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Anti-GM-CSF antibody reduced CAR T-cell toxicity
HOUSTON – Neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) may be an effective strategy not only to manage toxicities associated with chimeric antigen receptor (CAR) T-cell therapy, but also to enhance CAR-T cell function, an investigator reported at the Transplantation & Cellular Therapy Meetings.
The GM-CSF targeted monoclonal antibody lenzilumab reduced neurotoxicity and cytokine release syndrome (CRS) related to CD19-targeted CAR T-cell therapy in a patient-derived xenograft model, said investigator Rosalie M. Sterner, an MD-PhD student in the department of immunology at Mayo Clinic, Rochester, Minn.
Other investigations showed that neutralizing or knocking out GM-CSF enhanced the antitumor functions of the CAR T cells, Ms. Sterner said in a podium presentation at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
“GM-CSF blockade does not impair CAR T-cell effector function, and in fact, enhances CAR T-cell effector functions in certain models, and actually can help to ameliorate CAR T-cell associated toxicities,” Ms. Sterner said.
Based on these early findings, the investigators have designed a phase 2 clinical trial to see if lenzilumab can prevent CAR T cell-related toxicities in patients with diffuse large B-cell lymphoma.
GM-CSF, a cytokine produced by T cells and myeloid cells, is the most statistically significantly elevated serum marker in patients with severe neurotoxicity related to CAR T-cell therapy, Ms. Sterner told attendees.
Investigations have shown that the combination of lenzilumab plus CD19-targeted T-cell therapy did not impair CAR T-cell function in vivo or in vitro, she said.
In other studies, they investigated the impact of GM-CSF neutralization in mice engrafted with primary acute lymphocytic leukemia (ALL) blasts and treated with high doses of CD19 CAR T-cells, lenzilumab, and a murine GM-CSF blocking antibody to neutralize the mouse GM-CSF. That strategy prevented weight loss, decreased myeloid cytokines, reduced cerebral edema, and enhanced disease control, Ms. Sterner said.
Investigators also reported on CD19 CAR T-cells with reduced GM-CSF secretion due to CRISPR/Cas9 gene editing of the GM-CSF gene during the CAR T-cell manufacturing process. Xenograft model results showed a slight enhancement of disease control for those GM-CSF knockout CAR T cells versus standard CAR T cells.
More details of the investigations were recently published in Blood (2019;133:697-709).
Taken together, the investigations highlight GM-CSF inhibition as a novel approach to reducing neurotoxicity and CRS that may also enhance CAR T-cell effector functions, Ms. Sterner said.
Ms. Sterner reported having no financial disclosures related to her presentation.
SOURCE: Sterner R et al. TCT 2019, Abstract 5.
HOUSTON – Neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) may be an effective strategy not only to manage toxicities associated with chimeric antigen receptor (CAR) T-cell therapy, but also to enhance CAR-T cell function, an investigator reported at the Transplantation & Cellular Therapy Meetings.
The GM-CSF targeted monoclonal antibody lenzilumab reduced neurotoxicity and cytokine release syndrome (CRS) related to CD19-targeted CAR T-cell therapy in a patient-derived xenograft model, said investigator Rosalie M. Sterner, an MD-PhD student in the department of immunology at Mayo Clinic, Rochester, Minn.
Other investigations showed that neutralizing or knocking out GM-CSF enhanced the antitumor functions of the CAR T cells, Ms. Sterner said in a podium presentation at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
“GM-CSF blockade does not impair CAR T-cell effector function, and in fact, enhances CAR T-cell effector functions in certain models, and actually can help to ameliorate CAR T-cell associated toxicities,” Ms. Sterner said.
Based on these early findings, the investigators have designed a phase 2 clinical trial to see if lenzilumab can prevent CAR T cell-related toxicities in patients with diffuse large B-cell lymphoma.
GM-CSF, a cytokine produced by T cells and myeloid cells, is the most statistically significantly elevated serum marker in patients with severe neurotoxicity related to CAR T-cell therapy, Ms. Sterner told attendees.
Investigations have shown that the combination of lenzilumab plus CD19-targeted T-cell therapy did not impair CAR T-cell function in vivo or in vitro, she said.
In other studies, they investigated the impact of GM-CSF neutralization in mice engrafted with primary acute lymphocytic leukemia (ALL) blasts and treated with high doses of CD19 CAR T-cells, lenzilumab, and a murine GM-CSF blocking antibody to neutralize the mouse GM-CSF. That strategy prevented weight loss, decreased myeloid cytokines, reduced cerebral edema, and enhanced disease control, Ms. Sterner said.
Investigators also reported on CD19 CAR T-cells with reduced GM-CSF secretion due to CRISPR/Cas9 gene editing of the GM-CSF gene during the CAR T-cell manufacturing process. Xenograft model results showed a slight enhancement of disease control for those GM-CSF knockout CAR T cells versus standard CAR T cells.
More details of the investigations were recently published in Blood (2019;133:697-709).
Taken together, the investigations highlight GM-CSF inhibition as a novel approach to reducing neurotoxicity and CRS that may also enhance CAR T-cell effector functions, Ms. Sterner said.
Ms. Sterner reported having no financial disclosures related to her presentation.
SOURCE: Sterner R et al. TCT 2019, Abstract 5.
HOUSTON – Neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) may be an effective strategy not only to manage toxicities associated with chimeric antigen receptor (CAR) T-cell therapy, but also to enhance CAR-T cell function, an investigator reported at the Transplantation & Cellular Therapy Meetings.
The GM-CSF targeted monoclonal antibody lenzilumab reduced neurotoxicity and cytokine release syndrome (CRS) related to CD19-targeted CAR T-cell therapy in a patient-derived xenograft model, said investigator Rosalie M. Sterner, an MD-PhD student in the department of immunology at Mayo Clinic, Rochester, Minn.
Other investigations showed that neutralizing or knocking out GM-CSF enhanced the antitumor functions of the CAR T cells, Ms. Sterner said in a podium presentation at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
“GM-CSF blockade does not impair CAR T-cell effector function, and in fact, enhances CAR T-cell effector functions in certain models, and actually can help to ameliorate CAR T-cell associated toxicities,” Ms. Sterner said.
