

However, women who do respond to immune checkpoint inhibition tend to have durable and sustainable responses, she said, explaining that suboptimal immune responsiveness is likely a result of a lack of tumor antigen expression and/or recognition, as well as multiple suppressive signals in the tumor microenvironment.

Should the novel strategy tested in this study for converting breast cancers into immune responsive tumors facilitate improved response to immune checkpoint agents, it has the potential to significantly extend survival in breast cancer patients, she concluded.

This study was funded by grants from the National Institutes of Health, Bloomberg Kimmel Institute for Immunotherapy, NCCN, and the Mary Kay Foundation, as well as a V Foundation award. Dr. Connolly reported having no disclosures

[email protected]

SOURCE: Connolly RM et al. NCCN, Poster 3.

ORLANDO – The novel combination of entinostat and nivolumab with or without ipilimumab showed encouraging safety, tolerability, and antitumor activity in early results from an ongoing phase 1 trial of patients with advanced breast cancer.

Of 30 patients who were enrolled and treated in the dose-escalation phase of the study as of Feb. 24, 2018, 20 had evaluable responses, and of those, 3 had a partial response for an overall response rate of 15%. An additional 12 had stable disease, and 5 had disease progression, Roisin M. Connolly, MD, reported in a poster at the annual conference of the National Comprehensive Cancer Network.

Sharon Worcester/MDedge News

“The rationale for the study was based on preclinical work suggesting that epigenetic modifiers might be able to enhance the efficacy of immune therapies, and this would be particularly important for ‘colder’ tumor types like breast cancer that might not have the same sort of responses that we see in other tumor types,” Dr. Connolly explained in an interview. “The lab work suggested, for example, that the [histone deacetylase] inhibitor entinostat might affect myeloid-derived suppressor and regulatory T cells that might prevent cytotoxic T cells from fighting the cancer.”

There may be other mechanisms for this activity as well, she noted.

The run-in period with entinostat alone allowed collection of pre- and posttreatment biopsies to examine the effects on the tissues, such as whether treatment affects T cells, myeloid-derived suppressor cells, or their pathways, she said.

“We’re seeing [the] same types of toxicities seen with combination immune-oncology strategies, and we’re seeing some tumor responses that are of interest. Now we will delve into the tissue biopsies and blood samples we’ve collected to explore the mechanisms in more detail. In the near future we will open our breast cancer expansion cohort to look in more detail at what these drugs might be doing in breast cancer,” she added.

Specifically, she and her colleagues are evaluating the effects of treatment on immune-related biomarkers, measuring tumor-specific mutations and mutant neoantigens recognized by patient T cells in tumor biopsies, evaluating changes in the frequency of T cells recognizing tumor-specific mutant neoantigens in peripheral blood lymphocytes pre- and posttherapy, and looking at epigenetic changes pre- and posttherapy.

These preliminary findings suggest that the combination of entinostat and nivolumab with or without ipilimumab is safe and tolerable, with expected rates of immune-related adverse events, Dr. Connolly said, noting that the recommended phase 2 dose to be used in the dose expansion phase of the study has yet to be determined.

The findings, should they be confirmed as the trial progresses, could have important implications because immune checkpoint inhibitors, which work best in patients with immunogenic cancers that naturally attract T-cell infiltration into their tumor microenvironment, have limited single-agent activity in tumors, such as breast cancer, that are not believed to be immunogenic, she reported. Such cancers have thus far had only modest responses to single-agent immune checkpoint inhibition in advanced triple-negative and HER2+ breast cancer, with overall response rates of 5%-20%.

However, women who do respond to immune checkpoint inhibition tend to have durable and sustainable responses, she said, explaining that suboptimal immune responsiveness is likely a result of a lack of tumor antigen expression and/or recognition, as well as multiple suppressive signals in the tumor microenvironment.

Should the novel strategy tested in this study for converting breast cancers into immune responsive tumors facilitate improved response to immune checkpoint agents, it has the potential to significantly extend survival in breast cancer patients, she concluded.

This study was funded by grants from the National Institutes of Health, Bloomberg Kimmel Institute for Immunotherapy, NCCN, and the Mary Kay Foundation, as well as a V Foundation award. Dr. Connolly reported having no disclosures

[email protected]

SOURCE: Connolly RM et al. NCCN, Poster 3.

