Immunotherapy

Among patients with B-cell acute lymphoblastic leukemia (ALL) who received an infusion of 19-28z CAR T cells, patients with low disease burden had better survival outcomes and fewer toxic effects than did patients with a high disease burden, according to long-term follow-up results of a phase 1 study.

Median overall survival for B-cell ALL patients with low disease burden was 20.1 months, compared with 12.4 months for those with a high disease burden (P = .02), and 12.9 months for the entire cohort, according to results published in the New England Journal of Medicine.

The 12.9-month overall survival for the full study cohort “compares favorably” to results from another recently reported clinical trial showing overall survival of 7.7 months for adult B-cell ALL patients treated with blinatumomab, an anti–CD19/CD3 bispecific T-cell engager, wrote Jae H. Park, MD, of the Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, and his coauthors.

The CAR T-cell and blinatumomab results cannot be directly compared owing to the differences in study design, patient characteristics, and posttreatment consolidation, but “the observation of patients with durable remissions in these two studies highlights the potential of CD19-targeted immunotherapies,” Dr. Park and his colleagues wrote in their report.

The phase 1 trial by Dr. Park and his colleagues included 53 adults with relapsed B-cell ALL who received a single infusion of 19-28z CAR T-cell therapy manufactured at Memorial Sloan Kettering Cancer Center.

After the infusion, 41% of patients with high disease burden (at least 5% bone marrow blasts or extramedullary disease) experienced severe cytokine release syndrome, compared with 5% of those with low disease burden, according to the report.

Likewise, neurotoxic effects were seen in 59% of high disease burden B-ALL patients, compared with 14% of those with low disease burden, the investigators reported.

Low disease burden was associated with a higher rate of complete remission, but this finding did not reach statistical significance. However, low disease burden patients not only had improved overall survival, as noted, but also had a significantly longer event-free survival versus high disease burden patients (10.6 and 5.3 months, respectively; P = .01).

Robust expansion of CAR T cells in vivo was a good predictor of short-term response and toxic effects but did not correlate with longer-term efficacy, according to the researchers. Instead, the ratio of peak CAR T-cell expansion to tumor burden correlated significantly with event-free and overall survival.

That finding “raises the hypothesis that an effective ratio of CAR T cells to target CD19+ leukemia cells is more likely to occur in patients with a low disease burden than in those with a high disease burden, despite a smaller number of expanded T cells in patients with a low disease burden,” the investigators wrote.

The study was funded by the Commonwealth Foundation for Cancer Research, Juno Therapeutics, and others. Several study authors reported ties to Juno Therapeutics and other pharmaceutical companies.

SOURCE: Park JH et al. N Engl J Med 2018 Feb 1;378:449-59.

Among patients with B-cell acute lymphoblastic leukemia (ALL) who received an infusion of 19-28z CAR T cells, patients with low disease burden had better survival outcomes and fewer toxic effects than did patients with a high disease burden, according to long-term follow-up results of a phase 1 study.

Median overall survival for B-cell ALL patients with low disease burden was 20.1 months, compared with 12.4 months for those with a high disease burden (P = .02), and 12.9 months for the entire cohort, according to results published in the New England Journal of Medicine.

The 12.9-month overall survival for the full study cohort “compares favorably” to results from another recently reported clinical trial showing overall survival of 7.7 months for adult B-cell ALL patients treated with blinatumomab, an anti–CD19/CD3 bispecific T-cell engager, wrote Jae H. Park, MD, of the Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, and his coauthors.

The CAR T-cell and blinatumomab results cannot be directly compared owing to the differences in study design, patient characteristics, and posttreatment consolidation, but “the observation of patients with durable remissions in these two studies highlights the potential of CD19-targeted immunotherapies,” Dr. Park and his colleagues wrote in their report.

The phase 1 trial by Dr. Park and his colleagues included 53 adults with relapsed B-cell ALL who received a single infusion of 19-28z CAR T-cell therapy manufactured at Memorial Sloan Kettering Cancer Center.

After the infusion, 41% of patients with high disease burden (at least 5% bone marrow blasts or extramedullary disease) experienced severe cytokine release syndrome, compared with 5% of those with low disease burden, according to the report.

Likewise, neurotoxic effects were seen in 59% of high disease burden B-ALL patients, compared with 14% of those with low disease burden, the investigators reported.

Low disease burden was associated with a higher rate of complete remission, but this finding did not reach statistical significance. However, low disease burden patients not only had improved overall survival, as noted, but also had a significantly longer event-free survival versus high disease burden patients (10.6 and 5.3 months, respectively; P = .01).

Robust expansion of CAR T cells in vivo was a good predictor of short-term response and toxic effects but did not correlate with longer-term efficacy, according to the researchers. Instead, the ratio of peak CAR T-cell expansion to tumor burden correlated significantly with event-free and overall survival.

That finding “raises the hypothesis that an effective ratio of CAR T cells to target CD19+ leukemia cells is more likely to occur in patients with a low disease burden than in those with a high disease burden, despite a smaller number of expanded T cells in patients with a low disease burden,” the investigators wrote.

The study was funded by the Commonwealth Foundation for Cancer Research, Juno Therapeutics, and others. Several study authors reported ties to Juno Therapeutics and other pharmaceutical companies.

SOURCE: Park JH et al. N Engl J Med 2018 Feb 1;378:449-59.

Among patients with B-cell acute lymphoblastic leukemia (ALL) who received an infusion of 19-28z CAR T cells, patients with low disease burden had better survival outcomes and fewer toxic effects than did patients with a high disease burden, according to long-term follow-up results of a phase 1 study.

Median overall survival for B-cell ALL patients with low disease burden was 20.1 months, compared with 12.4 months for those with a high disease burden (P = .02), and 12.9 months for the entire cohort, according to results published in the New England Journal of Medicine.

The 12.9-month overall survival for the full study cohort “compares favorably” to results from another recently reported clinical trial showing overall survival of 7.7 months for adult B-cell ALL patients treated with blinatumomab, an anti–CD19/CD3 bispecific T-cell engager, wrote Jae H. Park, MD, of the Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, and his coauthors.

The CAR T-cell and blinatumomab results cannot be directly compared owing to the differences in study design, patient characteristics, and posttreatment consolidation, but “the observation of patients with durable remissions in these two studies highlights the potential of CD19-targeted immunotherapies,” Dr. Park and his colleagues wrote in their report.

The phase 1 trial by Dr. Park and his colleagues included 53 adults with relapsed B-cell ALL who received a single infusion of 19-28z CAR T-cell therapy manufactured at Memorial Sloan Kettering Cancer Center.

After the infusion, 41% of patients with high disease burden (at least 5% bone marrow blasts or extramedullary disease) experienced severe cytokine release syndrome, compared with 5% of those with low disease burden, according to the report.

Likewise, neurotoxic effects were seen in 59% of high disease burden B-ALL patients, compared with 14% of those with low disease burden, the investigators reported.

Low disease burden was associated with a higher rate of complete remission, but this finding did not reach statistical significance. However, low disease burden patients not only had improved overall survival, as noted, but also had a significantly longer event-free survival versus high disease burden patients (10.6 and 5.3 months, respectively; P = .01).

Robust expansion of CAR T cells in vivo was a good predictor of short-term response and toxic effects but did not correlate with longer-term efficacy, according to the researchers. Instead, the ratio of peak CAR T-cell expansion to tumor burden correlated significantly with event-free and overall survival.

That finding “raises the hypothesis that an effective ratio of CAR T cells to target CD19+ leukemia cells is more likely to occur in patients with a low disease burden than in those with a high disease burden, despite a smaller number of expanded T cells in patients with a low disease burden,” the investigators wrote.

The study was funded by the Commonwealth Foundation for Cancer Research, Juno Therapeutics, and others. Several study authors reported ties to Juno Therapeutics and other pharmaceutical companies.

SOURCE: Park JH et al. N Engl J Med 2018 Feb 1;378:449-59.

SAN FRANCISCO – Combination immunotherapy is efficacious for treating metastatic colorectal cancer that is deficient in mismatch repair (dMMR), giving rise to high microsatellite instability (MSI-H), according to the first report of results for the full cohort of the CheckMate-142 trial.

“Approximately 4% of patients with metastatic colorectal cancer have a deficiency in the DNA mismatch repair system. These patients benefit less from conventional chemotherapy than other patients,” lead investigator Thierry André, MD, chief of Medical Oncology at the Saint-Antoine Hospital, Paris, said at the 2018 GI Cancers Symposium.

Findings in context

“This is the largest study to date of anti-PD-1 and anti-CTLA-4 inhibitor combination in MSI-H colon cancer,” noted invited discussant Zsofia K. Stadler, MD, of Memorial Sloan Kettering Cancer Center in New York. Taken together, the results are promising.

“Is this sufficient evidence that combination therapy is superior to monotherapy with anti–PD-1? No. This trial was not intended for comparison or to show superiority,” she maintained. “This will require a large randomized comparison as has been done, for example, in melanoma. Even then, cost and value become important factors in the decision of whom to select for combination therapy.”

Study details

In CheckMate-142, the 55% overall response rate with the combination of nivolumab and ipilimumab consisted of complete response in 3.4% of patients and partial response in 51.3%, Dr. André reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. (The overall rate with nivolumab monotherapy at the same median follow-up was 31%, all partial responses.) The disease control rate was 80% with combination therapy (69% with monotherapy).

The combination achieved a similar response rate regardless of tumor PD-L1 expression and BRAF and KRAS mutational status. It was 71% in patients with a history of Lynch syndrome and 48% in those without such history.

The 12-month rates of progression-free survival and overall survival were 71% and 85%, respectively. “The PFS curve shows a plateau,” Dr. André pointed out. “This is a curve we dream about having in the first line. It’s very unusual to have that with a medical therapy in advanced disease.” (The corresponding rates with nivolumab monotherapy were 50% and 73%.)

Patients had significant, clinically meaningful improvements from baseline in quality of life with combination immunotherapy out to 91 weeks. “In my experience, this is really the first time I have had a very large number of patients going back to work in this very advanced disease,” he commented.

“No new safety signals or treatment-related deaths were reported,” Dr. André noted. The rate of treatment-related adverse events of grade 3 or 4 was 32% with the combination therapy (20% with monotherapy). The rate of events leading to discontinuation was 13% (7% with monotherapy).
 

Long-term outcomes with monotherapy

In a related presentation, Michael J. Overman, MD, an associate professor at the University of Texas MD Anderson Cancer Center, Houston, reported long-term outcomes with nivolumab monotherapy on CheckMate-142 according to prior lines of therapy.

Patients given monotherapy were classified as more heavily pretreated (at least three prior therapies, including a fluoropyrimidine, oxaliplatin, and irinotecan) and less heavily pretreated (at most two prior therapies, usually excluding irinotecan).

Findings in context

“This secondary analysis is of interest, but this is an unplanned retrospective subgroup analysis of this data,” commented Dr. Stadler, the discussant. “I think the take-home message here is that both the heavily pretreated and not-so-heavily pretreated groups have clinical benefit from this therapy. Certainly, longer-term follow-up continues to support the use of nivolumab monotherapy in previously treated dMMR colorectal cancer.”

The findings for the whole nivolumab monotherapy cohort generally mirror those seen with pembrolizumab (Keytruda), another anti–PD-1 antibody, in this patient population, except for a shorter time to response with the former, she noted. “This suggests that both nivolumab and pembrolizumab are reasonable monotherapies in metastatic MSI-H colorectal cancer.”

“Evaluation of anti–PD-1 therapies in the first-line setting is certainly warranted,” Dr. Stadler concluded. “In fact, the KEYNOTE-177 trial is a phase 3 randomized study of pembrolizumab versus investigator-choice chemotherapy for mismatch repair–deficient colorectal cancer that is already investigating this question and that is nearing completion of accrual.”

Dr. Andre disclosed that he receives honoraria from Baxter, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, MSD Oncology, Novartis, Roche/Genentech, Sanofi, Servier, and Xbiotech; that he has a consulting or advisory role with Amgen, Bristol-Myers Squibb, HalioDX, MSD Oncology, Mundipharma, Roche/Genentech, and Servier; and that he receives travel expenses from Amgen, Bristol-Myers Squibb, and Roche/Genentech. Dr. Overman disclosed that he has a consulting or advisory role with Bristol-Myers Squibb, Merrimack, and Roche/Genentech, and receives research funding Amgen, Bristol-Myers Squibb, Celgene, MedImmune, Merck, and Roche. The trial was sponsored by Bristol-Myers Squibb.

[email protected]

SOURCES: André T et al. GI Cancers Symposium Abstract 553, Overman MJ et al. GI Cancer Symposium Abstract 554.