Based on these early findings, the investigators have designed a phase 2 clinical trial to see if lenzilumab can prevent CAR T cell-related toxicities in patients with diffuse large B-cell lymphoma.
GM-CSF, a cytokine produced by T cells and myeloid cells, is the most statistically significantly elevated serum marker in patients with severe neurotoxicity related to CAR T-cell therapy, Ms. Sterner told attendees.
Investigations have shown that the combination of lenzilumab plus CD19-targeted T-cell therapy did not impair CAR T-cell function in vivo or in vitro, she said.
In other studies, they investigated the impact of GM-CSF neutralization in mice engrafted with primary acute lymphocytic leukemia (ALL) blasts and treated with high doses of CD19 CAR T-cells, lenzilumab, and a murine GM-CSF blocking antibody to neutralize the mouse GM-CSF. That strategy prevented weight loss, decreased myeloid cytokines, reduced cerebral edema, and enhanced disease control, Ms. Sterner said.
Investigators also reported on CD19 CAR T-cells with reduced GM-CSF secretion due to CRISPR/Cas9 gene editing of the GM-CSF gene during the CAR T-cell manufacturing process. Xenograft model results showed a slight enhancement of disease control for those GM-CSF knockout CAR T cells versus standard CAR T cells.
More details of the investigations were recently published in Blood (2019;133:697-709).
Taken together, the investigations highlight GM-CSF inhibition as a novel approach to reducing neurotoxicity and CRS that may also enhance CAR T-cell effector functions, Ms. Sterner said.
Ms. Sterner reported having no financial disclosures related to her presentation.
SOURCE: Sterner R et al. TCT 2019, Abstract 5.
REPORTING FROM TCT 2019
First-line avelumab/axitinib for RCC benefits wide range of patients
SAN FRANCISCO – subgroup analyses of the JAVELIN Renal 101 trial have shown. Results were reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Previous research had shown that avelumab (Bavencio), an immune checkpoint inhibitor targeting programmed death-ligand 1 (PD-L1), is active when used alone for advanced RCC, noted lead investigator Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston. And axitinib (Inlyta), a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, is approved for use in the second line. In an early-phase trial among patients being treated in the first line, a combination of the two drugs led to an impressive 58% objective response rate (ORR) and had a favorable safety profile (Lancet Oncol. 2018 Apr;19(4):451-60).
JAVELIN Renal 101 (NCT02684006), a phase 3 randomized, controlled trial, enrolled 886 patients with treatment-naive advanced RCC having a clear cell component regardless of their tumor’s PD-L1 status. They were randomized to the combination of avelumab/axitinib or to the VEGF tyrosine kinase inhibitor sunitinib (Sutent) alone.
Full trial results, published during the symposium in the New England Journal of Medicine (2019 Feb 16. doi: 10.1056/NEJMoa1816047), showed significant progression-free and overall survival benefits of avelumab/axitinib over sunitinib in the 63.2% of patients with PD-L1–positive tumors – the trial’s primary endpoints – as well as a progression-free survival benefit in the entire trial population.
In the subgroup analyses reported at the symposium, the combination reduced risk of progression or death by roughly 20%-50% across patients having different statuses in regard to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group, Memorial Sloan Kettering Cancer Center (MSKCC) risk group, and tumor PD-L1, as well as other characteristics. Findings were similar for ORR, with the combination roughly doubling to quadrupling the odds of response, irrespective of patient and disease characteristics.
“The progression-free survival and response rate benefit was observed in all patients, regardless of PD-L1 status, regardless of prognostic risk group. At this time, the study continues to follow up for overall survival,” Dr. Choueiri commented. Taken together, “the results do support avelumab plus axitinib as a new first-line standard of care for patients with advanced RCC.”
JAVELIN Renal 101 complemented two other noteworthy trials exploring first-line checkpoint inhibitors for which new data were reported at the symposium. One, KEYNOTE-426 (NCT02853331), established that the combination of the immune checkpoint inhibitor pembrolizumab (Keytruda) and axitinib was superior to sunitinib. The other, CheckMate 214 (NCT02231749), established that the combination of two immune checkpoint inhibitors, nivolumab (Opdivo) and ipilimumab (Yervoy), was superior to sunitinib.
Weighing new options
“So a new standard of care in 2019 is present: The majority of patients with advanced clear cell RCC will be eligible to receive the combination of a checkpoint inhibitor and axitinib,” commented invited discussant Lori Wood, MD, a professor in the division of medical oncology at Dalhousie University, Halifax, Canada. “The questions now are: Which treatment should we choose? can we afford it? and perhaps more importantly, can we safely deliver this therapy to all patients?”
When it comes to selecting among the three combinations above, “I don’t think PD-L1 expression is going to help us at all,” she said. In contrast, IMDC risk category is likely still helpful because, in CheckMate 214, there was no progression-free or overall survival benefit of ipilimumab/nivolumab in patients with favorable-risk disease.
Differences in rates of discontinuation of all treatment because of treatment-related adverse events are hard to assess because CheckMate 214 had restrictions on allowing patients in the combination group to receive single-agent nivolumab, according to Dr. Wood. Financial costs are a major consideration, but so are time and staffing costs: Compared with single-agent sunitinib, the combinations as much as triple physician visits, nurse visits, infusions, and unscheduled visits.
Safely administering the combinations – through use of education, judicious patient selection, and attention to logistics – is a challenge, she maintained. “I tell the residents, you can probably give cisplatin/gemcitabine to 10 patients and you can probably give sunitinib to 20 patients and get a good sense of what’s going to happen. But every single patient that I have put on immune therapy, I learn something new.”
Evolving issues, such as nuanced differences among the immune checkpoint inhibitors and whether the doses used in trials are really needed, have yet to be worked through. But combining these agents is likely better than sequencing them because only about half of RCC patients given first-line therapy go on to get second-line therapy, “so we might as well use our best therapy up front,” Dr. Wood said. Finally, it’s unclear whether cytoreductive nephrectomy is needed to achieve a complete response with these combinations because all trials predated the CARMENA trial (NCT00930033), so most patients underwent this surgery.