Two critical factors – prior exposure to chemotherapy and a glycolytic metabolism – appear to degrade the potential of T cells to become chimeric antigen receptor–T cells.

Chemotherapy, especially with cyclophosphamide and doxorubicin, seems particularly toxic to T cells, damaging the mitochondria and decreasing the cells’ spare respiratory capacity – a measure of mitochondrial health, David Barrett, MD, said during a press briefing held in advance of the annual meeting of the American Association for Cancer Research.

They examined how well the cells grew in the transformation and expansion process. A “pass” was considered a fivefold expansion in response to CD3/CD28 exposure for 7 days. Normal donor cells typically expand 20- to 30-fold in this time.

Only T cells taken from ALL and Wilms tumor patients before chemotherapy achieved a pass, Dr. Barrett said. Most of the ALL expansions (80%) and half of the Wilms tumor expansions passed. “We noted very poor CAR T-cell potential in all the other tumor types – less than a 30% pass. We noted a decline in potential with cumulative chemotherapy in all cases, though this was particularly significant in children less than 3 years old.”

The team also used RNA profiling to look at the cells’ metabolic pathways. Dr. Barrett noted that T cells are highly metabolically adaptable, capable of using several different fuel types and switching from one to another. Glucose and fatty acids are frequent fuels. Most of the cells from patients with solid tumors exhibited a glycolytic metabolism, while cells from patients with ALL and Wilms tumor appeared to rely more on fatty acids.

“One is not inherently worse than the other,” he said. “But glycolysis appears to be a bad thing when we’re trying to turn them into CAR T cells. Those T cells were too exhausted to do anything.”

However, Dr. Barrett encouraged the cells to switch fuels by treating them in vitro with palmitic acid, the most common fatty acid in plants and animals.

“We were growing the cells in a media containing sugar, fatty acids, and amino acids,” he explained. “We just started overloading them with palmitic acid, which has a natural transporter on the T-cell surface, so it already had a good pathway to get into the cell. It helped restore some of the performance of these T cells in some assays, although it wasn’t a complete reversal. But it was encouraging that something as simple as providing an alternate fuel was enough to get some positive effect. Whether or not we would also have to block glucose use to get it to really work is something we continue to study.”

T cells that had been exposed to chemotherapy also did poorly. Cyclophosphamide and doxorubicin seemed particularly toxic. Cells with exposure to these two agents had severely depleted CAR T cell potential with very poor spare respiratory capacity. This is a marker of mitochondrial injury, Dr. Barrett said. “That wasn’t a huge surprise. We already knew that cyclophosphamide is very toxic to T cells.”

But the finding did suggest the simple intervention of harvesting T cells before chemotherapy, which is what Dr. Barrett and his colleagues now do in their high-risk ALL patients. Whether or not this would improve response in patients with solid tumors is still unknown.

He had no financial disclosures. This study was supported by the AACR, the Doris Duke Charitable Foundation Clinical Science Development Award, the Jeffrey Pride Foundation Research Award, and the St. Baldrick’s Foundation Scholar Award.

[email protected]

SOURCE: Barrett DM et al. AACR 2018, Abstract 1631.

Two critical factors – prior exposure to chemotherapy and a glycolytic metabolism – appear to degrade the potential of T cells to become chimeric antigen receptor–T cells.

Chemotherapy, especially with cyclophosphamide and doxorubicin, seems particularly toxic to T cells, damaging the mitochondria and decreasing the cells’ spare respiratory capacity – a measure of mitochondrial health, David Barrett, MD, said during a press briefing held in advance of the annual meeting of the American Association for Cancer Research.

They examined how well the cells grew in the transformation and expansion process. A “pass” was considered a fivefold expansion in response to CD3/CD28 exposure for 7 days. Normal donor cells typically expand 20- to 30-fold in this time.

Only T cells taken from ALL and Wilms tumor patients before chemotherapy achieved a pass, Dr. Barrett said. Most of the ALL expansions (80%) and half of the Wilms tumor expansions passed. “We noted very poor CAR T-cell potential in all the other tumor types – less than a 30% pass. We noted a decline in potential with cumulative chemotherapy in all cases, though this was particularly significant in children less than 3 years old.”

The team also used RNA profiling to look at the cells’ metabolic pathways. Dr. Barrett noted that T cells are highly metabolically adaptable, capable of using several different fuel types and switching from one to another. Glucose and fatty acids are frequent fuels. Most of the cells from patients with solid tumors exhibited a glycolytic metabolism, while cells from patients with ALL and Wilms tumor appeared to rely more on fatty acids.