SAN FRANCISCO – Combination immunotherapy is efficacious for treating metastatic colorectal cancer that is deficient in mismatch repair (dMMR), giving rise to high microsatellite instability (MSI-H), according to the first report of results for the full cohort of the CheckMate-142 trial.

“Approximately 4% of patients with metastatic colorectal cancer have a deficiency in the DNA mismatch repair system. These patients benefit less from conventional chemotherapy than other patients,” lead investigator Thierry André, MD, chief of Medical Oncology at the Saint-Antoine Hospital, Paris, said at the 2018 GI Cancers Symposium.

Findings in context

“This is the largest study to date of anti-PD-1 and anti-CTLA-4 inhibitor combination in MSI-H colon cancer,” noted invited discussant Zsofia K. Stadler, MD, of Memorial Sloan Kettering Cancer Center in New York. Taken together, the results are promising.

“Is this sufficient evidence that combination therapy is superior to monotherapy with anti–PD-1? No. This trial was not intended for comparison or to show superiority,” she maintained. “This will require a large randomized comparison as has been done, for example, in melanoma. Even then, cost and value become important factors in the decision of whom to select for combination therapy.”

Study details

In CheckMate-142, the 55% overall response rate with the combination of nivolumab and ipilimumab consisted of complete response in 3.4% of patients and partial response in 51.3%, Dr. André reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. (The overall rate with nivolumab monotherapy at the same median follow-up was 31%, all partial responses.) The disease control rate was 80% with combination therapy (69% with monotherapy).

The combination achieved a similar response rate regardless of tumor PD-L1 expression and BRAF and KRAS mutational status. It was 71% in patients with a history of Lynch syndrome and 48% in those without such history.

The 12-month rates of progression-free survival and overall survival were 71% and 85%, respectively. “The PFS curve shows a plateau,” Dr. André pointed out. “This is a curve we dream about having in the first line. It’s very unusual to have that with a medical therapy in advanced disease.” (The corresponding rates with nivolumab monotherapy were 50% and 73%.)

Patients had significant, clinically meaningful improvements from baseline in quality of life with combination immunotherapy out to 91 weeks. “In my experience, this is really the first time I have had a very large number of patients going back to work in this very advanced disease,” he commented.

“No new safety signals or treatment-related deaths were reported,” Dr. André noted. The rate of treatment-related adverse events of grade 3 or 4 was 32% with the combination therapy (20% with monotherapy). The rate of events leading to discontinuation was 13% (7% with monotherapy).
 

Long-term outcomes with monotherapy

In a related presentation, Michael J. Overman, MD, an associate professor at the University of Texas MD Anderson Cancer Center, Houston, reported long-term outcomes with nivolumab monotherapy on CheckMate-142 according to prior lines of therapy.

Patients given monotherapy were classified as more heavily pretreated (at least three prior therapies, including a fluoropyrimidine, oxaliplatin, and irinotecan) and less heavily pretreated (at most two prior therapies, usually excluding irinotecan).

Findings in context

“This secondary analysis is of interest, but this is an unplanned retrospective subgroup analysis of this data,” commented Dr. Stadler, the discussant. “I think the take-home message here is that both the heavily pretreated and not-so-heavily pretreated groups have clinical benefit from this therapy. Certainly, longer-term follow-up continues to support the use of nivolumab monotherapy in previously treated dMMR colorectal cancer.”

The findings for the whole nivolumab monotherapy cohort generally mirror those seen with pembrolizumab (Keytruda), another anti–PD-1 antibody, in this patient population, except for a shorter time to response with the former, she noted. “This suggests that both nivolumab and pembrolizumab are reasonable monotherapies in metastatic MSI-H colorectal cancer.”

“Evaluation of anti–PD-1 therapies in the first-line setting is certainly warranted,” Dr. Stadler concluded. “In fact, the KEYNOTE-177 trial is a phase 3 randomized study of pembrolizumab versus investigator-choice chemotherapy for mismatch repair–deficient colorectal cancer that is already investigating this question and that is nearing completion of accrual.”

Dr. Andre disclosed that he receives honoraria from Baxter, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, MSD Oncology, Novartis, Roche/Genentech, Sanofi, Servier, and Xbiotech; that he has a consulting or advisory role with Amgen, Bristol-Myers Squibb, HalioDX, MSD Oncology, Mundipharma, Roche/Genentech, and Servier; and that he receives travel expenses from Amgen, Bristol-Myers Squibb, and Roche/Genentech. Dr. Overman disclosed that he has a consulting or advisory role with Bristol-Myers Squibb, Merrimack, and Roche/Genentech, and receives research funding Amgen, Bristol-Myers Squibb, Celgene, MedImmune, Merck, and Roche. The trial was sponsored by Bristol-Myers Squibb.

[email protected]

SOURCES: André T et al. GI Cancers Symposium Abstract 553, Overman MJ et al. GI Cancer Symposium Abstract 554.

SAN FRANCISCO – Combination immunotherapy is efficacious for treating metastatic colorectal cancer that is deficient in mismatch repair (dMMR), giving rise to high microsatellite instability (MSI-H), according to the first report of results for the full cohort of the CheckMate-142 trial.

“Approximately 4% of patients with metastatic colorectal cancer have a deficiency in the DNA mismatch repair system. These patients benefit less from conventional chemotherapy than other patients,” lead investigator Thierry André, MD, chief of Medical Oncology at the Saint-Antoine Hospital, Paris, said at the 2018 GI Cancers Symposium.

Findings in context

“This is the largest study to date of anti-PD-1 and anti-CTLA-4 inhibitor combination in MSI-H colon cancer,” noted invited discussant Zsofia K. Stadler, MD, of Memorial Sloan Kettering Cancer Center in New York. Taken together, the results are promising.

“Is this sufficient evidence that combination therapy is superior to monotherapy with anti–PD-1? No. This trial was not intended for comparison or to show superiority,” she maintained. “This will require a large randomized comparison as has been done, for example, in melanoma. Even then, cost and value become important factors in the decision of whom to select for combination therapy.”

Study details

In CheckMate-142, the 55% overall response rate with the combination of nivolumab and ipilimumab consisted of complete response in 3.4% of patients and partial response in 51.3%, Dr. André reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. (The overall rate with nivolumab monotherapy at the same median follow-up was 31%, all partial responses.) The disease control rate was 80% with combination therapy (69% with monotherapy).

The combination achieved a similar response rate regardless of tumor PD-L1 expression and BRAF and KRAS mutational status. It was 71% in patients with a history of Lynch syndrome and 48% in those without such history.

The 12-month rates of progression-free survival and overall survival were 71% and 85%, respectively. “The PFS curve shows a plateau,” Dr. André pointed out. “This is a curve we dream about having in the first line. It’s very unusual to have that with a medical therapy in advanced disease.” (The corresponding rates with nivolumab monotherapy were 50% and 73%.)

Patients had significant, clinically meaningful improvements from baseline in quality of life with combination immunotherapy out to 91 weeks. “In my experience, this is really the first time I have had a very large number of patients going back to work in this very advanced disease,” he commented.

“No new safety signals or treatment-related deaths were reported,” Dr. André noted. The rate of treatment-related adverse events of grade 3 or 4 was 32% with the combination therapy (20% with monotherapy). The rate of events leading to discontinuation was 13% (7% with monotherapy).
 

Long-term outcomes with monotherapy

In a related presentation, Michael J. Overman, MD, an associate professor at the University of Texas MD Anderson Cancer Center, Houston, reported long-term outcomes with nivolumab monotherapy on CheckMate-142 according to prior lines of therapy.

Patients given monotherapy were classified as more heavily pretreated (at least three prior therapies, including a fluoropyrimidine, oxaliplatin, and irinotecan) and less heavily pretreated (at most two prior therapies, usually excluding irinotecan).

Findings in context

“This secondary analysis is of interest, but this is an unplanned retrospective subgroup analysis of this data,” commented Dr. Stadler, the discussant. “I think the take-home message here is that both the heavily pretreated and not-so-heavily pretreated groups have clinical benefit from this therapy. Certainly, longer-term follow-up continues to support the use of nivolumab monotherapy in previously treated dMMR colorectal cancer.”

The findings for the whole nivolumab monotherapy cohort generally mirror those seen with pembrolizumab (Keytruda), another anti–PD-1 antibody, in this patient population, except for a shorter time to response with the former, she noted. “This suggests that both nivolumab and pembrolizumab are reasonable monotherapies in metastatic MSI-H colorectal cancer.”

“Evaluation of anti–PD-1 therapies in the first-line setting is certainly warranted,” Dr. Stadler concluded. “In fact, the KEYNOTE-177 trial is a phase 3 randomized study of pembrolizumab versus investigator-choice chemotherapy for mismatch repair–deficient colorectal cancer that is already investigating this question and that is nearing completion of accrual.”

Dr. Andre disclosed that he receives honoraria from Baxter, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, MSD Oncology, Novartis, Roche/Genentech, Sanofi, Servier, and Xbiotech; that he has a consulting or advisory role with Amgen, Bristol-Myers Squibb, HalioDX, MSD Oncology, Mundipharma, Roche/Genentech, and Servier; and that he receives travel expenses from Amgen, Bristol-Myers Squibb, and Roche/Genentech. Dr. Overman disclosed that he has a consulting or advisory role with Bristol-Myers Squibb, Merrimack, and Roche/Genentech, and receives research funding Amgen, Bristol-Myers Squibb, Celgene, MedImmune, Merck, and Roche. The trial was sponsored by Bristol-Myers Squibb.

[email protected]

SOURCES: André T et al. GI Cancers Symposium Abstract 553, Overman MJ et al. GI Cancer Symposium Abstract 554.

After decades of hype, dashed hopes, and setbacks, gene therapy has finally arrived and is poised to transform the treatment paradigm for many diseases, according to Cynthia E. Dunbar, MD, senior investigator at the Hematology Branch of the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health.

Hematologists can expect more developments that build on current successes with chimeric antigen receptor (CAR) T-cell therapy and gene therapy advances for hemophilia, as well as emerging advances in gene editing techniques including the CRISPR/Cas9 approach, Dr. Dunbar said in an interview.

Courtesy National Heart, Lung, and Blood Institute

Milestones

A new approach to cancer treatment was ushered in on Aug. 30, 2017, with the Food and Drug Administration approval of tisagenlecleucel, the first-ever gene therapy available in the United States. The CD19-directed CAR T-cell therapy is indicated for treatment of certain pediatric or young adult patients with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse.

Soon afterward, FDA approved another CD19-directed CAR T-cell therapy, axicabtagene ciloleucel, for adult patients with large B-cell lymphoma after two or more lines of systemic therapy.

“It’s a very interesting time for immunotherapies in general,” Dr. Dunbar said. “There’s a huge number of options in terms of PD-1 inhibitors and other pharmacologics or antibodies that allow the patient’s own immune system to attack tumors. CAR T-cell therapy is an obvious step beyond that, in terms of arming your own T cells to very specifically target tumor cells.”

But randomized trials or meta-analyses may be necessary to determine the place of CAR T-cell therapy in the treatment armamentarium for acute lymphoblastic leukemia and large B-cell lymphoma given their cost and the availability of other therapeutic options, Dr. Dunbar suggested.

“Gene therapies have a large upfront cost, but if they’re truly curative and a one-time treatment, then they may in the long run be much cheaper than doing failed multiple transplants or needing monoclonal antibody infusion every 2 weeks for the rest of your life,” she said.

Another major success story still in the works, according to Dr. Dunbar, is the treatment of hemophilia A and B with gene therapy approaches. The positive data include a recent report showing that transgene-derived factor IX coagulant activity allowed for the termination of baseline prophylaxis, and the near elimination of bleeding and factor use, in patients with hemophilia B (N Engl J Med. 2017 Dec 7;377[23]:2215-27).

While gene therapy for hemophilia A has been more challenging, another recent report nevertheless demonstrated sustained normalization of factor VIII activity level with a single intravenous infusion of adeno-associated virus serotype 5 vector encoding a B-domain–deleted human factor VIII (N Engl J Med. 2017 Dec 28;377[26]:2519-30).

“The proof-of-principle was already there in hemophilia B,” Dr. Dunbar said. “It really was just a question of figuring out a way to package and deliver a Factor VIII that would work in the constraints of an AAV [adeno-associated virus] vector.”

Meanwhile, myeloma trials of CAR T-cell therapy seem very promising so far, but the challenge in that disease could be finding a place for gene therapy in a “much more diverse treatment landscape” that includes multiple effective regimens, according to Dr. Dunbar.
 

Future trends, challenges

Looking forward, gene editing with methods including the CRISPR/Cas9 approach have the potential to revolutionize treatment in HIV, b-thalassemia, and sickle cell disease, she said.

Notably, genome editing approaches to treat sickle cell anemia are likely to move forward in the near future, according to Dr. Dunbar, following reports validating an erythroid enhancer of human BCL11A as a target for reinduction of fetal hemoglobin (Nature. 2015 Nov 12;527[7577]:192-7).