“These are exciting times. I think that for the first-line metastatic renal cell patient with favorable-, intermediate-, or poor-risk disease, a checkpoint inhibitor/axitinib combination will be a new standard of care in many parts of the world, not all,” she summarized. “For intermediate- and poor-risk patients, there’s no clear winner in my mind at this current time between ipilimumab/nivolumab and checkpoint inhibitor/axitinib. Decisions will need to be based on overall survival, complete response rates, toxicities, and then practical aspects, as well as costs.”
“But we cannot safely and effectively deliver this new standard of care without true infrastructure and system changes to accommodate more doctor and nurse visits, more infusion time, all of these extra visits, and more education for everybody who is both delivering and receiving these agents,” Dr. Wood concluded.
Study details
The subgroup analyses showed that, compared with sunitinib, avelumab/axitinib yielded better progression-free survival across patients differing with respect to IMDC risk group (range of hazard ratios, 0.539-0.736), MSKCC risk group (range of HRs, 0.495-0.715), tumor PD-L1 status (range of HRs, 0.626-0.827), prior nephrectomy status (range of HRs, 0.673-0.748), smoking status (range of HRs, 0.663-0.711), and body mass index (range of HRs, 0.667-0.674), Dr. Choueiri reported at the symposium. However, the 95% confidence intervals crossed 1 in some cases.
Overall, 20.8% of the avelumab/axitinib group and 39.2% of the sunitinib group went on to receive a follow-up anticancer drug therapy. The most common was cabozantinib (Cabometyx) in the former and nivolumab (Opdivo) in the latter.
The rate of progression-free survival 2 could not be estimated for the avelumab/axitinib group and was 18.4 months for the sunitinib group (HR, 0.56). “In theory, the first-line treatment could change the biology of the disease and therefore lead to substantially shorter benefit of second-line treatment, and progression-free survival 2 is actually a potentially important endpoint for regulatory and reimbursement evaluation,” Dr. Choueiri explained. “This suggests at least no negative impact of first-line treatment with the combination on subsequent benefit from second-line treatment.”
Compared with sunitinib, avelumab/axitinib also yielded better odds of objective response regardless of IMDC risk group (range of odds ratios, 3.099-3.556), MSKCC risk group (range of ORs, 3.061-4.686), PD-L1 status (range of ORs, 2.240-3.594), prior nephrectomy status (range of ORs, 2.592-3.249), smoking status (range of ORs, 2.649-3.798), and body mass index (range of ORs, 3.086-3.292). Here, virtually all 95% confidence intervals excluded 1.
Mean duration of response was more than 4 months longer with the combination than with sunitinib. Moreover, responses were deeper for the combination patients.
In updated safety results, the avelumab/axitinib group had higher rates of any-grade treatment-related diarrhea (54% vs. 45%) and hypothyroidism (24% vs. 13%). But there were few of these adverse events of grade 3 or 4 in either group.
Dr. Choueiri disclosed that he receives honoraria from, has a consulting or advisory role with, and receives institutional research funding from Merck and Pfizer – among other disclosures. The trial was sponsored by Pfizer.
SOURCE: Choueiri TK et al. GUCS 2019, Abstract 544.
“For first-line therapy of metastatic clear-cell renal cancer, we now have two regimens that have demonstrated a survival advantage over first-line sunitinib,” Walter M. Stadler, MD, said in an interview. For first-line therapy, there is the combination of nivolumab and ipilimumab in intermediate- and poor-risk patients and also the combination of pembrolizumab and axitinib.
Dr. Stadler is the Fred C. Buffett Professor of Medicine and Surgery, chief of the section of hematology/oncology, director of the genitourinary oncology program, and deputy director of the Comprehensive Cancer Center at the University of Chicago.
“For first-line therapy of metastatic clear-cell renal cancer, we now have two regimens that have demonstrated a survival advantage over first-line sunitinib,” Walter M. Stadler, MD, said in an interview. For first-line therapy, there is the combination of nivolumab and ipilimumab in intermediate- and poor-risk patients and also the combination of pembrolizumab and axitinib.
Dr. Stadler is the Fred C. Buffett Professor of Medicine and Surgery, chief of the section of hematology/oncology, director of the genitourinary oncology program, and deputy director of the Comprehensive Cancer Center at the University of Chicago.
“For first-line therapy of metastatic clear-cell renal cancer, we now have two regimens that have demonstrated a survival advantage over first-line sunitinib,” Walter M. Stadler, MD, said in an interview. For first-line therapy, there is the combination of nivolumab and ipilimumab in intermediate- and poor-risk patients and also the combination of pembrolizumab and axitinib.
Dr. Stadler is the Fred C. Buffett Professor of Medicine and Surgery, chief of the section of hematology/oncology, director of the genitourinary oncology program, and deputy director of the Comprehensive Cancer Center at the University of Chicago.
SAN FRANCISCO – subgroup analyses of the JAVELIN Renal 101 trial have shown. Results were reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Previous research had shown that avelumab (Bavencio), an immune checkpoint inhibitor targeting programmed death-ligand 1 (PD-L1), is active when used alone for advanced RCC, noted lead investigator Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston. And axitinib (Inlyta), a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, is approved for use in the second line. In an early-phase trial among patients being treated in the first line, a combination of the two drugs led to an impressive 58% objective response rate (ORR) and had a favorable safety profile (Lancet Oncol. 2018 Apr;19(4):451-60).
JAVELIN Renal 101 (NCT02684006), a phase 3 randomized, controlled trial, enrolled 886 patients with treatment-naive advanced RCC having a clear cell component regardless of their tumor’s PD-L1 status. They were randomized to the combination of avelumab/axitinib or to the VEGF tyrosine kinase inhibitor sunitinib (Sutent) alone.
Full trial results, published during the symposium in the New England Journal of Medicine (2019 Feb 16. doi: 10.1056/NEJMoa1816047), showed significant progression-free and overall survival benefits of avelumab/axitinib over sunitinib in the 63.2% of patients with PD-L1–positive tumors – the trial’s primary endpoints – as well as a progression-free survival benefit in the entire trial population.