“One is not inherently worse than the other,” he said. “But glycolysis appears to be a bad thing when we’re trying to turn them into CAR T cells. Those T cells were too exhausted to do anything.”

However, Dr. Barrett encouraged the cells to switch fuels by treating them in vitro with palmitic acid, the most common fatty acid in plants and animals.

“We were growing the cells in a media containing sugar, fatty acids, and amino acids,” he explained. “We just started overloading them with palmitic acid, which has a natural transporter on the T-cell surface, so it already had a good pathway to get into the cell. It helped restore some of the performance of these T cells in some assays, although it wasn’t a complete reversal. But it was encouraging that something as simple as providing an alternate fuel was enough to get some positive effect. Whether or not we would also have to block glucose use to get it to really work is something we continue to study.”

T cells that had been exposed to chemotherapy also did poorly. Cyclophosphamide and doxorubicin seemed particularly toxic. Cells with exposure to these two agents had severely depleted CAR T cell potential with very poor spare respiratory capacity. This is a marker of mitochondrial injury, Dr. Barrett said. “That wasn’t a huge surprise. We already knew that cyclophosphamide is very toxic to T cells.”

But the finding did suggest the simple intervention of harvesting T cells before chemotherapy, which is what Dr. Barrett and his colleagues now do in their high-risk ALL patients. Whether or not this would improve response in patients with solid tumors is still unknown.

He had no financial disclosures. This study was supported by the AACR, the Doris Duke Charitable Foundation Clinical Science Development Award, the Jeffrey Pride Foundation Research Award, and the St. Baldrick’s Foundation Scholar Award.

[email protected]

SOURCE: Barrett DM et al. AACR 2018, Abstract 1631.

Two critical factors – prior exposure to chemotherapy and a glycolytic metabolism – appear to degrade the potential of T cells to become chimeric antigen receptor–T cells.

Chemotherapy, especially with cyclophosphamide and doxorubicin, seems particularly toxic to T cells, damaging the mitochondria and decreasing the cells’ spare respiratory capacity – a measure of mitochondrial health, David Barrett, MD, said during a press briefing held in advance of the annual meeting of the American Association for Cancer Research.

They examined how well the cells grew in the transformation and expansion process. A “pass” was considered a fivefold expansion in response to CD3/CD28 exposure for 7 days. Normal donor cells typically expand 20- to 30-fold in this time.

Only T cells taken from ALL and Wilms tumor patients before chemotherapy achieved a pass, Dr. Barrett said. Most of the ALL expansions (80%) and half of the Wilms tumor expansions passed. “We noted very poor CAR T-cell potential in all the other tumor types – less than a 30% pass. We noted a decline in potential with cumulative chemotherapy in all cases, though this was particularly significant in children less than 3 years old.”

The team also used RNA profiling to look at the cells’ metabolic pathways. Dr. Barrett noted that T cells are highly metabolically adaptable, capable of using several different fuel types and switching from one to another. Glucose and fatty acids are frequent fuels. Most of the cells from patients with solid tumors exhibited a glycolytic metabolism, while cells from patients with ALL and Wilms tumor appeared to rely more on fatty acids.

“One is not inherently worse than the other,” he said. “But glycolysis appears to be a bad thing when we’re trying to turn them into CAR T cells. Those T cells were too exhausted to do anything.”

However, Dr. Barrett encouraged the cells to switch fuels by treating them in vitro with palmitic acid, the most common fatty acid in plants and animals.

“We were growing the cells in a media containing sugar, fatty acids, and amino acids,” he explained. “We just started overloading them with palmitic acid, which has a natural transporter on the T-cell surface, so it already had a good pathway to get into the cell. It helped restore some of the performance of these T cells in some assays, although it wasn’t a complete reversal. But it was encouraging that something as simple as providing an alternate fuel was enough to get some positive effect. Whether or not we would also have to block glucose use to get it to really work is something we continue to study.”

T cells that had been exposed to chemotherapy also did poorly. Cyclophosphamide and doxorubicin seemed particularly toxic. Cells with exposure to these two agents had severely depleted CAR T cell potential with very poor spare respiratory capacity. This is a marker of mitochondrial injury, Dr. Barrett said. “That wasn’t a huge surprise. We already knew that cyclophosphamide is very toxic to T cells.”