But all of this gene therapy development creates an educational challenge for frontline clinicians, even if the administration of CAR T-cell therapy and other advanced treatments is limited to highly specialized centers.

“There’s a lot of training that needs to go on with hematologists, oncologists, and other doctors about how to care for these patients after these treatments, in terms of what to look for and how to intervene early to prevent, for instance, severe toxicity from cytokine release syndrome,” Dr. Dunbar said.

Dr. Dunbar reported having no relevant financial disclosures.

After decades of hype, dashed hopes, and setbacks, gene therapy has finally arrived and is poised to transform the treatment paradigm for many diseases, according to Cynthia E. Dunbar, MD, senior investigator at the Hematology Branch of the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health.

Hematologists can expect more developments that build on current successes with chimeric antigen receptor (CAR) T-cell therapy and gene therapy advances for hemophilia, as well as emerging advances in gene editing techniques including the CRISPR/Cas9 approach, Dr. Dunbar said in an interview.

Courtesy National Heart, Lung, and Blood Institute

Milestones

A new approach to cancer treatment was ushered in on Aug. 30, 2017, with the Food and Drug Administration approval of tisagenlecleucel, the first-ever gene therapy available in the United States. The CD19-directed CAR T-cell therapy is indicated for treatment of certain pediatric or young adult patients with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse.

Soon afterward, FDA approved another CD19-directed CAR T-cell therapy, axicabtagene ciloleucel, for adult patients with large B-cell lymphoma after two or more lines of systemic therapy.

“It’s a very interesting time for immunotherapies in general,” Dr. Dunbar said. “There’s a huge number of options in terms of PD-1 inhibitors and other pharmacologics or antibodies that allow the patient’s own immune system to attack tumors. CAR T-cell therapy is an obvious step beyond that, in terms of arming your own T cells to very specifically target tumor cells.”

But randomized trials or meta-analyses may be necessary to determine the place of CAR T-cell therapy in the treatment armamentarium for acute lymphoblastic leukemia and large B-cell lymphoma given their cost and the availability of other therapeutic options, Dr. Dunbar suggested.

“Gene therapies have a large upfront cost, but if they’re truly curative and a one-time treatment, then they may in the long run be much cheaper than doing failed multiple transplants or needing monoclonal antibody infusion every 2 weeks for the rest of your life,” she said.

Another major success story still in the works, according to Dr. Dunbar, is the treatment of hemophilia A and B with gene therapy approaches. The positive data include a recent report showing that transgene-derived factor IX coagulant activity allowed for the termination of baseline prophylaxis, and the near elimination of bleeding and factor use, in patients with hemophilia B (N Engl J Med. 2017 Dec 7;377[23]:2215-27).

While gene therapy for hemophilia A has been more challenging, another recent report nevertheless demonstrated sustained normalization of factor VIII activity level with a single intravenous infusion of adeno-associated virus serotype 5 vector encoding a B-domain–deleted human factor VIII (N Engl J Med. 2017 Dec 28;377[26]:2519-30).

“The proof-of-principle was already there in hemophilia B,” Dr. Dunbar said. “It really was just a question of figuring out a way to package and deliver a Factor VIII that would work in the constraints of an AAV [adeno-associated virus] vector.”

Meanwhile, myeloma trials of CAR T-cell therapy seem very promising so far, but the challenge in that disease could be finding a place for gene therapy in a “much more diverse treatment landscape” that includes multiple effective regimens, according to Dr. Dunbar.
 

Future trends, challenges

Looking forward, gene editing with methods including the CRISPR/Cas9 approach have the potential to revolutionize treatment in HIV, b-thalassemia, and sickle cell disease, she said.

Notably, genome editing approaches to treat sickle cell anemia are likely to move forward in the near future, according to Dr. Dunbar, following reports validating an erythroid enhancer of human BCL11A as a target for reinduction of fetal hemoglobin (Nature. 2015 Nov 12;527[7577]:192-7).

But all of this gene therapy development creates an educational challenge for frontline clinicians, even if the administration of CAR T-cell therapy and other advanced treatments is limited to highly specialized centers.

“There’s a lot of training that needs to go on with hematologists, oncologists, and other doctors about how to care for these patients after these treatments, in terms of what to look for and how to intervene early to prevent, for instance, severe toxicity from cytokine release syndrome,” Dr. Dunbar said.

Dr. Dunbar reported having no relevant financial disclosures.

After decades of hype, dashed hopes, and setbacks, gene therapy has finally arrived and is poised to transform the treatment paradigm for many diseases, according to Cynthia E. Dunbar, MD, senior investigator at the Hematology Branch of the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health.

Hematologists can expect more developments that build on current successes with chimeric antigen receptor (CAR) T-cell therapy and gene therapy advances for hemophilia, as well as emerging advances in gene editing techniques including the CRISPR/Cas9 approach, Dr. Dunbar said in an interview.

Courtesy National Heart, Lung, and Blood Institute

Milestones

A new approach to cancer treatment was ushered in on Aug. 30, 2017, with the Food and Drug Administration approval of tisagenlecleucel, the first-ever gene therapy available in the United States. The CD19-directed CAR T-cell therapy is indicated for treatment of certain pediatric or young adult patients with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse.

Soon afterward, FDA approved another CD19-directed CAR T-cell therapy, axicabtagene ciloleucel, for adult patients with large B-cell lymphoma after two or more lines of systemic therapy.

“It’s a very interesting time for immunotherapies in general,” Dr. Dunbar said. “There’s a huge number of options in terms of PD-1 inhibitors and other pharmacologics or antibodies that allow the patient’s own immune system to attack tumors. CAR T-cell therapy is an obvious step beyond that, in terms of arming your own T cells to very specifically target tumor cells.”

But randomized trials or meta-analyses may be necessary to determine the place of CAR T-cell therapy in the treatment armamentarium for acute lymphoblastic leukemia and large B-cell lymphoma given their cost and the availability of other therapeutic options, Dr. Dunbar suggested.

“Gene therapies have a large upfront cost, but if they’re truly curative and a one-time treatment, then they may in the long run be much cheaper than doing failed multiple transplants or needing monoclonal antibody infusion every 2 weeks for the rest of your life,” she said.

Another major success story still in the works, according to Dr. Dunbar, is the treatment of hemophilia A and B with gene therapy approaches. The positive data include a recent report showing that transgene-derived factor IX coagulant activity allowed for the termination of baseline prophylaxis, and the near elimination of bleeding and factor use, in patients with hemophilia B (N Engl J Med. 2017 Dec 7;377[23]:2215-27).

While gene therapy for hemophilia A has been more challenging, another recent report nevertheless demonstrated sustained normalization of factor VIII activity level with a single intravenous infusion of adeno-associated virus serotype 5 vector encoding a B-domain–deleted human factor VIII (N Engl J Med. 2017 Dec 28;377[26]:2519-30).

“The proof-of-principle was already there in hemophilia B,” Dr. Dunbar said. “It really was just a question of figuring out a way to package and deliver a Factor VIII that would work in the constraints of an AAV [adeno-associated virus] vector.”

Meanwhile, myeloma trials of CAR T-cell therapy seem very promising so far, but the challenge in that disease could be finding a place for gene therapy in a “much more diverse treatment landscape” that includes multiple effective regimens, according to Dr. Dunbar.
 

Future trends, challenges

Looking forward, gene editing with methods including the CRISPR/Cas9 approach have the potential to revolutionize treatment in HIV, b-thalassemia, and sickle cell disease, she said.

Notably, genome editing approaches to treat sickle cell anemia are likely to move forward in the near future, according to Dr. Dunbar, following reports validating an erythroid enhancer of human BCL11A as a target for reinduction of fetal hemoglobin (Nature. 2015 Nov 12;527[7577]:192-7).

But all of this gene therapy development creates an educational challenge for frontline clinicians, even if the administration of CAR T-cell therapy and other advanced treatments is limited to highly specialized centers.

“There’s a lot of training that needs to go on with hematologists, oncologists, and other doctors about how to care for these patients after these treatments, in terms of what to look for and how to intervene early to prevent, for instance, severe toxicity from cytokine release syndrome,” Dr. Dunbar said.

Dr. Dunbar reported having no relevant financial disclosures.

NATIONAL HARBOR, MD. – Pegylated human interleukin-10 in combination with anti–PD-1 therapy is well tolerated and shows promise for the treatment of both renal cell carcinoma and non–small cell lung cancer, according to findings from a phase 1 study.

The IL-10 product, AM0010 (pegilodecakin), was shown to be well tolerated as monotherapy, and was evaluated in combination with anti–PD-1 therapy in the two expansion cohorts included in the current analysis, Martin Oft, MD, said at the annual meeting of the Society for Immunotherapy of Cancer.

Of 34 evaluable renal cell carcinoma (RCC) patients included in one expansion cohort, 15 (44%) had an objective response at a median follow-up of 27 months, and two of those had a complete response (CR), Dr. Oft of ARMO BioSciences, Redwood City, Calif. reported.

In contrast, only 4 of 16 evaluable patients who received AM0010 monotherapy (25%) had an objective response, he said.

In eight patients who received AM0010 + pembrolizumab (Keytruda), the objective response rate was 50%, and both patients who had a complete response were in that group. The median progression-free survival (PFS) was 16.7 months. In 26 who received AM0010 + nivolumab (Opdivo), 11 had an objective response, but neither the complete response nor PFS rates had been reached in patients in that group, he noted.

The responses were durable.

“In fact, we had one patient who stopped treatment after a year in [complete remission] and is now 1 year in total remission without any further treatment,” he said.

Patients with non–small cell lung cancer (NSCLC) also experienced some benefit from the combination therapy. Objective responses were observed in 11 of 27 evaluable NSCLC patients (41%) who were treated with AM0010 and an anti–PD-1(9 of 22 [41%] who received AM0010 and nivolumab, and 2 of 5 [40%] who received AM0010 and pembrolizumab).

Progression-free survival was not reached in this cohort.

An analysis by PD-L1 status showed that 33% of NSCLC patients with PD-L1 levels less than 1% achieved a response, 67% of those with PD-L1 levels of 1%-49% achieved a response, and 80% of those with PD-L1 levels of 50% or greater achieved a response, he said, adding that the responses were very durable in all three groups.

Of note, NSCLC patients with liver metastasis have been shown in prior trials to have a lower overall response rate to immune checkpoint inhibition, but in this trial, 7 of 9 patients with NSCLC metastasis to the liver had a partial response (PR), Dr. Oft said.

The RCC and NSCLC patients had a median of 1 and 2 prior therapies, respectively.

AM0010 was given subcutaneously at a dose of 10 or 20 mcg/kg daily, pembrolizumab was given intravenously at 2mg/kg every 3 weeks, and nivolumab was given intravenously at a dose of 3 mg/kg every 2 weeks.

Treatment-related adverse events included anemia, thrombocytopenia, and fatigue, and all were reversible and transient, Dr. Oft said, noting that grade 3 or 4 adverse events were mostly absent in patients receiving the lower dose; thus the recommended phase 2 dose is 10 mcg/kg.

“It’s important to note that three of those six patients [receiving the lower dose] in fact had a PR or CR so this lower dose did not come at the expense of efficacy,” he added.

The mechanistic rationale for combining AM0010 and anti-PD1 for the treatment of cancer patients lies in the fact that IL‐10 has anti‐inflammatory functions and stimulates the cytotoxicity and proliferation of antigen-activated CD8+ T cells. T cell receptor–mediated activation of CD8+ T cells elevates IL‐10 receptors and PD‐1, Dr. Oft explained.

The robust efficacy data and the observed CD8+ T cell activation seen in these expansion cohorts is promising and encourages the continued study of AM0010 in combination with PD-1 inhibition, he concluded, noting that larger studies are planned for the coming year.

Dr. Oft is a founder and employee of ARMO BioSciences, which sponsored this study.

[email protected]

SOURCE: Naing A et al. SITC Abstract 012.

NATIONAL HARBOR, MD. – Pegylated human interleukin-10 in combination with anti–PD-1 therapy is well tolerated and shows promise for the treatment of both renal cell carcinoma and non–small cell lung cancer, according to findings from a phase 1 study.

The IL-10 product, AM0010 (pegilodecakin), was shown to be well tolerated as monotherapy, and was evaluated in combination with anti–PD-1 therapy in the two expansion cohorts included in the current analysis, Martin Oft, MD, said at the annual meeting of the Society for Immunotherapy of Cancer.

Of 34 evaluable renal cell carcinoma (RCC) patients included in one expansion cohort, 15 (44%) had an objective response at a median follow-up of 27 months, and two of those had a complete response (CR), Dr. Oft of ARMO BioSciences, Redwood City, Calif. reported.