In the subgroup analyses reported at the symposium, the combination reduced risk of progression or death by roughly 20%-50% across patients having different statuses in regard to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group, Memorial Sloan Kettering Cancer Center (MSKCC) risk group, and tumor PD-L1, as well as other characteristics. Findings were similar for ORR, with the combination roughly doubling to quadrupling the odds of response, irrespective of patient and disease characteristics.
“The progression-free survival and response rate benefit was observed in all patients, regardless of PD-L1 status, regardless of prognostic risk group. At this time, the study continues to follow up for overall survival,” Dr. Choueiri commented. Taken together, “the results do support avelumab plus axitinib as a new first-line standard of care for patients with advanced RCC.”
JAVELIN Renal 101 complemented two other noteworthy trials exploring first-line checkpoint inhibitors for which new data were reported at the symposium. One, KEYNOTE-426 (NCT02853331), established that the combination of the immune checkpoint inhibitor pembrolizumab (Keytruda) and axitinib was superior to sunitinib. The other, CheckMate 214 (NCT02231749), established that the combination of two immune checkpoint inhibitors, nivolumab (Opdivo) and ipilimumab (Yervoy), was superior to sunitinib.
Weighing new options
“So a new standard of care in 2019 is present: The majority of patients with advanced clear cell RCC will be eligible to receive the combination of a checkpoint inhibitor and axitinib,” commented invited discussant Lori Wood, MD, a professor in the division of medical oncology at Dalhousie University, Halifax, Canada. “The questions now are: Which treatment should we choose? can we afford it? and perhaps more importantly, can we safely deliver this therapy to all patients?”
When it comes to selecting among the three combinations above, “I don’t think PD-L1 expression is going to help us at all,” she said. In contrast, IMDC risk category is likely still helpful because, in CheckMate 214, there was no progression-free or overall survival benefit of ipilimumab/nivolumab in patients with favorable-risk disease.
Differences in rates of discontinuation of all treatment because of treatment-related adverse events are hard to assess because CheckMate 214 had restrictions on allowing patients in the combination group to receive single-agent nivolumab, according to Dr. Wood. Financial costs are a major consideration, but so are time and staffing costs: Compared with single-agent sunitinib, the combinations as much as triple physician visits, nurse visits, infusions, and unscheduled visits.
Safely administering the combinations – through use of education, judicious patient selection, and attention to logistics – is a challenge, she maintained. “I tell the residents, you can probably give cisplatin/gemcitabine to 10 patients and you can probably give sunitinib to 20 patients and get a good sense of what’s going to happen. But every single patient that I have put on immune therapy, I learn something new.”
Evolving issues, such as nuanced differences among the immune checkpoint inhibitors and whether the doses used in trials are really needed, have yet to be worked through. But combining these agents is likely better than sequencing them because only about half of RCC patients given first-line therapy go on to get second-line therapy, “so we might as well use our best therapy up front,” Dr. Wood said. Finally, it’s unclear whether cytoreductive nephrectomy is needed to achieve a complete response with these combinations because all trials predated the CARMENA trial (NCT00930033), so most patients underwent this surgery.
“These are exciting times. I think that for the first-line metastatic renal cell patient with favorable-, intermediate-, or poor-risk disease, a checkpoint inhibitor/axitinib combination will be a new standard of care in many parts of the world, not all,” she summarized. “For intermediate- and poor-risk patients, there’s no clear winner in my mind at this current time between ipilimumab/nivolumab and checkpoint inhibitor/axitinib. Decisions will need to be based on overall survival, complete response rates, toxicities, and then practical aspects, as well as costs.”
“But we cannot safely and effectively deliver this new standard of care without true infrastructure and system changes to accommodate more doctor and nurse visits, more infusion time, all of these extra visits, and more education for everybody who is both delivering and receiving these agents,” Dr. Wood concluded.
Study details
The subgroup analyses showed that, compared with sunitinib, avelumab/axitinib yielded better progression-free survival across patients differing with respect to IMDC risk group (range of hazard ratios, 0.539-0.736), MSKCC risk group (range of HRs, 0.495-0.715), tumor PD-L1 status (range of HRs, 0.626-0.827), prior nephrectomy status (range of HRs, 0.673-0.748), smoking status (range of HRs, 0.663-0.711), and body mass index (range of HRs, 0.667-0.674), Dr. Choueiri reported at the symposium. However, the 95% confidence intervals crossed 1 in some cases.
Overall, 20.8% of the avelumab/axitinib group and 39.2% of the sunitinib group went on to receive a follow-up anticancer drug therapy. The most common was cabozantinib (Cabometyx) in the former and nivolumab (Opdivo) in the latter.
The rate of progression-free survival 2 could not be estimated for the avelumab/axitinib group and was 18.4 months for the sunitinib group (HR, 0.56). “In theory, the first-line treatment could change the biology of the disease and therefore lead to substantially shorter benefit of second-line treatment, and progression-free survival 2 is actually a potentially important endpoint for regulatory and reimbursement evaluation,” Dr. Choueiri explained. “This suggests at least no negative impact of first-line treatment with the combination on subsequent benefit from second-line treatment.”
Compared with sunitinib, avelumab/axitinib also yielded better odds of objective response regardless of IMDC risk group (range of odds ratios, 3.099-3.556), MSKCC risk group (range of ORs, 3.061-4.686), PD-L1 status (range of ORs, 2.240-3.594), prior nephrectomy status (range of ORs, 2.592-3.249), smoking status (range of ORs, 2.649-3.798), and body mass index (range of ORs, 3.086-3.292). Here, virtually all 95% confidence intervals excluded 1.
Mean duration of response was more than 4 months longer with the combination than with sunitinib. Moreover, responses were deeper for the combination patients.
In updated safety results, the avelumab/axitinib group had higher rates of any-grade treatment-related diarrhea (54% vs. 45%) and hypothyroidism (24% vs. 13%). But there were few of these adverse events of grade 3 or 4 in either group.
Dr. Choueiri disclosed that he receives honoraria from, has a consulting or advisory role with, and receives institutional research funding from Merck and Pfizer – among other disclosures. The trial was sponsored by Pfizer.
SOURCE: Choueiri TK et al. GUCS 2019, Abstract 544.