But the finding did suggest the simple intervention of harvesting T cells before chemotherapy, which is what Dr. Barrett and his colleagues now do in their high-risk ALL patients. Whether or not this would improve response in patients with solid tumors is still unknown.

He had no financial disclosures. This study was supported by the AACR, the Doris Duke Charitable Foundation Clinical Science Development Award, the Jeffrey Pride Foundation Research Award, and the St. Baldrick’s Foundation Scholar Award.

[email protected]

SOURCE: Barrett DM et al. AACR 2018, Abstract 1631.

The American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) have released new guidelines designed to help clinicians manage the unique and sometimes severe side effects associated with cancer immunotherapy agents.

These guidelines meet a growing need to help practicing clinicians identify and best manage immune-related adverse events, according to Bryan J. Schneider, MD, of the University of Michigan Comprehensive Cancer Center, and vice chair of the NCCN Panel on Management of Immunotherapy-Related Toxicities.

“The mechanism of action of these anticancer therapies is so much different from anything that we’re used to,” Dr. Schneider said in an interview.

Critical need for guidance

The ASCO and NCCN guidelines are “critically important” to ensure uniform management of common immune-related adverse events, according to Stephen M. Ansell, MD, PhD, professor of medicine and chair of the Lymphoma Group at Mayo Clinic, Rochester, Minn.

“I think it also specifically highlights a few side effects that many people may not necessarily think about, from eye toxicities to thyroid effects, or the type of things that the average oncologist who is now using this in their practice quite regularly may not necessarily think about,” Dr. Ansell said. “Those kind of effects are now clearly outlined with clear guidance about what should be done, and I think that allows oncologists a resource to go and look at this carefully so that they do the right thing.”

Stepwise approach

Side effects of checkpoint inhibitors are typically mild, but they can be severe and sometimes life-threatening, according to ASCO and NCCN.

If immune-related adverse events are mild (i.e., grade 1), treatment can continue with close monitoring, according to the guidelines. By contrast, moderate to severe immune-related adverse events can lead to severe declines in organ function and quality of life, or even fatal outcomes, so early detection and proper management are needed.

Grade 2 toxicities warrant suspending immune checkpoint inhibitor treatment, and resuming it once symptoms subside to grade 1 or less, according to the guidelines. Grade 3 toxicities should also prompt suspension of treatment, plus initiation of high-dose corticosteroids tapered over at least 4-6 weeks.

For most toxicities that reach grade 4, permanent discontinuation of checkpoint inhibitors is recommended.

A thoughtful discussion of potential risks and benefits is needed before using immune checkpoint inhibitors in patients who have autoimmune disease or prior organ transplant, according to the guidelines.

Vigilance required

Checkpoint inhibitors have been approved by the Food and Drug Administration to treat a variety of cancers, including melanoma, lung cancer, and Hodgkin lymphoma, as well as lung, liver, kidney, and bladder cancers.

Clinicians managing patients on checkpoint inhibitors should always be vigilant because immune-related adverse event symptoms can be subtle, according to Julie Brahmer, MD, of The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore.

“Everyone has to work as a team, which includes being educated on possible side effects to immunotherapy prior to prescribing it,” said Dr. Brahmer, chair of the ASCO panel and vice chair of the NCCN panel that developed the guidelines.

The guidelines were published Feb. 14 in two documents that are similar in content, but different in format. The ASCO guideline was published in the Journal of Clinical Oncology (doi: 10.1200/JCO.2017.77.6385) and the NCCN Clinical Practice Guidelines in Oncology were posted on the NCCN website.

While the first edition of the guidelines focuses specifically on immune checkpoint inhibitors, an update anticipated for 2019 will include guidance on chimeric antigen receptor (CAR) T-cell therapy, which is associated with several important side effects, notably cytokine release syndrome.

[email protected]

The American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) have released new guidelines designed to help clinicians manage the unique and sometimes severe side effects associated with cancer immunotherapy agents.

These guidelines meet a growing need to help practicing clinicians identify and best manage immune-related adverse events, according to Bryan J. Schneider, MD, of the University of Michigan Comprehensive Cancer Center, and vice chair of the NCCN Panel on Management of Immunotherapy-Related Toxicities.

“The mechanism of action of these anticancer therapies is so much different from anything that we’re used to,” Dr. Schneider said in an interview.