In contrast, only 4 of 16 evaluable patients who received AM0010 monotherapy (25%) had an objective response, he said.

In eight patients who received AM0010 + pembrolizumab (Keytruda), the objective response rate was 50%, and both patients who had a complete response were in that group. The median progression-free survival (PFS) was 16.7 months. In 26 who received AM0010 + nivolumab (Opdivo), 11 had an objective response, but neither the complete response nor PFS rates had been reached in patients in that group, he noted.

The responses were durable.

“In fact, we had one patient who stopped treatment after a year in [complete remission] and is now 1 year in total remission without any further treatment,” he said.

Patients with non–small cell lung cancer (NSCLC) also experienced some benefit from the combination therapy. Objective responses were observed in 11 of 27 evaluable NSCLC patients (41%) who were treated with AM0010 and an anti–PD-1(9 of 22 [41%] who received AM0010 and nivolumab, and 2 of 5 [40%] who received AM0010 and pembrolizumab).

Progression-free survival was not reached in this cohort.

An analysis by PD-L1 status showed that 33% of NSCLC patients with PD-L1 levels less than 1% achieved a response, 67% of those with PD-L1 levels of 1%-49% achieved a response, and 80% of those with PD-L1 levels of 50% or greater achieved a response, he said, adding that the responses were very durable in all three groups.

Of note, NSCLC patients with liver metastasis have been shown in prior trials to have a lower overall response rate to immune checkpoint inhibition, but in this trial, 7 of 9 patients with NSCLC metastasis to the liver had a partial response (PR), Dr. Oft said.

The RCC and NSCLC patients had a median of 1 and 2 prior therapies, respectively.

AM0010 was given subcutaneously at a dose of 10 or 20 mcg/kg daily, pembrolizumab was given intravenously at 2mg/kg every 3 weeks, and nivolumab was given intravenously at a dose of 3 mg/kg every 2 weeks.

Treatment-related adverse events included anemia, thrombocytopenia, and fatigue, and all were reversible and transient, Dr. Oft said, noting that grade 3 or 4 adverse events were mostly absent in patients receiving the lower dose; thus the recommended phase 2 dose is 10 mcg/kg.

“It’s important to note that three of those six patients [receiving the lower dose] in fact had a PR or CR so this lower dose did not come at the expense of efficacy,” he added.

The mechanistic rationale for combining AM0010 and anti-PD1 for the treatment of cancer patients lies in the fact that IL‐10 has anti‐inflammatory functions and stimulates the cytotoxicity and proliferation of antigen-activated CD8+ T cells. T cell receptor–mediated activation of CD8+ T cells elevates IL‐10 receptors and PD‐1, Dr. Oft explained.

The robust efficacy data and the observed CD8+ T cell activation seen in these expansion cohorts is promising and encourages the continued study of AM0010 in combination with PD-1 inhibition, he concluded, noting that larger studies are planned for the coming year.

Dr. Oft is a founder and employee of ARMO BioSciences, which sponsored this study.

[email protected]

SOURCE: Naing A et al. SITC Abstract 012.

NATIONAL HARBOR, MD. – Pegylated human interleukin-10 in combination with anti–PD-1 therapy is well tolerated and shows promise for the treatment of both renal cell carcinoma and non–small cell lung cancer, according to findings from a phase 1 study.

The IL-10 product, AM0010 (pegilodecakin), was shown to be well tolerated as monotherapy, and was evaluated in combination with anti–PD-1 therapy in the two expansion cohorts included in the current analysis, Martin Oft, MD, said at the annual meeting of the Society for Immunotherapy of Cancer.

Of 34 evaluable renal cell carcinoma (RCC) patients included in one expansion cohort, 15 (44%) had an objective response at a median follow-up of 27 months, and two of those had a complete response (CR), Dr. Oft of ARMO BioSciences, Redwood City, Calif. reported.

In contrast, only 4 of 16 evaluable patients who received AM0010 monotherapy (25%) had an objective response, he said.

In eight patients who received AM0010 + pembrolizumab (Keytruda), the objective response rate was 50%, and both patients who had a complete response were in that group. The median progression-free survival (PFS) was 16.7 months. In 26 who received AM0010 + nivolumab (Opdivo), 11 had an objective response, but neither the complete response nor PFS rates had been reached in patients in that group, he noted.

The responses were durable.

“In fact, we had one patient who stopped treatment after a year in [complete remission] and is now 1 year in total remission without any further treatment,” he said.

Patients with non–small cell lung cancer (NSCLC) also experienced some benefit from the combination therapy. Objective responses were observed in 11 of 27 evaluable NSCLC patients (41%) who were treated with AM0010 and an anti–PD-1(9 of 22 [41%] who received AM0010 and nivolumab, and 2 of 5 [40%] who received AM0010 and pembrolizumab).

Progression-free survival was not reached in this cohort.

An analysis by PD-L1 status showed that 33% of NSCLC patients with PD-L1 levels less than 1% achieved a response, 67% of those with PD-L1 levels of 1%-49% achieved a response, and 80% of those with PD-L1 levels of 50% or greater achieved a response, he said, adding that the responses were very durable in all three groups.

Of note, NSCLC patients with liver metastasis have been shown in prior trials to have a lower overall response rate to immune checkpoint inhibition, but in this trial, 7 of 9 patients with NSCLC metastasis to the liver had a partial response (PR), Dr. Oft said.

The RCC and NSCLC patients had a median of 1 and 2 prior therapies, respectively.

AM0010 was given subcutaneously at a dose of 10 or 20 mcg/kg daily, pembrolizumab was given intravenously at 2mg/kg every 3 weeks, and nivolumab was given intravenously at a dose of 3 mg/kg every 2 weeks.

Treatment-related adverse events included anemia, thrombocytopenia, and fatigue, and all were reversible and transient, Dr. Oft said, noting that grade 3 or 4 adverse events were mostly absent in patients receiving the lower dose; thus the recommended phase 2 dose is 10 mcg/kg.

“It’s important to note that three of those six patients [receiving the lower dose] in fact had a PR or CR so this lower dose did not come at the expense of efficacy,” he added.

The mechanistic rationale for combining AM0010 and anti-PD1 for the treatment of cancer patients lies in the fact that IL‐10 has anti‐inflammatory functions and stimulates the cytotoxicity and proliferation of antigen-activated CD8+ T cells. T cell receptor–mediated activation of CD8+ T cells elevates IL‐10 receptors and PD‐1, Dr. Oft explained.

The robust efficacy data and the observed CD8+ T cell activation seen in these expansion cohorts is promising and encourages the continued study of AM0010 in combination with PD-1 inhibition, he concluded, noting that larger studies are planned for the coming year.

Dr. Oft is a founder and employee of ARMO BioSciences, which sponsored this study.

[email protected]

SOURCE: Naing A et al. SITC Abstract 012.

ATLANTA – More than one-third of patients with refractory large B-cell lymphomas treated with the chimeric antigen receptor (CAR) T-cell product axicabtagene ciloleucel (Yescarta), often called axi-cel, had durable responses, with some patients having complete responses lasting more than 1 year after a single infusion, according to investigators in the ZUMA-1 trial.

Neil Osterweil/Frontline Medical News

Updated combined phase 1 and phase 2 results in 108 patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL) showed an objective response rate (ORR) of 82%, including 58% complete responses, after a median follow-up of 15.4 months, reported Sattva S. Neelapu, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“Axi-cel is highly effective in patients with large B-cell lymphoma who otherwise have no curative treatment options,” he said in a briefing at the annual meeting of the American Society of Hematology, prior to his presentation of the data in an oral session.

The trial results were also published simultaneously in the New England Journal of Medicine.As previously reported, in the multicenter phase 2 ZUMA-1 trial, 111 patients with treatment refractory DLBCL, PMBCL, or TFL were enrolled and treated with axi-cel at a target dose of 2 x 10⁶ cells/kg, following a conditioning regimen with low-dose cyclophosphamide and fludarabine.

The median patient age was 58 years. Patients had stage III or IV disease, 48% had International Prognostic Index scores of 3-4, 76% had disease that was refractory to third-line therapies or beyond, and 21% had disease that relapsed within 12 months of an autologous bone marrow transplant

Axi-cel was successfully manufactured with sufficient cells for transfusion in all but one of the 111 patients, and 101 patients eventually received infusions in phase 2 (modified intention-to-treat population). The average turnaround time from apheresis to the clinical site was 17 days.

Dr. Neelapu also presented data on seven patients enrolled in phase 1; the data were combined with the phase 2 results for an updated analysis of those patients who had at least 1 year of follow-up.

The phase 2 trial met its primary endpoint at the time of the primary analysis, with an 82% ORR, consisting of 54% complete responses and 28% partial responses at a median follow-up of 8.7 months.

In the updated analysis, the ORR and respective remission rates were 82%, 58%, and 34%, at a median of 15.4 months follow-up.

The median duration of response in the updated analysis was 11.1 months. The median duration of complete responses had not been reached at the time of data cutoff in August 2017. The median duration of partial responses was 1.9 months.

At the 15.4-month mark, 42% of patients remained free of disease progression, and 56% were alive, with the median overall survival not yet reached.

The treatment had generally acceptable toxicities, with only 13% of patients in phase 2 experiencing grade 3 or greater cytokine release syndrome (CRS), although one patient with CRS died from hemophagocytic lymphohistiocytosis, and one with CRS died from cardiac arrest. Grade 3 or greater neurologic events occurred in 28% of patients, and included encephalopathy, confusional state, aphasia, and somnolence.

The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.

Since the primary analysis with at least 6 months of follow-up, there have been no new axi-cel–related cases of CRS, neurologic events, or deaths.

Dr. Neelapu also presented safety data on serious adverse events occurring more than 6 months after therapy in 10 patients who developed symptoms after the data cutoff.

Grade 3 events in these patients included lung infection, recurrent upper respiratory viral infection, and rotavirus infection, pneumonias, atrial fibrillation with rapid ventricular response, lung infection, febrile neutropenia, and influenza B infection. One patient had grade 4 sepsis.

In an editorial accompanying the study in the New England Journal of Medicine, Eric Tran, PhD, and Walter J. Urba, MD, PhD, from the Earle A. Chiles Research Institute and the Providence Portland (Ore.) Medical Center, and Dan L. Longo, MD, deputy editor of the journal, praised ZUMA-1 as “a landmark study because it involved 22 institutions and showed that a personalized gene-engineered T-cell product could be rapidly generated at a centralized cell-manufacturing facility and safely administered to patients at transplantation-capable medical centers.”

They noted, however, that about half of all patients with relapsed or refractory large B-cell lymphomas will not have durable responses to CAR T-cell therapy directed against CD19, and that new strategies will be needed to improve responses (N Engl J Med. 2017 Dec 10; doi: 10.1056/NEJMe1714680).

In the question and answer session at the end of the briefing, Dr. Neelapu said the preliminary observations of mechanisms of relapse or disease progression in some patients may be related to the loss of the CD19 antigen, which occurs in about one-third of patients who experience relapse, and to high expression of the programmed death ligand-1, which can potentially inhibit CAR-T cell function. A clinical trial is currently underway to evaluate potential strategies for improving response rates to CAR-T therapies, he said.

ZUMA-1 is supported by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program. Dr. Neelapu reported receiving advisory board fees from the company. Myriad coauthors also reported financial relationship with multiple companies.

SOURCE: Neelapu S et al. ASH 2017 Abstract 578.

ATLANTA – More than one-third of patients with refractory large B-cell lymphomas treated with the chimeric antigen receptor (CAR) T-cell product axicabtagene ciloleucel (Yescarta), often called axi-cel, had durable responses, with some patients having complete responses lasting more than 1 year after a single infusion, according to investigators in the ZUMA-1 trial.

Neil Osterweil/Frontline Medical News

Updated combined phase 1 and phase 2 results in 108 patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL) showed an objective response rate (ORR) of 82%, including 58% complete responses, after a median follow-up of 15.4 months, reported Sattva S. Neelapu, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“Axi-cel is highly effective in patients with large B-cell lymphoma who otherwise have no curative treatment options,” he said in a briefing at the annual meeting of the American Society of Hematology, prior to his presentation of the data in an oral session.

The trial results were also published simultaneously in the New England Journal of Medicine.As previously reported, in the multicenter phase 2 ZUMA-1 trial, 111 patients with treatment refractory DLBCL, PMBCL, or TFL were enrolled and treated with axi-cel at a target dose of 2 x 10⁶ cells/kg, following a conditioning regimen with low-dose cyclophosphamide and fludarabine.