SAN FRANCISCO – subgroup analyses of the JAVELIN Renal 101 trial have shown. Results were reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Previous research had shown that avelumab (Bavencio), an immune checkpoint inhibitor targeting programmed death-ligand 1 (PD-L1), is active when used alone for advanced RCC, noted lead investigator Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston. And axitinib (Inlyta), a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, is approved for use in the second line. In an early-phase trial among patients being treated in the first line, a combination of the two drugs led to an impressive 58% objective response rate (ORR) and had a favorable safety profile (Lancet Oncol. 2018 Apr;19(4):451-60).
JAVELIN Renal 101 (NCT02684006), a phase 3 randomized, controlled trial, enrolled 886 patients with treatment-naive advanced RCC having a clear cell component regardless of their tumor’s PD-L1 status. They were randomized to the combination of avelumab/axitinib or to the VEGF tyrosine kinase inhibitor sunitinib (Sutent) alone.
Full trial results, published during the symposium in the New England Journal of Medicine (2019 Feb 16. doi: 10.1056/NEJMoa1816047), showed significant progression-free and overall survival benefits of avelumab/axitinib over sunitinib in the 63.2% of patients with PD-L1–positive tumors – the trial’s primary endpoints – as well as a progression-free survival benefit in the entire trial population.
In the subgroup analyses reported at the symposium, the combination reduced risk of progression or death by roughly 20%-50% across patients having different statuses in regard to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group, Memorial Sloan Kettering Cancer Center (MSKCC) risk group, and tumor PD-L1, as well as other characteristics. Findings were similar for ORR, with the combination roughly doubling to quadrupling the odds of response, irrespective of patient and disease characteristics.
“The progression-free survival and response rate benefit was observed in all patients, regardless of PD-L1 status, regardless of prognostic risk group. At this time, the study continues to follow up for overall survival,” Dr. Choueiri commented. Taken together, “the results do support avelumab plus axitinib as a new first-line standard of care for patients with advanced RCC.”
JAVELIN Renal 101 complemented two other noteworthy trials exploring first-line checkpoint inhibitors for which new data were reported at the symposium. One, KEYNOTE-426 (NCT02853331), established that the combination of the immune checkpoint inhibitor pembrolizumab (Keytruda) and axitinib was superior to sunitinib. The other, CheckMate 214 (NCT02231749), established that the combination of two immune checkpoint inhibitors, nivolumab (Opdivo) and ipilimumab (Yervoy), was superior to sunitinib.
Weighing new options
“So a new standard of care in 2019 is present: The majority of patients with advanced clear cell RCC will be eligible to receive the combination of a checkpoint inhibitor and axitinib,” commented invited discussant Lori Wood, MD, a professor in the division of medical oncology at Dalhousie University, Halifax, Canada. “The questions now are: Which treatment should we choose? can we afford it? and perhaps more importantly, can we safely deliver this therapy to all patients?”
When it comes to selecting among the three combinations above, “I don’t think PD-L1 expression is going to help us at all,” she said. In contrast, IMDC risk category is likely still helpful because, in CheckMate 214, there was no progression-free or overall survival benefit of ipilimumab/nivolumab in patients with favorable-risk disease.
Differences in rates of discontinuation of all treatment because of treatment-related adverse events are hard to assess because CheckMate 214 had restrictions on allowing patients in the combination group to receive single-agent nivolumab, according to Dr. Wood. Financial costs are a major consideration, but so are time and staffing costs: Compared with single-agent sunitinib, the combinations as much as triple physician visits, nurse visits, infusions, and unscheduled visits.
Safely administering the combinations – through use of education, judicious patient selection, and attention to logistics – is a challenge, she maintained. “I tell the residents, you can probably give cisplatin/gemcitabine to 10 patients and you can probably give sunitinib to 20 patients and get a good sense of what’s going to happen. But every single patient that I have put on immune therapy, I learn something new.”
Evolving issues, such as nuanced differences among the immune checkpoint inhibitors and whether the doses used in trials are really needed, have yet to be worked through. But combining these agents is likely better than sequencing them because only about half of RCC patients given first-line therapy go on to get second-line therapy, “so we might as well use our best therapy up front,” Dr. Wood said. Finally, it’s unclear whether cytoreductive nephrectomy is needed to achieve a complete response with these combinations because all trials predated the CARMENA trial (NCT00930033), so most patients underwent this surgery.
“These are exciting times. I think that for the first-line metastatic renal cell patient with favorable-, intermediate-, or poor-risk disease, a checkpoint inhibitor/axitinib combination will be a new standard of care in many parts of the world, not all,” she summarized. “For intermediate- and poor-risk patients, there’s no clear winner in my mind at this current time between ipilimumab/nivolumab and checkpoint inhibitor/axitinib. Decisions will need to be based on overall survival, complete response rates, toxicities, and then practical aspects, as well as costs.”
“But we cannot safely and effectively deliver this new standard of care without true infrastructure and system changes to accommodate more doctor and nurse visits, more infusion time, all of these extra visits, and more education for everybody who is both delivering and receiving these agents,” Dr. Wood concluded.
Study details
The subgroup analyses showed that, compared with sunitinib, avelumab/axitinib yielded better progression-free survival across patients differing with respect to IMDC risk group (range of hazard ratios, 0.539-0.736), MSKCC risk group (range of HRs, 0.495-0.715), tumor PD-L1 status (range of HRs, 0.626-0.827), prior nephrectomy status (range of HRs, 0.673-0.748), smoking status (range of HRs, 0.663-0.711), and body mass index (range of HRs, 0.667-0.674), Dr. Choueiri reported at the symposium. However, the 95% confidence intervals crossed 1 in some cases.
Overall, 20.8% of the avelumab/axitinib group and 39.2% of the sunitinib group went on to receive a follow-up anticancer drug therapy. The most common was cabozantinib (Cabometyx) in the former and nivolumab (Opdivo) in the latter.
The rate of progression-free survival 2 could not be estimated for the avelumab/axitinib group and was 18.4 months for the sunitinib group (HR, 0.56). “In theory, the first-line treatment could change the biology of the disease and therefore lead to substantially shorter benefit of second-line treatment, and progression-free survival 2 is actually a potentially important endpoint for regulatory and reimbursement evaluation,” Dr. Choueiri explained. “This suggests at least no negative impact of first-line treatment with the combination on subsequent benefit from second-line treatment.”