Critical need for guidance

The ASCO and NCCN guidelines are “critically important” to ensure uniform management of common immune-related adverse events, according to Stephen M. Ansell, MD, PhD, professor of medicine and chair of the Lymphoma Group at Mayo Clinic, Rochester, Minn.

“I think it also specifically highlights a few side effects that many people may not necessarily think about, from eye toxicities to thyroid effects, or the type of things that the average oncologist who is now using this in their practice quite regularly may not necessarily think about,” Dr. Ansell said. “Those kind of effects are now clearly outlined with clear guidance about what should be done, and I think that allows oncologists a resource to go and look at this carefully so that they do the right thing.”

Stepwise approach

Side effects of checkpoint inhibitors are typically mild, but they can be severe and sometimes life-threatening, according to ASCO and NCCN.

If immune-related adverse events are mild (i.e., grade 1), treatment can continue with close monitoring, according to the guidelines. By contrast, moderate to severe immune-related adverse events can lead to severe declines in organ function and quality of life, or even fatal outcomes, so early detection and proper management are needed.

Grade 2 toxicities warrant suspending immune checkpoint inhibitor treatment, and resuming it once symptoms subside to grade 1 or less, according to the guidelines. Grade 3 toxicities should also prompt suspension of treatment, plus initiation of high-dose corticosteroids tapered over at least 4-6 weeks.

For most toxicities that reach grade 4, permanent discontinuation of checkpoint inhibitors is recommended.

A thoughtful discussion of potential risks and benefits is needed before using immune checkpoint inhibitors in patients who have autoimmune disease or prior organ transplant, according to the guidelines.

Vigilance required

Checkpoint inhibitors have been approved by the Food and Drug Administration to treat a variety of cancers, including melanoma, lung cancer, and Hodgkin lymphoma, as well as lung, liver, kidney, and bladder cancers.

Clinicians managing patients on checkpoint inhibitors should always be vigilant because immune-related adverse event symptoms can be subtle, according to Julie Brahmer, MD, of The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore.

“Everyone has to work as a team, which includes being educated on possible side effects to immunotherapy prior to prescribing it,” said Dr. Brahmer, chair of the ASCO panel and vice chair of the NCCN panel that developed the guidelines.

The guidelines were published Feb. 14 in two documents that are similar in content, but different in format. The ASCO guideline was published in the Journal of Clinical Oncology (doi: 10.1200/JCO.2017.77.6385) and the NCCN Clinical Practice Guidelines in Oncology were posted on the NCCN website.

While the first edition of the guidelines focuses specifically on immune checkpoint inhibitors, an update anticipated for 2019 will include guidance on chimeric antigen receptor (CAR) T-cell therapy, which is associated with several important side effects, notably cytokine release syndrome.

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The American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) have released new guidelines designed to help clinicians manage the unique and sometimes severe side effects associated with cancer immunotherapy agents.

These guidelines meet a growing need to help practicing clinicians identify and best manage immune-related adverse events, according to Bryan J. Schneider, MD, of the University of Michigan Comprehensive Cancer Center, and vice chair of the NCCN Panel on Management of Immunotherapy-Related Toxicities.

“The mechanism of action of these anticancer therapies is so much different from anything that we’re used to,” Dr. Schneider said in an interview.

Critical need for guidance

The ASCO and NCCN guidelines are “critically important” to ensure uniform management of common immune-related adverse events, according to Stephen M. Ansell, MD, PhD, professor of medicine and chair of the Lymphoma Group at Mayo Clinic, Rochester, Minn.

“I think it also specifically highlights a few side effects that many people may not necessarily think about, from eye toxicities to thyroid effects, or the type of things that the average oncologist who is now using this in their practice quite regularly may not necessarily think about,” Dr. Ansell said. “Those kind of effects are now clearly outlined with clear guidance about what should be done, and I think that allows oncologists a resource to go and look at this carefully so that they do the right thing.”

Stepwise approach

Side effects of checkpoint inhibitors are typically mild, but they can be severe and sometimes life-threatening, according to ASCO and NCCN.

If immune-related adverse events are mild (i.e., grade 1), treatment can continue with close monitoring, according to the guidelines. By contrast, moderate to severe immune-related adverse events can lead to severe declines in organ function and quality of life, or even fatal outcomes, so early detection and proper management are needed.