The median patient age was 58 years. Patients had stage III or IV disease, 48% had International Prognostic Index scores of 3-4, 76% had disease that was refractory to third-line therapies or beyond, and 21% had disease that relapsed within 12 months of an autologous bone marrow transplant

Axi-cel was successfully manufactured with sufficient cells for transfusion in all but one of the 111 patients, and 101 patients eventually received infusions in phase 2 (modified intention-to-treat population). The average turnaround time from apheresis to the clinical site was 17 days.

Dr. Neelapu also presented data on seven patients enrolled in phase 1; the data were combined with the phase 2 results for an updated analysis of those patients who had at least 1 year of follow-up.

The phase 2 trial met its primary endpoint at the time of the primary analysis, with an 82% ORR, consisting of 54% complete responses and 28% partial responses at a median follow-up of 8.7 months.

In the updated analysis, the ORR and respective remission rates were 82%, 58%, and 34%, at a median of 15.4 months follow-up.

The median duration of response in the updated analysis was 11.1 months. The median duration of complete responses had not been reached at the time of data cutoff in August 2017. The median duration of partial responses was 1.9 months.

At the 15.4-month mark, 42% of patients remained free of disease progression, and 56% were alive, with the median overall survival not yet reached.

The treatment had generally acceptable toxicities, with only 13% of patients in phase 2 experiencing grade 3 or greater cytokine release syndrome (CRS), although one patient with CRS died from hemophagocytic lymphohistiocytosis, and one with CRS died from cardiac arrest. Grade 3 or greater neurologic events occurred in 28% of patients, and included encephalopathy, confusional state, aphasia, and somnolence.

The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.

Since the primary analysis with at least 6 months of follow-up, there have been no new axi-cel–related cases of CRS, neurologic events, or deaths.

Dr. Neelapu also presented safety data on serious adverse events occurring more than 6 months after therapy in 10 patients who developed symptoms after the data cutoff.

Grade 3 events in these patients included lung infection, recurrent upper respiratory viral infection, and rotavirus infection, pneumonias, atrial fibrillation with rapid ventricular response, lung infection, febrile neutropenia, and influenza B infection. One patient had grade 4 sepsis.

In an editorial accompanying the study in the New England Journal of Medicine, Eric Tran, PhD, and Walter J. Urba, MD, PhD, from the Earle A. Chiles Research Institute and the Providence Portland (Ore.) Medical Center, and Dan L. Longo, MD, deputy editor of the journal, praised ZUMA-1 as “a landmark study because it involved 22 institutions and showed that a personalized gene-engineered T-cell product could be rapidly generated at a centralized cell-manufacturing facility and safely administered to patients at transplantation-capable medical centers.”

They noted, however, that about half of all patients with relapsed or refractory large B-cell lymphomas will not have durable responses to CAR T-cell therapy directed against CD19, and that new strategies will be needed to improve responses (N Engl J Med. 2017 Dec 10; doi: 10.1056/NEJMe1714680).

In the question and answer session at the end of the briefing, Dr. Neelapu said the preliminary observations of mechanisms of relapse or disease progression in some patients may be related to the loss of the CD19 antigen, which occurs in about one-third of patients who experience relapse, and to high expression of the programmed death ligand-1, which can potentially inhibit CAR-T cell function. A clinical trial is currently underway to evaluate potential strategies for improving response rates to CAR-T therapies, he said.

ZUMA-1 is supported by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program. Dr. Neelapu reported receiving advisory board fees from the company. Myriad coauthors also reported financial relationship with multiple companies.

SOURCE: Neelapu S et al. ASH 2017 Abstract 578.

ATLANTA – More than one-third of patients with refractory large B-cell lymphomas treated with the chimeric antigen receptor (CAR) T-cell product axicabtagene ciloleucel (Yescarta), often called axi-cel, had durable responses, with some patients having complete responses lasting more than 1 year after a single infusion, according to investigators in the ZUMA-1 trial.

Neil Osterweil/Frontline Medical News

Updated combined phase 1 and phase 2 results in 108 patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL) showed an objective response rate (ORR) of 82%, including 58% complete responses, after a median follow-up of 15.4 months, reported Sattva S. Neelapu, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“Axi-cel is highly effective in patients with large B-cell lymphoma who otherwise have no curative treatment options,” he said in a briefing at the annual meeting of the American Society of Hematology, prior to his presentation of the data in an oral session.

The trial results were also published simultaneously in the New England Journal of Medicine.As previously reported, in the multicenter phase 2 ZUMA-1 trial, 111 patients with treatment refractory DLBCL, PMBCL, or TFL were enrolled and treated with axi-cel at a target dose of 2 x 10⁶ cells/kg, following a conditioning regimen with low-dose cyclophosphamide and fludarabine.

The median patient age was 58 years. Patients had stage III or IV disease, 48% had International Prognostic Index scores of 3-4, 76% had disease that was refractory to third-line therapies or beyond, and 21% had disease that relapsed within 12 months of an autologous bone marrow transplant

Axi-cel was successfully manufactured with sufficient cells for transfusion in all but one of the 111 patients, and 101 patients eventually received infusions in phase 2 (modified intention-to-treat population). The average turnaround time from apheresis to the clinical site was 17 days.

Dr. Neelapu also presented data on seven patients enrolled in phase 1; the data were combined with the phase 2 results for an updated analysis of those patients who had at least 1 year of follow-up.

The phase 2 trial met its primary endpoint at the time of the primary analysis, with an 82% ORR, consisting of 54% complete responses and 28% partial responses at a median follow-up of 8.7 months.

In the updated analysis, the ORR and respective remission rates were 82%, 58%, and 34%, at a median of 15.4 months follow-up.

The median duration of response in the updated analysis was 11.1 months. The median duration of complete responses had not been reached at the time of data cutoff in August 2017. The median duration of partial responses was 1.9 months.

At the 15.4-month mark, 42% of patients remained free of disease progression, and 56% were alive, with the median overall survival not yet reached.

The treatment had generally acceptable toxicities, with only 13% of patients in phase 2 experiencing grade 3 or greater cytokine release syndrome (CRS), although one patient with CRS died from hemophagocytic lymphohistiocytosis, and one with CRS died from cardiac arrest. Grade 3 or greater neurologic events occurred in 28% of patients, and included encephalopathy, confusional state, aphasia, and somnolence.

The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.

Since the primary analysis with at least 6 months of follow-up, there have been no new axi-cel–related cases of CRS, neurologic events, or deaths.

Dr. Neelapu also presented safety data on serious adverse events occurring more than 6 months after therapy in 10 patients who developed symptoms after the data cutoff.

Grade 3 events in these patients included lung infection, recurrent upper respiratory viral infection, and rotavirus infection, pneumonias, atrial fibrillation with rapid ventricular response, lung infection, febrile neutropenia, and influenza B infection. One patient had grade 4 sepsis.

In an editorial accompanying the study in the New England Journal of Medicine, Eric Tran, PhD, and Walter J. Urba, MD, PhD, from the Earle A. Chiles Research Institute and the Providence Portland (Ore.) Medical Center, and Dan L. Longo, MD, deputy editor of the journal, praised ZUMA-1 as “a landmark study because it involved 22 institutions and showed that a personalized gene-engineered T-cell product could be rapidly generated at a centralized cell-manufacturing facility and safely administered to patients at transplantation-capable medical centers.”

They noted, however, that about half of all patients with relapsed or refractory large B-cell lymphomas will not have durable responses to CAR T-cell therapy directed against CD19, and that new strategies will be needed to improve responses (N Engl J Med. 2017 Dec 10; doi: 10.1056/NEJMe1714680).

In the question and answer session at the end of the briefing, Dr. Neelapu said the preliminary observations of mechanisms of relapse or disease progression in some patients may be related to the loss of the CD19 antigen, which occurs in about one-third of patients who experience relapse, and to high expression of the programmed death ligand-1, which can potentially inhibit CAR-T cell function. A clinical trial is currently underway to evaluate potential strategies for improving response rates to CAR-T therapies, he said.

ZUMA-1 is supported by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program. Dr. Neelapu reported receiving advisory board fees from the company. Myriad coauthors also reported financial relationship with multiple companies.

SOURCE: Neelapu S et al. ASH 2017 Abstract 578.

NATIONAL HARBOR, MD. – Combining programmed death (PD)-1 blockade with tumor-targeted T-cell activation by a novel DNA vaccine safely enhanced antitumor immune responses in metastatic castration-resistant prostate cancer (mCRPC) patients in a randomized clinical study.

Of 26 patients with mCRPC who were evaluable for response, 13 received treatment with an investigational DNA vaccine (pTVG-HP) that encodes prostatic acid phosphatase (PAP) and concurrent PD-1 blockade, and 13 received sequential vaccination and PD-1 blockade. No difference was seen between the groups with respect to progression-free survival at 6 months, but of eight patients in the concurrent therapy arm who had measurable disease, one experienced a partial response and two experienced a reduction in tumor volume, Douglas G. McNeel, MD, PhD, reported at the annual meeting of the Society for Immunotherapy of Cancer.

“We did not see objective responses in [six patients with measurable disease in the sequential treatment arm], said Dr. McNeel, a professor at the University of Wisconsin, Madison.

Prostate specific antigen (PSA) responses, which may be a more sensitive marker, were also more common in the concurrent treatment group; 8 of 13 patients in that group had a PSA decline from baseline, and 4 of those had a decline of greater than 25% from baseline, whereas only 1 of the 13 patients in the sequential treatment arm experienced any decline in PSA vs. baseline, Dr. McNeel said.

Responses to the vaccine’s target antigen, prostatic acid phosphatase, were seen in both arms, but only those who received the combined treatment and who had evidence of immune response experienced PSA decline, he added.

Pre- and postvaccination biopsies of metastatic sites showed that concurrent treatment, compared with sequential treatment, elicited tumor-infiltrating CD8+ T cells, PD-L1 expression in tumors, and changes associated with CD8+ T-cell activation, he said, adding that immunization with concurrent PD-1 blockade also elicits changes in proliferation detected by (¹⁸F) fluorothymidine PET/CT.

“We’ve been interested in vaccines for cancer, because we know that having the right kind of T cells in the tumor microenvironment is associated with better long-term outcomes,” Dr. McNeel said, noting that the ability of vaccines to activate T cells and augment cytolytic T cells, in particular, should have anticancer activity.

However, the clinical activity of single-agent tumor vaccines has been underwhelming, he noted.

PAP has been a focus in vaccine development, because it is essentially restricted to prostate tissue in humans. A nearly identical prostate-specific rat homologue was used in early studies, and PAP permits evaluation of serum PSA as an independent assessment of response in human trials, he explained.

“It’s the same target as the sipuleucel-T vaccine,” he said, referring to a Food and Drug Administration–approved vaccine for prostate cancer(Provenge).

Two prior phase 1/2 trials looking at DNA vaccine encoding PAP in patients with early biochemically recurrent prostate cancer showed that PAP-specific T-cell immune responses were elicited and that no significant adverse events occurred.

In both trials, the development of persistent PAP-specific, interferon-gamma–secreting T cells was associated with favorable change in PSA doubling time (suggesting a possible impact on the disease), and with PD-L1 expression in circulating tumor cells (suggesting a potential mechanism of resistance), he said.

Laboratory studies helped identify mechanisms of immune resistance following DNA immunization, he said, explaining that immunization elicits T cells secreting interferon-gamma, which leads to an increase in PD-L1 expression on tumor cells.

Encoding epitopes with increased major histocompatibility complex class 1 affinity elicited CD+ t cells with increased and persistent PD-1 expression, and blockade of PD-1 or PD-L1 with vaccination led to improved antitumor responses, he said.

The findings led to the new model focused on timing of PD-1 blockade with vaccine T-cell activation studied in the current trial.

It was hypothesized that PD-1 blockade at the time of T-cell activation with vaccination would be more effective than was blockade of PD-1-regulated T cells previously elicited with vaccination.

Study subjects had mCRPC and evidence of disease progression. Previous treatment with abiraterone(Zytiga), enzalutamide(Xtandi), or chemotherapy, was allowed, but patients with prior sipuleucel-T vaccine exposure were excluded.

Patients in the concurrent treatment arm received both the vaccine and PD-1 blockade with pembrolizumab (Keytruda)over 12 weeks, and those in the sequential therapy arm received vaccination first followed by PD-1 blockade, each for 12 weeks.

Both approaches were well tolerated.

“Essentially, we saw nothing that was unexpected,” Dr. McNeel said.

Adverse events greater than grade 2 included fatigue in one patient, diarrhea in one patient, and autoimmune hepatitis in one patient. No patients discontinued treatment from toxicity, he noted.

One death occurred during follow-up in a patient who had evidence of progression and refused further follow-up, therefore it could not be determined if the death was related to treatment.

The current findings, which are notable in part because PD-1 pathway inhibitors have demonstrated little clinical activity when used as single agents for prostate cancer and which expand upon data presented in a scientific poster at SITC 2016, demonstrate that combining this blockade with tumor-targeted T-cell activation by a DNA vaccine is safe and can augment tumor-specific T cells – as detectable within the peripheral blood and by imaging – and can result in objective antitumor changes.