Compared with sunitinib, avelumab/axitinib also yielded better odds of objective response regardless of IMDC risk group (range of odds ratios, 3.099-3.556), MSKCC risk group (range of ORs, 3.061-4.686), PD-L1 status (range of ORs, 2.240-3.594), prior nephrectomy status (range of ORs, 2.592-3.249), smoking status (range of ORs, 2.649-3.798), and body mass index (range of ORs, 3.086-3.292). Here, virtually all 95% confidence intervals excluded 1.
Mean duration of response was more than 4 months longer with the combination than with sunitinib. Moreover, responses were deeper for the combination patients.
In updated safety results, the avelumab/axitinib group had higher rates of any-grade treatment-related diarrhea (54% vs. 45%) and hypothyroidism (24% vs. 13%). But there were few of these adverse events of grade 3 or 4 in either group.
Dr. Choueiri disclosed that he receives honoraria from, has a consulting or advisory role with, and receives institutional research funding from Merck and Pfizer – among other disclosures. The trial was sponsored by Pfizer.
SOURCE: Choueiri TK et al. GUCS 2019, Abstract 544.
REPORTING FROM GUCS 2019
FDA approves pembrolizumab for completely resected melanoma
The Food and Drug Administration has approved pembrolizumab (Keytruda) for the adjuvant treatment of patients with melanoma with lymph node involvement following resection.
FDA approval is based on results from the randomized, double-blind, placebo-controlled EORTC1325/KEYNOTE‑054 trial, in which 1,019 patients with completely resected stage III melanoma received either a placebo or 200 mg of pembrolizumab every 3 weeks for up to 1 year until disease recurrence or unacceptable toxicity.
Recurrence-free survival was significantly better in the pembrolizumab group than in the placebo group (hazard ratio, 0.57; 95% confidence interval, 0.46-0.70; P less than .001). The median recurrence-free survival time was 20.4 months in the placebo group and was not reached in the pembrolizumab group, the FDA said in a press release.
About three-quarters of patients received pembrolizumab for at least 6 months, while 14% of patients had to stop pembrolizumab treatment because of adverse events. The most common adverse events in pembrolizumab-treated patients included diarrhea, pruritus, nausea, arthralgia, hypothyroidism, cough, rash, asthenia, influenzalike illness, weight loss, and hyperthyroidism.
“The recommended pembrolizumab dose and schedule for the adjuvant treatment of melanoma is 200 mg administered as an IV infusion over 30 minutes every 3 weeks until disease recurrence or unacceptable toxicity, for a maximum of 1 year,” the FDA said in the press release.
The Food and Drug Administration has approved pembrolizumab (Keytruda) for the adjuvant treatment of patients with melanoma with lymph node involvement following resection.
FDA approval is based on results from the randomized, double-blind, placebo-controlled EORTC1325/KEYNOTE‑054 trial, in which 1,019 patients with completely resected stage III melanoma received either a placebo or 200 mg of pembrolizumab every 3 weeks for up to 1 year until disease recurrence or unacceptable toxicity.
Recurrence-free survival was significantly better in the pembrolizumab group than in the placebo group (hazard ratio, 0.57; 95% confidence interval, 0.46-0.70; P less than .001). The median recurrence-free survival time was 20.4 months in the placebo group and was not reached in the pembrolizumab group, the FDA said in a press release.
About three-quarters of patients received pembrolizumab for at least 6 months, while 14% of patients had to stop pembrolizumab treatment because of adverse events. The most common adverse events in pembrolizumab-treated patients included diarrhea, pruritus, nausea, arthralgia, hypothyroidism, cough, rash, asthenia, influenzalike illness, weight loss, and hyperthyroidism.
“The recommended pembrolizumab dose and schedule for the adjuvant treatment of melanoma is 200 mg administered as an IV infusion over 30 minutes every 3 weeks until disease recurrence or unacceptable toxicity, for a maximum of 1 year,” the FDA said in the press release.
The Food and Drug Administration has approved pembrolizumab (Keytruda) for the adjuvant treatment of patients with melanoma with lymph node involvement following resection.
FDA approval is based on results from the randomized, double-blind, placebo-controlled EORTC1325/KEYNOTE‑054 trial, in which 1,019 patients with completely resected stage III melanoma received either a placebo or 200 mg of pembrolizumab every 3 weeks for up to 1 year until disease recurrence or unacceptable toxicity.
Recurrence-free survival was significantly better in the pembrolizumab group than in the placebo group (hazard ratio, 0.57; 95% confidence interval, 0.46-0.70; P less than .001). The median recurrence-free survival time was 20.4 months in the placebo group and was not reached in the pembrolizumab group, the FDA said in a press release.
About three-quarters of patients received pembrolizumab for at least 6 months, while 14% of patients had to stop pembrolizumab treatment because of adverse events. The most common adverse events in pembrolizumab-treated patients included diarrhea, pruritus, nausea, arthralgia, hypothyroidism, cough, rash, asthenia, influenzalike illness, weight loss, and hyperthyroidism.
“The recommended pembrolizumab dose and schedule for the adjuvant treatment of melanoma is 200 mg administered as an IV infusion over 30 minutes every 3 weeks until disease recurrence or unacceptable toxicity, for a maximum of 1 year,” the FDA said in the press release.
CAR T-cell therapies difficult to compare
One chimeric antigen receptor (CAR) T-cell therapy may appear better than another, but confounding factors make it difficult to compare these therapies effectively, according to a review published in the Journal of Clinical Oncology.
Caron A. Jacobson, MD, of the Dana-Farber Cancer Institute in Boston, reviewed results from three trials of CAR T-cell therapies in patients with B-cell non-Hodgkin lymphoma (B-NHL).
She noted that cross-trial comparisons are always limited, but such comparisons of CAR T-cell therapies are hindered by several confounding factors.