Grade 2 toxicities warrant suspending immune checkpoint inhibitor treatment, and resuming it once symptoms subside to grade 1 or less, according to the guidelines. Grade 3 toxicities should also prompt suspension of treatment, plus initiation of high-dose corticosteroids tapered over at least 4-6 weeks.

For most toxicities that reach grade 4, permanent discontinuation of checkpoint inhibitors is recommended.

A thoughtful discussion of potential risks and benefits is needed before using immune checkpoint inhibitors in patients who have autoimmune disease or prior organ transplant, according to the guidelines.

Vigilance required

Checkpoint inhibitors have been approved by the Food and Drug Administration to treat a variety of cancers, including melanoma, lung cancer, and Hodgkin lymphoma, as well as lung, liver, kidney, and bladder cancers.

Clinicians managing patients on checkpoint inhibitors should always be vigilant because immune-related adverse event symptoms can be subtle, according to Julie Brahmer, MD, of The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore.

“Everyone has to work as a team, which includes being educated on possible side effects to immunotherapy prior to prescribing it,” said Dr. Brahmer, chair of the ASCO panel and vice chair of the NCCN panel that developed the guidelines.

The guidelines were published Feb. 14 in two documents that are similar in content, but different in format. The ASCO guideline was published in the Journal of Clinical Oncology (doi: 10.1200/JCO.2017.77.6385) and the NCCN Clinical Practice Guidelines in Oncology were posted on the NCCN website.

While the first edition of the guidelines focuses specifically on immune checkpoint inhibitors, an update anticipated for 2019 will include guidance on chimeric antigen receptor (CAR) T-cell therapy, which is associated with several important side effects, notably cytokine release syndrome.

[email protected]

Alterations in DNA damage response and repair genes may be useful biomarkers for response to immune checkpoint inhibitors in patients with urothelial carcinoma, investigators contend.

Among 60 patients with urothelial carcinoma in prospective trials of antibodies directed against the immune checkpoint inhibitor programmed cell death protein-1 and its ligand (PD-1/PD-L1), 28 (47%) had a damage response and repair (DDR) gene of any kind, and 15 (25%) had DDR mutations that are thought to be deleterious. Patients with any DDR mutations were more likely to have a clinical response to anti–PD-1/PD-L1 therapy, especially patients with likely deleterious mutations, reported Jonathan E. Rosenberg, MD and colleagues from Memorial Sloan Kettering Cancer Center, New York.

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SOURCE: Rosenberg JE et al. J Clin Oncol. 2018 Feb 28. doi: 10.1200/JCO.2017.75.7740.

Alterations in DNA damage response and repair genes may be useful biomarkers for response to immune checkpoint inhibitors in patients with urothelial carcinoma, investigators contend.

Among 60 patients with urothelial carcinoma in prospective trials of antibodies directed against the immune checkpoint inhibitor programmed cell death protein-1 and its ligand (PD-1/PD-L1), 28 (47%) had a damage response and repair (DDR) gene of any kind, and 15 (25%) had DDR mutations that are thought to be deleterious. Patients with any DDR mutations were more likely to have a clinical response to anti–PD-1/PD-L1 therapy, especially patients with likely deleterious mutations, reported Jonathan E. Rosenberg, MD and colleagues from Memorial Sloan Kettering Cancer Center, New York.

[email protected]

SOURCE: Rosenberg JE et al. J Clin Oncol. 2018 Feb 28. doi: 10.1200/JCO.2017.75.7740.

Alterations in DNA damage response and repair genes may be useful biomarkers for response to immune checkpoint inhibitors in patients with urothelial carcinoma, investigators contend.

Among 60 patients with urothelial carcinoma in prospective trials of antibodies directed against the immune checkpoint inhibitor programmed cell death protein-1 and its ligand (PD-1/PD-L1), 28 (47%) had a damage response and repair (DDR) gene of any kind, and 15 (25%) had DDR mutations that are thought to be deleterious. Patients with any DDR mutations were more likely to have a clinical response to anti–PD-1/PD-L1 therapy, especially patients with likely deleterious mutations, reported Jonathan E. Rosenberg, MD and colleagues from Memorial Sloan Kettering Cancer Center, New York.

[email protected]

SOURCE: Rosenberg JE et al. J Clin Oncol. 2018 Feb 28. doi: 10.1200/JCO.2017.75.7740.