“To summarize, plasmid DNA vaccines can elicit antigen-specific CD8+ T cells; immunization can increase PD-L1 expression on tumor cells – and we’ve demonstrated, in mice anyway, that this is mediated by the T cells elicited with immunization; PD-1 expression increases on CD8+ T cells following vaccination; and we think this is an opportunity to use checkpoint blockade at the point of vaccination to improve antitumor responses,” Dr. McNeel said.

“So we can look at this as PD-1 blockade to improve the effect of vaccination, but we can also look at it the other way around, and that is that anti-tumor vaccines can elicit the tumor-specific CD8+ T cells needed to enable PD-1 blockade to work,” he said. “ I think this has implications for the choice of vaccine approach, the antigen, and the timing of PD-1 blockade.”

Based on these results, an expansion arm has been opened to evaluate the safety and clinical efficacy of combination treatment beyond 12 weeks, and future studies will look at the combination of two different vaccines to improve antitumor response, he said.

Dr. McNeel disclosed financial relationships (intellectual property rights/patent holder, consultant, ownership interest) with Madison Vaccines Inc. The study is funded by a 2014 Movember PCF Challenge Award and Madison Vaccines.

[email protected]

SOURCE: McNeel D et al., J Immunother Cancer. 2017 5(Suppl 2):86 Abstract O11.

NATIONAL HARBOR, MD. – Combining programmed death (PD)-1 blockade with tumor-targeted T-cell activation by a novel DNA vaccine safely enhanced antitumor immune responses in metastatic castration-resistant prostate cancer (mCRPC) patients in a randomized clinical study.

Of 26 patients with mCRPC who were evaluable for response, 13 received treatment with an investigational DNA vaccine (pTVG-HP) that encodes prostatic acid phosphatase (PAP) and concurrent PD-1 blockade, and 13 received sequential vaccination and PD-1 blockade. No difference was seen between the groups with respect to progression-free survival at 6 months, but of eight patients in the concurrent therapy arm who had measurable disease, one experienced a partial response and two experienced a reduction in tumor volume, Douglas G. McNeel, MD, PhD, reported at the annual meeting of the Society for Immunotherapy of Cancer.

“We did not see objective responses in [six patients with measurable disease in the sequential treatment arm], said Dr. McNeel, a professor at the University of Wisconsin, Madison.

Prostate specific antigen (PSA) responses, which may be a more sensitive marker, were also more common in the concurrent treatment group; 8 of 13 patients in that group had a PSA decline from baseline, and 4 of those had a decline of greater than 25% from baseline, whereas only 1 of the 13 patients in the sequential treatment arm experienced any decline in PSA vs. baseline, Dr. McNeel said.

Responses to the vaccine’s target antigen, prostatic acid phosphatase, were seen in both arms, but only those who received the combined treatment and who had evidence of immune response experienced PSA decline, he added.

Pre- and postvaccination biopsies of metastatic sites showed that concurrent treatment, compared with sequential treatment, elicited tumor-infiltrating CD8+ T cells, PD-L1 expression in tumors, and changes associated with CD8+ T-cell activation, he said, adding that immunization with concurrent PD-1 blockade also elicits changes in proliferation detected by (¹⁸F) fluorothymidine PET/CT.

“We’ve been interested in vaccines for cancer, because we know that having the right kind of T cells in the tumor microenvironment is associated with better long-term outcomes,” Dr. McNeel said, noting that the ability of vaccines to activate T cells and augment cytolytic T cells, in particular, should have anticancer activity.

However, the clinical activity of single-agent tumor vaccines has been underwhelming, he noted.

PAP has been a focus in vaccine development, because it is essentially restricted to prostate tissue in humans. A nearly identical prostate-specific rat homologue was used in early studies, and PAP permits evaluation of serum PSA as an independent assessment of response in human trials, he explained.

“It’s the same target as the sipuleucel-T vaccine,” he said, referring to a Food and Drug Administration–approved vaccine for prostate cancer(Provenge).

Two prior phase 1/2 trials looking at DNA vaccine encoding PAP in patients with early biochemically recurrent prostate cancer showed that PAP-specific T-cell immune responses were elicited and that no significant adverse events occurred.

In both trials, the development of persistent PAP-specific, interferon-gamma–secreting T cells was associated with favorable change in PSA doubling time (suggesting a possible impact on the disease), and with PD-L1 expression in circulating tumor cells (suggesting a potential mechanism of resistance), he said.

Laboratory studies helped identify mechanisms of immune resistance following DNA immunization, he said, explaining that immunization elicits T cells secreting interferon-gamma, which leads to an increase in PD-L1 expression on tumor cells.

Encoding epitopes with increased major histocompatibility complex class 1 affinity elicited CD+ t cells with increased and persistent PD-1 expression, and blockade of PD-1 or PD-L1 with vaccination led to improved antitumor responses, he said.

The findings led to the new model focused on timing of PD-1 blockade with vaccine T-cell activation studied in the current trial.

It was hypothesized that PD-1 blockade at the time of T-cell activation with vaccination would be more effective than was blockade of PD-1-regulated T cells previously elicited with vaccination.

Study subjects had mCRPC and evidence of disease progression. Previous treatment with abiraterone(Zytiga), enzalutamide(Xtandi), or chemotherapy, was allowed, but patients with prior sipuleucel-T vaccine exposure were excluded.

Patients in the concurrent treatment arm received both the vaccine and PD-1 blockade with pembrolizumab (Keytruda)over 12 weeks, and those in the sequential therapy arm received vaccination first followed by PD-1 blockade, each for 12 weeks.

Both approaches were well tolerated.

“Essentially, we saw nothing that was unexpected,” Dr. McNeel said.

Adverse events greater than grade 2 included fatigue in one patient, diarrhea in one patient, and autoimmune hepatitis in one patient. No patients discontinued treatment from toxicity, he noted.

One death occurred during follow-up in a patient who had evidence of progression and refused further follow-up, therefore it could not be determined if the death was related to treatment.

The current findings, which are notable in part because PD-1 pathway inhibitors have demonstrated little clinical activity when used as single agents for prostate cancer and which expand upon data presented in a scientific poster at SITC 2016, demonstrate that combining this blockade with tumor-targeted T-cell activation by a DNA vaccine is safe and can augment tumor-specific T cells – as detectable within the peripheral blood and by imaging – and can result in objective antitumor changes.

“To summarize, plasmid DNA vaccines can elicit antigen-specific CD8+ T cells; immunization can increase PD-L1 expression on tumor cells – and we’ve demonstrated, in mice anyway, that this is mediated by the T cells elicited with immunization; PD-1 expression increases on CD8+ T cells following vaccination; and we think this is an opportunity to use checkpoint blockade at the point of vaccination to improve antitumor responses,” Dr. McNeel said.

“So we can look at this as PD-1 blockade to improve the effect of vaccination, but we can also look at it the other way around, and that is that anti-tumor vaccines can elicit the tumor-specific CD8+ T cells needed to enable PD-1 blockade to work,” he said. “ I think this has implications for the choice of vaccine approach, the antigen, and the timing of PD-1 blockade.”

Based on these results, an expansion arm has been opened to evaluate the safety and clinical efficacy of combination treatment beyond 12 weeks, and future studies will look at the combination of two different vaccines to improve antitumor response, he said.

Dr. McNeel disclosed financial relationships (intellectual property rights/patent holder, consultant, ownership interest) with Madison Vaccines Inc. The study is funded by a 2014 Movember PCF Challenge Award and Madison Vaccines.

[email protected]

SOURCE: McNeel D et al., J Immunother Cancer. 2017 5(Suppl 2):86 Abstract O11.

NATIONAL HARBOR, MD. – Combining programmed death (PD)-1 blockade with tumor-targeted T-cell activation by a novel DNA vaccine safely enhanced antitumor immune responses in metastatic castration-resistant prostate cancer (mCRPC) patients in a randomized clinical study.

Of 26 patients with mCRPC who were evaluable for response, 13 received treatment with an investigational DNA vaccine (pTVG-HP) that encodes prostatic acid phosphatase (PAP) and concurrent PD-1 blockade, and 13 received sequential vaccination and PD-1 blockade. No difference was seen between the groups with respect to progression-free survival at 6 months, but of eight patients in the concurrent therapy arm who had measurable disease, one experienced a partial response and two experienced a reduction in tumor volume, Douglas G. McNeel, MD, PhD, reported at the annual meeting of the Society for Immunotherapy of Cancer.

“We did not see objective responses in [six patients with measurable disease in the sequential treatment arm], said Dr. McNeel, a professor at the University of Wisconsin, Madison.

Prostate specific antigen (PSA) responses, which may be a more sensitive marker, were also more common in the concurrent treatment group; 8 of 13 patients in that group had a PSA decline from baseline, and 4 of those had a decline of greater than 25% from baseline, whereas only 1 of the 13 patients in the sequential treatment arm experienced any decline in PSA vs. baseline, Dr. McNeel said.

Responses to the vaccine’s target antigen, prostatic acid phosphatase, were seen in both arms, but only those who received the combined treatment and who had evidence of immune response experienced PSA decline, he added.

Pre- and postvaccination biopsies of metastatic sites showed that concurrent treatment, compared with sequential treatment, elicited tumor-infiltrating CD8+ T cells, PD-L1 expression in tumors, and changes associated with CD8+ T-cell activation, he said, adding that immunization with concurrent PD-1 blockade also elicits changes in proliferation detected by (¹⁸F) fluorothymidine PET/CT.

“We’ve been interested in vaccines for cancer, because we know that having the right kind of T cells in the tumor microenvironment is associated with better long-term outcomes,” Dr. McNeel said, noting that the ability of vaccines to activate T cells and augment cytolytic T cells, in particular, should have anticancer activity.

However, the clinical activity of single-agent tumor vaccines has been underwhelming, he noted.

PAP has been a focus in vaccine development, because it is essentially restricted to prostate tissue in humans. A nearly identical prostate-specific rat homologue was used in early studies, and PAP permits evaluation of serum PSA as an independent assessment of response in human trials, he explained.

“It’s the same target as the sipuleucel-T vaccine,” he said, referring to a Food and Drug Administration–approved vaccine for prostate cancer(Provenge).

Two prior phase 1/2 trials looking at DNA vaccine encoding PAP in patients with early biochemically recurrent prostate cancer showed that PAP-specific T-cell immune responses were elicited and that no significant adverse events occurred.

In both trials, the development of persistent PAP-specific, interferon-gamma–secreting T cells was associated with favorable change in PSA doubling time (suggesting a possible impact on the disease), and with PD-L1 expression in circulating tumor cells (suggesting a potential mechanism of resistance), he said.

Laboratory studies helped identify mechanisms of immune resistance following DNA immunization, he said, explaining that immunization elicits T cells secreting interferon-gamma, which leads to an increase in PD-L1 expression on tumor cells.

Encoding epitopes with increased major histocompatibility complex class 1 affinity elicited CD+ t cells with increased and persistent PD-1 expression, and blockade of PD-1 or PD-L1 with vaccination led to improved antitumor responses, he said.

The findings led to the new model focused on timing of PD-1 blockade with vaccine T-cell activation studied in the current trial.

It was hypothesized that PD-1 blockade at the time of T-cell activation with vaccination would be more effective than was blockade of PD-1-regulated T cells previously elicited with vaccination.

Study subjects had mCRPC and evidence of disease progression. Previous treatment with abiraterone(Zytiga), enzalutamide(Xtandi), or chemotherapy, was allowed, but patients with prior sipuleucel-T vaccine exposure were excluded.

Patients in the concurrent treatment arm received both the vaccine and PD-1 blockade with pembrolizumab (Keytruda)over 12 weeks, and those in the sequential therapy arm received vaccination first followed by PD-1 blockade, each for 12 weeks.

Both approaches were well tolerated.

“Essentially, we saw nothing that was unexpected,” Dr. McNeel said.

Adverse events greater than grade 2 included fatigue in one patient, diarrhea in one patient, and autoimmune hepatitis in one patient. No patients discontinued treatment from toxicity, he noted.

One death occurred during follow-up in a patient who had evidence of progression and refused further follow-up, therefore it could not be determined if the death was related to treatment.

The current findings, which are notable in part because PD-1 pathway inhibitors have demonstrated little clinical activity when used as single agents for prostate cancer and which expand upon data presented in a scientific poster at SITC 2016, demonstrate that combining this blockade with tumor-targeted T-cell activation by a DNA vaccine is safe and can augment tumor-specific T cells – as detectable within the peripheral blood and by imaging – and can result in objective antitumor changes.