Dr. Jacobson said differences in manufacturing procedures and turnaround time, differences in patient eligibility and management, and the complexity of CAR T-cell therapies make it difficult to compare results from three CAR-T trials in B-NHL:
• The ZUMA-1 trial (NCT02348216) of axicabtagene ciloleucel (axi-cel, Yescarta)
• The JULIET trial (NCT02445248) of tisagenlecleucel (t-cel, Kymriah)
• The TRANSCEND-NHL-001 trial (NCT02631044) of lisocabtagene maraleucel (liso-cel, JCAR017).
Looking at response rates alone, axi-cel appears the most promising. The overall response rate (ORR) was 82% with axi-cel, 75% with liso-cel, and 52% with t-cel.
When considering cytokine release syndrome (CRS), liso-cel appears the safest. The rate of CRS was 93% with axi-cel (13% grade 3 or higher), 58% with t-cel (22% grade 3 or higher), and 39% with liso-cel (1% grade 3 or higher).
However, as Dr. Jacobson pointed out, it’s impossible to know if these differences in efficacy and toxicity are “statistically meaningful.”
Dr. Jacobson also noted that bridging therapy may have affected these results, as it might reduce tumor burden and increase toxicity, but bridging therapy was not used uniformly across these trials.
Most patients received bridging therapy before t-cel, none received it before axi-cel, and the use of bridging therapy was not reported in the trial of liso-cel.
“It is not possible to know whether patients treated on the ZUMA-1 trial, who were more likely to receive their CAR T cells, were healthier and more fit than patients on other studies or, because they were not allowed to receive bridging therapy, were actually sicker with a higher tumor burden and were therefore at risk for greater toxicity,” Dr. Jacobson wrote.
The fact that ZUMA-1 patients were more likely to receive CAR T cells brings up another issue—the difference between the reported results and the intent-to-treat (ITT) results in these trials. Since most patients on ZUMA-1 received the study treatment, there isn't much difference between the reported results and ITT results. However, about a third of patients who underwent apheresis on the JULIET trial did not ultimately receive CAR T cells, which means a bigger difference between the reported results and ITT results.
In ZUMA-1, 111 patients underwent leukapheresis, and 101 received treatment with axi-cel and were evaluable for efficacy. So the ORR was 75% (83/111) in the ITT population, compared to 82% in the population evaluable for efficacy.
In JULIET, 165 patients underwent leukapheresis, 111 received t-cel, and 93 were evaluable. The ORR was 30% (48/161) in the ITT population, compared to 52% in the evaluable population.
In TRANSCEND-NHL-001, 134 patients underwent leukapheresis, 114 patients received liso-cel, and 102 were evaluable. The ORR was 63% (77/122) in the ITT population, compared to 75% in the evaluable population.
Dr. Jacobson said these differences can be explained, in part, by differences in manufacturing. The time to manufacture cells was longer on the JULIET trial than on ZUMA-1, which may have been due to differences in transfection and manufacturing procedures as well as manufacturing ability.
In addition, differences in patient eligibility may have played a role, as healthier patients might be able to tolerate a longer manufacturing period than sicker patients.
Unfortunately, these differences cannot be accounted for without a randomized trial, but Dr. Jacobson said a randomized trial of these therapies is unlikely to occur.
“[S]o perhaps the best answers will come from institutions that have experience with all three products,” she wrote. “And in these cases, physicians and institutions will have to decide to what extent they would sacrifice efficacy for improved safety or sacrifice safety for improved reliability and consistency of treatment delivery.”
Dr. Jacobson disclosed relationships with Kite Pharma/Gilead Sciences, Bayer AG, Pfizer, Precision BioSciences, Novartis, Celgene, and Cowen.
SOURCE: Jacobson CA. J Clin Oncol. 2019 Feb 1;37(4):328-35. doi: 10.1200/JCO.18.01457
One chimeric antigen receptor (CAR) T-cell therapy may appear better than another, but confounding factors make it difficult to compare these therapies effectively, according to a review published in the Journal of Clinical Oncology.
Caron A. Jacobson, MD, of the Dana-Farber Cancer Institute in Boston, reviewed results from three trials of CAR T-cell therapies in patients with B-cell non-Hodgkin lymphoma (B-NHL).
She noted that cross-trial comparisons are always limited, but such comparisons of CAR T-cell therapies are hindered by several confounding factors.
Dr. Jacobson said differences in manufacturing procedures and turnaround time, differences in patient eligibility and management, and the complexity of CAR T-cell therapies make it difficult to compare results from three CAR-T trials in B-NHL:
• The ZUMA-1 trial (NCT02348216) of axicabtagene ciloleucel (axi-cel, Yescarta)
• The JULIET trial (NCT02445248) of tisagenlecleucel (t-cel, Kymriah)
• The TRANSCEND-NHL-001 trial (NCT02631044) of lisocabtagene maraleucel (liso-cel, JCAR017).
Looking at response rates alone, axi-cel appears the most promising. The overall response rate (ORR) was 82% with axi-cel, 75% with liso-cel, and 52% with t-cel.
When considering cytokine release syndrome (CRS), liso-cel appears the safest. The rate of CRS was 93% with axi-cel (13% grade 3 or higher), 58% with t-cel (22% grade 3 or higher), and 39% with liso-cel (1% grade 3 or higher).
However, as Dr. Jacobson pointed out, it’s impossible to know if these differences in efficacy and toxicity are “statistically meaningful.”
Dr. Jacobson also noted that bridging therapy may have affected these results, as it might reduce tumor burden and increase toxicity, but bridging therapy was not used uniformly across these trials.
Most patients received bridging therapy before t-cel, none received it before axi-cel, and the use of bridging therapy was not reported in the trial of liso-cel.
“It is not possible to know whether patients treated on the ZUMA-1 trial, who were more likely to receive their CAR T cells, were healthier and more fit than patients on other studies or, because they were not allowed to receive bridging therapy, were actually sicker with a higher tumor burden and were therefore at risk for greater toxicity,” Dr. Jacobson wrote.
The fact that ZUMA-1 patients were more likely to receive CAR T cells brings up another issue—the difference between the reported results and the intent-to-treat (ITT) results in these trials. Since most patients on ZUMA-1 received the study treatment, there isn't much difference between the reported results and ITT results. However, about a third of patients who underwent apheresis on the JULIET trial did not ultimately receive CAR T cells, which means a bigger difference between the reported results and ITT results.