The immune checkpoint inhibitor avelumab (Bavencio), targeted against programmed cell death protein 1 and its ligand (PD1/PD-L1), appears to be well tolerated with a manageable safety profile, pooled data from two clinical trials suggest.

Of the 1,738 patients enrolled in the phase 1 JAVELIN solid tumor trial and the phase 2 JAVELIN Merkel 200 trial, 1,164 (67%) had a treatment-related adverse event (TRAE), and 177 (10.2%) had grade 3 or greater TRAEs. Grade 3 or greater immune-related adverse events (irAEs) occurred in just 2.2% of patients, reported Karen Kelly, MD, from the University of California, Davis, and her colleagues.

“Although conclusions drawn from cross-study comparisons should be made with caution, and to the best of our knowledge the number of pan-tumor clinical studies of [immune checkpoint inhibitor] monotherapy is limited, this analysis of a large population of patients across a broad scope of tumor types suggests that avelumab was associated with an incidence of irAEs that is consistent with that of other ICIs,” they wrote in Cancer.

Adverse events common with other immune checkpoint inhibitors include low-grade fatigue, pruritus, and rash, as well as serious irAEs, including high-grade pneumonitis and autoimmune-like side effects, the authors noted.

To characterize the adverse event profile of avelumab, they reviewed safety data on 1,650 patients enrolled in the solid tumor trial and 88 enrolled in the Merkel cell carcinoma trial, which included all patients in the trial who had received at least one dose of avelumab monotherapy by the cutoff date.

At the time of the analysis, 287 patients (16.5%) were continuing treatment, and 1,451 had discontinued therapy, largely because of disease progression.

Nearly all patients – 1,697 (97.6%) – had at least one adverse event of any grade or cause.

Four patients died from what investigators determined were TRAEs, including autoimmune hepatitis with peritoneal metastases and ascites in a patient with gastric cancer, liver metastases and acute liver failure in a patient with metastatic breast cancer, respiratory distress in a patient with breast cancer and multiple comorbidities, and treatment-related pneumonitis with ongoing Clostridium difficile colitis and diverticulitis not related to study treatment in a patient with urothelial carcinoma.

An additional 59 patients (3.4%) died from adverse events not deemed to be treatment-related, and 104 patient (6%) died from unknown or undocumented causes.

Any grade of irAE occurred in 247 patients (14.2%) and were grade 3 or greater in 39 (2.2%). Management of irAEs included systemic corticosteroids and nonsteroidal immunosuppressants.

In all, 439 patients (25.3%) had infusion-related reactions, which were treated generally with systemic corticosteroid. The protocol of the solid tumor trial was amended later to include diphenhydramine and acetaminophen before the first avelumab infusion as prophylaxis.

The study was sponsored by Merck and part of an alliance between Merck and Pfizer. Dr. Kelly reported no conflicts of interest. Multiple coauthors reported research funding, consulting fees, honoraria, or other consideration from various companies, and several coauthors are Merck employees.

The immune checkpoint inhibitor avelumab (Bavencio), targeted against programmed cell death protein 1 and its ligand (PD1/PD-L1), appears to be well tolerated with a manageable safety profile, pooled data from two clinical trials suggest.

Of the 1,738 patients enrolled in the phase 1 JAVELIN solid tumor trial and the phase 2 JAVELIN Merkel 200 trial, 1,164 (67%) had a treatment-related adverse event (TRAE), and 177 (10.2%) had grade 3 or greater TRAEs. Grade 3 or greater immune-related adverse events (irAEs) occurred in just 2.2% of patients, reported Karen Kelly, MD, from the University of California, Davis, and her colleagues.

“Although conclusions drawn from cross-study comparisons should be made with caution, and to the best of our knowledge the number of pan-tumor clinical studies of [immune checkpoint inhibitor] monotherapy is limited, this analysis of a large population of patients across a broad scope of tumor types suggests that avelumab was associated with an incidence of irAEs that is consistent with that of other ICIs,” they wrote in Cancer.

Adverse events common with other immune checkpoint inhibitors include low-grade fatigue, pruritus, and rash, as well as serious irAEs, including high-grade pneumonitis and autoimmune-like side effects, the authors noted.

To characterize the adverse event profile of avelumab, they reviewed safety data on 1,650 patients enrolled in the solid tumor trial and 88 enrolled in the Merkel cell carcinoma trial, which included all patients in the trial who had received at least one dose of avelumab monotherapy by the cutoff date.