“To summarize, plasmid DNA vaccines can elicit antigen-specific CD8+ T cells; immunization can increase PD-L1 expression on tumor cells – and we’ve demonstrated, in mice anyway, that this is mediated by the T cells elicited with immunization; PD-1 expression increases on CD8+ T cells following vaccination; and we think this is an opportunity to use checkpoint blockade at the point of vaccination to improve antitumor responses,” Dr. McNeel said.

“So we can look at this as PD-1 blockade to improve the effect of vaccination, but we can also look at it the other way around, and that is that anti-tumor vaccines can elicit the tumor-specific CD8+ T cells needed to enable PD-1 blockade to work,” he said. “ I think this has implications for the choice of vaccine approach, the antigen, and the timing of PD-1 blockade.”

Based on these results, an expansion arm has been opened to evaluate the safety and clinical efficacy of combination treatment beyond 12 weeks, and future studies will look at the combination of two different vaccines to improve antitumor response, he said.

Dr. McNeel disclosed financial relationships (intellectual property rights/patent holder, consultant, ownership interest) with Madison Vaccines Inc. The study is funded by a 2014 Movember PCF Challenge Award and Madison Vaccines.

[email protected]

SOURCE: McNeel D et al., J Immunother Cancer. 2017 5(Suppl 2):86 Abstract O11.

WASHINGTON – A multinational clinical trial has found that the metastatic cancer agent nivolumab can improve long-term survival and durable tumor responses in patients with advanced hepatocellular carcinoma (HCC) whether or not they’ve had previous treatment with a chemotherapy agent already approved for advanced primary liver cancer, a principal investigator reported at the annual meeting of the American Association for the Study of Liver Diseases.

“Nivolumab has demonstrated clinically meaningful efficacy across etiologies in sorafenib-naive and -experienced patients with extended follow-up,” Bruno Sangro, MD, of the University of Navarra in Pamplona, Spain, said in reporting results of the CheckMate-040 trial. “The median overall survival is 15 and 15.6 months in patients who were sorafenib-experienced in both the dose-escalation and expansion cohorts.”

WASHINGTON – A multinational clinical trial has found that the metastatic cancer agent nivolumab can improve long-term survival and durable tumor responses in patients with advanced hepatocellular carcinoma (HCC) whether or not they’ve had previous treatment with a chemotherapy agent already approved for advanced primary liver cancer, a principal investigator reported at the annual meeting of the American Association for the Study of Liver Diseases.

“Nivolumab has demonstrated clinically meaningful efficacy across etiologies in sorafenib-naive and -experienced patients with extended follow-up,” Bruno Sangro, MD, of the University of Navarra in Pamplona, Spain, said in reporting results of the CheckMate-040 trial. “The median overall survival is 15 and 15.6 months in patients who were sorafenib-experienced in both the dose-escalation and expansion cohorts.”

WASHINGTON – A multinational clinical trial has found that the metastatic cancer agent nivolumab can improve long-term survival and durable tumor responses in patients with advanced hepatocellular carcinoma (HCC) whether or not they’ve had previous treatment with a chemotherapy agent already approved for advanced primary liver cancer, a principal investigator reported at the annual meeting of the American Association for the Study of Liver Diseases.

“Nivolumab has demonstrated clinically meaningful efficacy across etiologies in sorafenib-naive and -experienced patients with extended follow-up,” Bruno Sangro, MD, of the University of Navarra in Pamplona, Spain, said in reporting results of the CheckMate-040 trial. “The median overall survival is 15 and 15.6 months in patients who were sorafenib-experienced in both the dose-escalation and expansion cohorts.”

MADRID – A combination of two immune checkpoint inhibitors was superior to the tyrosine kinase inhibitor (TKI) sunitinib (Sutent) in first-line treatment of patients with advanced or metastatic renal cell carcinoma (RCC), investigators reported

Median overall survival (OS) among 425 patients with intermediate- or poor-risk treatment-naive advanced/metastatic clear-cell RCC treated with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) was not reached after 32 months of follow-up. In contrast, the median OS for 422 patients treated with sunitinib was 26 months, reported Bernard Escudier, MD from the Institut Gustave Roussy in Villejuif, France.

[email protected]

MADRID – A combination of two immune checkpoint inhibitors was superior to the tyrosine kinase inhibitor (TKI) sunitinib (Sutent) in first-line treatment of patients with advanced or metastatic renal cell carcinoma (RCC), investigators reported

Median overall survival (OS) among 425 patients with intermediate- or poor-risk treatment-naive advanced/metastatic clear-cell RCC treated with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) was not reached after 32 months of follow-up. In contrast, the median OS for 422 patients treated with sunitinib was 26 months, reported Bernard Escudier, MD from the Institut Gustave Roussy in Villejuif, France.

[email protected]

MADRID – A combination of two immune checkpoint inhibitors was superior to the tyrosine kinase inhibitor (TKI) sunitinib (Sutent) in first-line treatment of patients with advanced or metastatic renal cell carcinoma (RCC), investigators reported

Median overall survival (OS) among 425 patients with intermediate- or poor-risk treatment-naive advanced/metastatic clear-cell RCC treated with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) was not reached after 32 months of follow-up. In contrast, the median OS for 422 patients treated with sunitinib was 26 months, reported Bernard Escudier, MD from the Institut Gustave Roussy in Villejuif, France.

[email protected]

CHICAGO – A baseline C-reactive protein (CRP) level above 50 mg/L independently predicted worse overall survival after immunotherapy in patients with advanced non–small cell lung cancer and small cell lung cancer in a retrospective study.

In 99 patients treated with nivolumab after a first-line platinum doublet, the median baseline CRP level was 22 mg/L. After a median follow-up of 8.5 months, 50% of patients were alive, and, based on univariate and multivariate analysis, both liver involvement and having a CRP level greater than 50 mg/L were significantly associated with inferior overall survival after immunotherapy.

The median overall survival after immunotherapy was 9.3 months versus 2.7 months with a CRP level of 50 mg/L or less versus above 50 mg/L, Abdul Rafeh Naqash, MD, of East Carolina University, Greenville, N.C., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

Notably, significant increases in CRP level, compared with baseline, were seen at the time of grade 2 to grade 4 immune-related adverse events, which occurred in 38.4% of patients. This is a hypothesis-generating finding in that it suggests there is dysregulation of the immune system, in the context of immune checkpoint blockade, that leads to a more proinflammatory state, which ultimately leads to immune-related adverse events, Dr. Naqash said.

Study subjects were adults with a median age of 65 years who were treated during April 2015-March 2017. Most were white (64.7%), were male (64.6%), and had non–small cell lung cancer (88%). Most had stage IV disease (70.7%), and the most common site for metastases was the bones (35.4%) and the liver (24.2%). Patients’ CRP levels were measured at anti-PD-1–treatment initiation and serially with subsequent doses.

The findings are important because the identification of predictive biomarkers in patients treated with anti-PD-1 therapy could provide valuable insights into underlying mechanisms regulating patient responses, elucidate resistance mechanisms, and help with optimal selection of patients for treatment with and development of patient-tailored treatment, Dr. Naqash said, noting that identifying such biomarkers has thus far been a challenge.

However, this study is limited by its retrospective design and limited follow-up; the findings require validation in prospective lung cancer trials, he concluded.

Dr. Naqash reported having no disclosures.

[email protected]
 

CHICAGO – A baseline C-reactive protein (CRP) level above 50 mg/L independently predicted worse overall survival after immunotherapy in patients with advanced non–small cell lung cancer and small cell lung cancer in a retrospective study.

In 99 patients treated with nivolumab after a first-line platinum doublet, the median baseline CRP level was 22 mg/L. After a median follow-up of 8.5 months, 50% of patients were alive, and, based on univariate and multivariate analysis, both liver involvement and having a CRP level greater than 50 mg/L were significantly associated with inferior overall survival after immunotherapy.

The median overall survival after immunotherapy was 9.3 months versus 2.7 months with a CRP level of 50 mg/L or less versus above 50 mg/L, Abdul Rafeh Naqash, MD, of East Carolina University, Greenville, N.C., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

Notably, significant increases in CRP level, compared with baseline, were seen at the time of grade 2 to grade 4 immune-related adverse events, which occurred in 38.4% of patients. This is a hypothesis-generating finding in that it suggests there is dysregulation of the immune system, in the context of immune checkpoint blockade, that leads to a more proinflammatory state, which ultimately leads to immune-related adverse events, Dr. Naqash said.

Study subjects were adults with a median age of 65 years who were treated during April 2015-March 2017. Most were white (64.7%), were male (64.6%), and had non–small cell lung cancer (88%). Most had stage IV disease (70.7%), and the most common site for metastases was the bones (35.4%) and the liver (24.2%). Patients’ CRP levels were measured at anti-PD-1–treatment initiation and serially with subsequent doses.

The findings are important because the identification of predictive biomarkers in patients treated with anti-PD-1 therapy could provide valuable insights into underlying mechanisms regulating patient responses, elucidate resistance mechanisms, and help with optimal selection of patients for treatment with and development of patient-tailored treatment, Dr. Naqash said, noting that identifying such biomarkers has thus far been a challenge.

However, this study is limited by its retrospective design and limited follow-up; the findings require validation in prospective lung cancer trials, he concluded.

Dr. Naqash reported having no disclosures.

[email protected]
 

CHICAGO – A baseline C-reactive protein (CRP) level above 50 mg/L independently predicted worse overall survival after immunotherapy in patients with advanced non–small cell lung cancer and small cell lung cancer in a retrospective study.

In 99 patients treated with nivolumab after a first-line platinum doublet, the median baseline CRP level was 22 mg/L. After a median follow-up of 8.5 months, 50% of patients were alive, and, based on univariate and multivariate analysis, both liver involvement and having a CRP level greater than 50 mg/L were significantly associated with inferior overall survival after immunotherapy.

The median overall survival after immunotherapy was 9.3 months versus 2.7 months with a CRP level of 50 mg/L or less versus above 50 mg/L, Abdul Rafeh Naqash, MD, of East Carolina University, Greenville, N.C., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

Notably, significant increases in CRP level, compared with baseline, were seen at the time of grade 2 to grade 4 immune-related adverse events, which occurred in 38.4% of patients. This is a hypothesis-generating finding in that it suggests there is dysregulation of the immune system, in the context of immune checkpoint blockade, that leads to a more proinflammatory state, which ultimately leads to immune-related adverse events, Dr. Naqash said.

Study subjects were adults with a median age of 65 years who were treated during April 2015-March 2017. Most were white (64.7%), were male (64.6%), and had non–small cell lung cancer (88%). Most had stage IV disease (70.7%), and the most common site for metastases was the bones (35.4%) and the liver (24.2%). Patients’ CRP levels were measured at anti-PD-1–treatment initiation and serially with subsequent doses.

The findings are important because the identification of predictive biomarkers in patients treated with anti-PD-1 therapy could provide valuable insights into underlying mechanisms regulating patient responses, elucidate resistance mechanisms, and help with optimal selection of patients for treatment with and development of patient-tailored treatment, Dr. Naqash said, noting that identifying such biomarkers has thus far been a challenge.

However, this study is limited by its retrospective design and limited follow-up; the findings require validation in prospective lung cancer trials, he concluded.

Dr. Naqash reported having no disclosures.

[email protected]
 

CHICAGO – Tocilizumab may be a therapeutic option for steroid-refractory immune-related adverse events that are secondary to PD-1 blockade, according to findings from a review of patients treated with nivolumab for various malignancies.

Of 87 patients who were treated with the PD-1 inhibitor between April 2015 and October 2016, 34 received tocilizumab for high-grade immune-related adverse events (irAEs) that were refractory to corticosteroids. Of those, 27 experienced clinical improvement, which was defined as documentation of symptom resolution or hospital discharge within 7 days, Aparna Hegde, MD, of East Carolina University, Greenville, N.C., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

The median time to discharge was 4 days, and no adverse effect on median overall survival was seen between those who received tocilizumab and those who did not (6.1 vs, 6.7 months, respectively), Dr. Hegde said.

There was, however, a trend toward inferior overall survival in patients who required more than one dose of tocilizumab, but the difference was not statistically significant (hazard ratio, 1.72), she noted.

“Immune checkpoint inhibitors are associated with an unprecedented clinical benefit in patients with lung cancer. However, they are also associated with a unique spectrum of immune-mediated adverse events. While the standard of care for initial management of these adverse events is corticosteroids, the management of steroid-refractory events is poorly defined,” she said, adding that data from randomized trials on which consensus guidelines could be based are lacking.

At East Carolina University, a significant proportion of patients treated with PD-1 inhibitors were presenting with systemic inflammatory response syndrome (SIRS)-like symptoms and immune-related organ toxicities similar to what has been described in cytokine release syndrome, Dr. Hegde said.