At the time of the analysis, 287 patients (16.5%) were continuing treatment, and 1,451 had discontinued therapy, largely because of disease progression.

Nearly all patients – 1,697 (97.6%) – had at least one adverse event of any grade or cause.

Four patients died from what investigators determined were TRAEs, including autoimmune hepatitis with peritoneal metastases and ascites in a patient with gastric cancer, liver metastases and acute liver failure in a patient with metastatic breast cancer, respiratory distress in a patient with breast cancer and multiple comorbidities, and treatment-related pneumonitis with ongoing Clostridium difficile colitis and diverticulitis not related to study treatment in a patient with urothelial carcinoma.

An additional 59 patients (3.4%) died from adverse events not deemed to be treatment-related, and 104 patient (6%) died from unknown or undocumented causes.

Any grade of irAE occurred in 247 patients (14.2%) and were grade 3 or greater in 39 (2.2%). Management of irAEs included systemic corticosteroids and nonsteroidal immunosuppressants.

In all, 439 patients (25.3%) had infusion-related reactions, which were treated generally with systemic corticosteroid. The protocol of the solid tumor trial was amended later to include diphenhydramine and acetaminophen before the first avelumab infusion as prophylaxis.

The study was sponsored by Merck and part of an alliance between Merck and Pfizer. Dr. Kelly reported no conflicts of interest. Multiple coauthors reported research funding, consulting fees, honoraria, or other consideration from various companies, and several coauthors are Merck employees.

The immune checkpoint inhibitor avelumab (Bavencio), targeted against programmed cell death protein 1 and its ligand (PD1/PD-L1), appears to be well tolerated with a manageable safety profile, pooled data from two clinical trials suggest.

Of the 1,738 patients enrolled in the phase 1 JAVELIN solid tumor trial and the phase 2 JAVELIN Merkel 200 trial, 1,164 (67%) had a treatment-related adverse event (TRAE), and 177 (10.2%) had grade 3 or greater TRAEs. Grade 3 or greater immune-related adverse events (irAEs) occurred in just 2.2% of patients, reported Karen Kelly, MD, from the University of California, Davis, and her colleagues.

“Although conclusions drawn from cross-study comparisons should be made with caution, and to the best of our knowledge the number of pan-tumor clinical studies of [immune checkpoint inhibitor] monotherapy is limited, this analysis of a large population of patients across a broad scope of tumor types suggests that avelumab was associated with an incidence of irAEs that is consistent with that of other ICIs,” they wrote in Cancer.

Adverse events common with other immune checkpoint inhibitors include low-grade fatigue, pruritus, and rash, as well as serious irAEs, including high-grade pneumonitis and autoimmune-like side effects, the authors noted.

To characterize the adverse event profile of avelumab, they reviewed safety data on 1,650 patients enrolled in the solid tumor trial and 88 enrolled in the Merkel cell carcinoma trial, which included all patients in the trial who had received at least one dose of avelumab monotherapy by the cutoff date.

At the time of the analysis, 287 patients (16.5%) were continuing treatment, and 1,451 had discontinued therapy, largely because of disease progression.

Nearly all patients – 1,697 (97.6%) – had at least one adverse event of any grade or cause.

Four patients died from what investigators determined were TRAEs, including autoimmune hepatitis with peritoneal metastases and ascites in a patient with gastric cancer, liver metastases and acute liver failure in a patient with metastatic breast cancer, respiratory distress in a patient with breast cancer and multiple comorbidities, and treatment-related pneumonitis with ongoing Clostridium difficile colitis and diverticulitis not related to study treatment in a patient with urothelial carcinoma.

An additional 59 patients (3.4%) died from adverse events not deemed to be treatment-related, and 104 patient (6%) died from unknown or undocumented causes.

Any grade of irAE occurred in 247 patients (14.2%) and were grade 3 or greater in 39 (2.2%). Management of irAEs included systemic corticosteroids and nonsteroidal immunosuppressants.

In all, 439 patients (25.3%) had infusion-related reactions, which were treated generally with systemic corticosteroid. The protocol of the solid tumor trial was amended later to include diphenhydramine and acetaminophen before the first avelumab infusion as prophylaxis.

The study was sponsored by Merck and part of an alliance between Merck and Pfizer. Dr. Kelly reported no conflicts of interest. Multiple coauthors reported research funding, consulting fees, honoraria, or other consideration from various companies, and several coauthors are Merck employees.