Such symptoms have also been reported with other types of immune therapy, such as CAR T-cell therapy and bispecific T-cell receptor–engaging antibodies in hematologic malignancies, she noted.

“In our experience, when we treated these patients with tocilizumab, which is an [anti-interleukin-6] receptor monoclonal antibody, we saw dramatic and rapid responses, not only in the SIRS symptoms, but also in other immune-related organ toxicities. Therefore, we adopted the use of tocilizumab as our standard treatment for high-grade immune-related adverse events,” she said, explaining that it has been well documented that interleukin (IL)-6 levels increase during cytokine release syndrome and are mediators of inflammation, suggesting that blocking IL-6 may treat irAEs without compromising the efficacy of immune therapy.

The current study was undertaken to look more closely at the responses to tocilizumab and to assess overall survival in those who received tocilizumab.

Study participants were being prospectively followed as part of another ongoing study looking at the relationship between systemic inflammation and cancer-related symptom burden. Most (77) were being treated for lung cancer and 10 had other types of malignancy. They received nivolumab at a dose of 3 mg/kg (or a flat dose of 240 mg after September 2016) every 2 weeks, and received tocilizumab at a dose of 4 mg/kg given over 1 hour. Those with grade 3 or 4 irAEs also received supportive care and corticosteroids. Median follow-up was 10.6 months.

C-reactive protein (CRP), a reliable surrogate marker of IL-6, was drawn at the first nivolumab infusion and before each subsequent infusion as part of the study in which the patients were enrolled, and for the current analysis was measured in relation to irAEs.

Significant reductions were seen in CRP levels after tocilizumab treatment; similar responses have been described in cytokine release syndrome, Dr. Hegde noted.

“Tocilizumab is a therapeutic option for management of immune-related adverse events in patients who are already on corticosteroids. CRP may be of clinical utility in detecting immune-related adverse events as well as monitoring the response to tocilizumab,” she said, adding that the current analysis is limited by the small patient number, single-center setting, use of tocilizumab outside of a clinical trial setting, and short follow-up.

Therefore, the findings require confirmation in multicenter randomized trials to determine “the definitive utility of tocilizumab, as well as CRP as an accompanying biomarker in the management of high-grade steroid refractory immune-related adverse events.”

Heather Wakelee, MD, an invited discussant at the symposium, commended Dr. Hegde and her colleagues for “coming up with a novel idea about how to treat [irAEs],” but also stressed the need for further study.

“This is a novel agent that has the potential ability to manage toxicity, and that’s important, because when you get beyond the steroids that we use as a first-line approach ... there’s not a whole lot else. We definitely have a clear unmet need,” said Dr. Wakelee of Stanford (Calif.) University.

However, she stressed that the approach must be evaluated in multicenter randomized trials “before we can be widely discussing this as a good thing to be doing.”

Dr. Hegde reported having no disclosures. Dr. Wakelee has been the institutional principal investigator for studies of nivolumab, tocilizumab, and other agents. She has consulted for Peregrine, ACEA, Pfizer, Helsinn, Genentech/Roche, Clovis, and Lilly, and received research/grant support from Clovis, Exelixis, AstraZeneca/Medimmune, Genentech/Roche, BMS, Gilead, Novartis, Xcovery, Pfizer, Celgene, Gilead, Pharmacyclics, and Lilly.

[email protected]

CHICAGO – Tocilizumab may be a therapeutic option for steroid-refractory immune-related adverse events that are secondary to PD-1 blockade, according to findings from a review of patients treated with nivolumab for various malignancies.

Of 87 patients who were treated with the PD-1 inhibitor between April 2015 and October 2016, 34 received tocilizumab for high-grade immune-related adverse events (irAEs) that were refractory to corticosteroids. Of those, 27 experienced clinical improvement, which was defined as documentation of symptom resolution or hospital discharge within 7 days, Aparna Hegde, MD, of East Carolina University, Greenville, N.C., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

The median time to discharge was 4 days, and no adverse effect on median overall survival was seen between those who received tocilizumab and those who did not (6.1 vs, 6.7 months, respectively), Dr. Hegde said.

There was, however, a trend toward inferior overall survival in patients who required more than one dose of tocilizumab, but the difference was not statistically significant (hazard ratio, 1.72), she noted.

“Immune checkpoint inhibitors are associated with an unprecedented clinical benefit in patients with lung cancer. However, they are also associated with a unique spectrum of immune-mediated adverse events. While the standard of care for initial management of these adverse events is corticosteroids, the management of steroid-refractory events is poorly defined,” she said, adding that data from randomized trials on which consensus guidelines could be based are lacking.

At East Carolina University, a significant proportion of patients treated with PD-1 inhibitors were presenting with systemic inflammatory response syndrome (SIRS)-like symptoms and immune-related organ toxicities similar to what has been described in cytokine release syndrome, Dr. Hegde said.

Such symptoms have also been reported with other types of immune therapy, such as CAR T-cell therapy and bispecific T-cell receptor–engaging antibodies in hematologic malignancies, she noted.

“In our experience, when we treated these patients with tocilizumab, which is an [anti-interleukin-6] receptor monoclonal antibody, we saw dramatic and rapid responses, not only in the SIRS symptoms, but also in other immune-related organ toxicities. Therefore, we adopted the use of tocilizumab as our standard treatment for high-grade immune-related adverse events,” she said, explaining that it has been well documented that interleukin (IL)-6 levels increase during cytokine release syndrome and are mediators of inflammation, suggesting that blocking IL-6 may treat irAEs without compromising the efficacy of immune therapy.

The current study was undertaken to look more closely at the responses to tocilizumab and to assess overall survival in those who received tocilizumab.

Study participants were being prospectively followed as part of another ongoing study looking at the relationship between systemic inflammation and cancer-related symptom burden. Most (77) were being treated for lung cancer and 10 had other types of malignancy. They received nivolumab at a dose of 3 mg/kg (or a flat dose of 240 mg after September 2016) every 2 weeks, and received tocilizumab at a dose of 4 mg/kg given over 1 hour. Those with grade 3 or 4 irAEs also received supportive care and corticosteroids. Median follow-up was 10.6 months.

C-reactive protein (CRP), a reliable surrogate marker of IL-6, was drawn at the first nivolumab infusion and before each subsequent infusion as part of the study in which the patients were enrolled, and for the current analysis was measured in relation to irAEs.

Significant reductions were seen in CRP levels after tocilizumab treatment; similar responses have been described in cytokine release syndrome, Dr. Hegde noted.

“Tocilizumab is a therapeutic option for management of immune-related adverse events in patients who are already on corticosteroids. CRP may be of clinical utility in detecting immune-related adverse events as well as monitoring the response to tocilizumab,” she said, adding that the current analysis is limited by the small patient number, single-center setting, use of tocilizumab outside of a clinical trial setting, and short follow-up.

Therefore, the findings require confirmation in multicenter randomized trials to determine “the definitive utility of tocilizumab, as well as CRP as an accompanying biomarker in the management of high-grade steroid refractory immune-related adverse events.”

Heather Wakelee, MD, an invited discussant at the symposium, commended Dr. Hegde and her colleagues for “coming up with a novel idea about how to treat [irAEs],” but also stressed the need for further study.

“This is a novel agent that has the potential ability to manage toxicity, and that’s important, because when you get beyond the steroids that we use as a first-line approach ... there’s not a whole lot else. We definitely have a clear unmet need,” said Dr. Wakelee of Stanford (Calif.) University.

However, she stressed that the approach must be evaluated in multicenter randomized trials “before we can be widely discussing this as a good thing to be doing.”

Dr. Hegde reported having no disclosures. Dr. Wakelee has been the institutional principal investigator for studies of nivolumab, tocilizumab, and other agents. She has consulted for Peregrine, ACEA, Pfizer, Helsinn, Genentech/Roche, Clovis, and Lilly, and received research/grant support from Clovis, Exelixis, AstraZeneca/Medimmune, Genentech/Roche, BMS, Gilead, Novartis, Xcovery, Pfizer, Celgene, Gilead, Pharmacyclics, and Lilly.

[email protected]

CHICAGO – Tocilizumab may be a therapeutic option for steroid-refractory immune-related adverse events that are secondary to PD-1 blockade, according to findings from a review of patients treated with nivolumab for various malignancies.

Of 87 patients who were treated with the PD-1 inhibitor between April 2015 and October 2016, 34 received tocilizumab for high-grade immune-related adverse events (irAEs) that were refractory to corticosteroids. Of those, 27 experienced clinical improvement, which was defined as documentation of symptom resolution or hospital discharge within 7 days, Aparna Hegde, MD, of East Carolina University, Greenville, N.C., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

The median time to discharge was 4 days, and no adverse effect on median overall survival was seen between those who received tocilizumab and those who did not (6.1 vs, 6.7 months, respectively), Dr. Hegde said.

There was, however, a trend toward inferior overall survival in patients who required more than one dose of tocilizumab, but the difference was not statistically significant (hazard ratio, 1.72), she noted.

“Immune checkpoint inhibitors are associated with an unprecedented clinical benefit in patients with lung cancer. However, they are also associated with a unique spectrum of immune-mediated adverse events. While the standard of care for initial management of these adverse events is corticosteroids, the management of steroid-refractory events is poorly defined,” she said, adding that data from randomized trials on which consensus guidelines could be based are lacking.

At East Carolina University, a significant proportion of patients treated with PD-1 inhibitors were presenting with systemic inflammatory response syndrome (SIRS)-like symptoms and immune-related organ toxicities similar to what has been described in cytokine release syndrome, Dr. Hegde said.

Such symptoms have also been reported with other types of immune therapy, such as CAR T-cell therapy and bispecific T-cell receptor–engaging antibodies in hematologic malignancies, she noted.

“In our experience, when we treated these patients with tocilizumab, which is an [anti-interleukin-6] receptor monoclonal antibody, we saw dramatic and rapid responses, not only in the SIRS symptoms, but also in other immune-related organ toxicities. Therefore, we adopted the use of tocilizumab as our standard treatment for high-grade immune-related adverse events,” she said, explaining that it has been well documented that interleukin (IL)-6 levels increase during cytokine release syndrome and are mediators of inflammation, suggesting that blocking IL-6 may treat irAEs without compromising the efficacy of immune therapy.

The current study was undertaken to look more closely at the responses to tocilizumab and to assess overall survival in those who received tocilizumab.

Study participants were being prospectively followed as part of another ongoing study looking at the relationship between systemic inflammation and cancer-related symptom burden. Most (77) were being treated for lung cancer and 10 had other types of malignancy. They received nivolumab at a dose of 3 mg/kg (or a flat dose of 240 mg after September 2016) every 2 weeks, and received tocilizumab at a dose of 4 mg/kg given over 1 hour. Those with grade 3 or 4 irAEs also received supportive care and corticosteroids. Median follow-up was 10.6 months.

C-reactive protein (CRP), a reliable surrogate marker of IL-6, was drawn at the first nivolumab infusion and before each subsequent infusion as part of the study in which the patients were enrolled, and for the current analysis was measured in relation to irAEs.

Significant reductions were seen in CRP levels after tocilizumab treatment; similar responses have been described in cytokine release syndrome, Dr. Hegde noted.

“Tocilizumab is a therapeutic option for management of immune-related adverse events in patients who are already on corticosteroids. CRP may be of clinical utility in detecting immune-related adverse events as well as monitoring the response to tocilizumab,” she said, adding that the current analysis is limited by the small patient number, single-center setting, use of tocilizumab outside of a clinical trial setting, and short follow-up.

Therefore, the findings require confirmation in multicenter randomized trials to determine “the definitive utility of tocilizumab, as well as CRP as an accompanying biomarker in the management of high-grade steroid refractory immune-related adverse events.”

Heather Wakelee, MD, an invited discussant at the symposium, commended Dr. Hegde and her colleagues for “coming up with a novel idea about how to treat [irAEs],” but also stressed the need for further study.

“This is a novel agent that has the potential ability to manage toxicity, and that’s important, because when you get beyond the steroids that we use as a first-line approach ... there’s not a whole lot else. We definitely have a clear unmet need,” said Dr. Wakelee of Stanford (Calif.) University.

However, she stressed that the approach must be evaluated in multicenter randomized trials “before we can be widely discussing this as a good thing to be doing.”

Dr. Hegde reported having no disclosures. Dr. Wakelee has been the institutional principal investigator for studies of nivolumab, tocilizumab, and other agents. She has consulted for Peregrine, ACEA, Pfizer, Helsinn, Genentech/Roche, Clovis, and Lilly, and received research/grant support from Clovis, Exelixis, AstraZeneca/Medimmune, Genentech/Roche, BMS, Gilead, Novartis, Xcovery, Pfizer, Celgene, Gilead, Pharmacyclics, and Lilly.

[email protected]