In ZUMA-1, 111 patients underwent leukapheresis, and 101 received treatment with axi-cel and were evaluable for efficacy. So the ORR was 75% (83/111) in the ITT population, compared to 82% in the population evaluable for efficacy.
In JULIET, 165 patients underwent leukapheresis, 111 received t-cel, and 93 were evaluable. The ORR was 30% (48/161) in the ITT population, compared to 52% in the evaluable population.
In TRANSCEND-NHL-001, 134 patients underwent leukapheresis, 114 patients received liso-cel, and 102 were evaluable. The ORR was 63% (77/122) in the ITT population, compared to 75% in the evaluable population.
Dr. Jacobson said these differences can be explained, in part, by differences in manufacturing. The time to manufacture cells was longer on the JULIET trial than on ZUMA-1, which may have been due to differences in transfection and manufacturing procedures as well as manufacturing ability.
In addition, differences in patient eligibility may have played a role, as healthier patients might be able to tolerate a longer manufacturing period than sicker patients.
Unfortunately, these differences cannot be accounted for without a randomized trial, but Dr. Jacobson said a randomized trial of these therapies is unlikely to occur.
“[S]o perhaps the best answers will come from institutions that have experience with all three products,” she wrote. “And in these cases, physicians and institutions will have to decide to what extent they would sacrifice efficacy for improved safety or sacrifice safety for improved reliability and consistency of treatment delivery.”
Dr. Jacobson disclosed relationships with Kite Pharma/Gilead Sciences, Bayer AG, Pfizer, Precision BioSciences, Novartis, Celgene, and Cowen.
SOURCE: Jacobson CA. J Clin Oncol. 2019 Feb 1;37(4):328-35. doi: 10.1200/JCO.18.01457
One chimeric antigen receptor (CAR) T-cell therapy may appear better than another, but confounding factors make it difficult to compare these therapies effectively, according to a review published in the Journal of Clinical Oncology.
Caron A. Jacobson, MD, of the Dana-Farber Cancer Institute in Boston, reviewed results from three trials of CAR T-cell therapies in patients with B-cell non-Hodgkin lymphoma (B-NHL).
She noted that cross-trial comparisons are always limited, but such comparisons of CAR T-cell therapies are hindered by several confounding factors.
Dr. Jacobson said differences in manufacturing procedures and turnaround time, differences in patient eligibility and management, and the complexity of CAR T-cell therapies make it difficult to compare results from three CAR-T trials in B-NHL:
• The ZUMA-1 trial (NCT02348216) of axicabtagene ciloleucel (axi-cel, Yescarta)
• The JULIET trial (NCT02445248) of tisagenlecleucel (t-cel, Kymriah)
• The TRANSCEND-NHL-001 trial (NCT02631044) of lisocabtagene maraleucel (liso-cel, JCAR017).
Looking at response rates alone, axi-cel appears the most promising. The overall response rate (ORR) was 82% with axi-cel, 75% with liso-cel, and 52% with t-cel.
When considering cytokine release syndrome (CRS), liso-cel appears the safest. The rate of CRS was 93% with axi-cel (13% grade 3 or higher), 58% with t-cel (22% grade 3 or higher), and 39% with liso-cel (1% grade 3 or higher).
However, as Dr. Jacobson pointed out, it’s impossible to know if these differences in efficacy and toxicity are “statistically meaningful.”
Dr. Jacobson also noted that bridging therapy may have affected these results, as it might reduce tumor burden and increase toxicity, but bridging therapy was not used uniformly across these trials.
Most patients received bridging therapy before t-cel, none received it before axi-cel, and the use of bridging therapy was not reported in the trial of liso-cel.
“It is not possible to know whether patients treated on the ZUMA-1 trial, who were more likely to receive their CAR T cells, were healthier and more fit than patients on other studies or, because they were not allowed to receive bridging therapy, were actually sicker with a higher tumor burden and were therefore at risk for greater toxicity,” Dr. Jacobson wrote.
The fact that ZUMA-1 patients were more likely to receive CAR T cells brings up another issue—the difference between the reported results and the intent-to-treat (ITT) results in these trials. Since most patients on ZUMA-1 received the study treatment, there isn't much difference between the reported results and ITT results. However, about a third of patients who underwent apheresis on the JULIET trial did not ultimately receive CAR T cells, which means a bigger difference between the reported results and ITT results.
In ZUMA-1, 111 patients underwent leukapheresis, and 101 received treatment with axi-cel and were evaluable for efficacy. So the ORR was 75% (83/111) in the ITT population, compared to 82% in the population evaluable for efficacy.
In JULIET, 165 patients underwent leukapheresis, 111 received t-cel, and 93 were evaluable. The ORR was 30% (48/161) in the ITT population, compared to 52% in the evaluable population.
In TRANSCEND-NHL-001, 134 patients underwent leukapheresis, 114 patients received liso-cel, and 102 were evaluable. The ORR was 63% (77/122) in the ITT population, compared to 75% in the evaluable population.
Dr. Jacobson said these differences can be explained, in part, by differences in manufacturing. The time to manufacture cells was longer on the JULIET trial than on ZUMA-1, which may have been due to differences in transfection and manufacturing procedures as well as manufacturing ability.
In addition, differences in patient eligibility may have played a role, as healthier patients might be able to tolerate a longer manufacturing period than sicker patients.
Unfortunately, these differences cannot be accounted for without a randomized trial, but Dr. Jacobson said a randomized trial of these therapies is unlikely to occur.
“[S]o perhaps the best answers will come from institutions that have experience with all three products,” she wrote. “And in these cases, physicians and institutions will have to decide to what extent they would sacrifice efficacy for improved safety or sacrifice safety for improved reliability and consistency of treatment delivery.”
Dr. Jacobson disclosed relationships with Kite Pharma/Gilead Sciences, Bayer AG, Pfizer, Precision BioSciences, Novartis, Celgene, and Cowen.
SOURCE: Jacobson CA. J Clin Oncol. 2019 Feb 1;37(4):328-35. doi: 10.1200/JCO.18.01457
FROM JOURNAL OF CLINICAL ONCOLOGY
CMS proposes coverage of CAR T-cell therapy in trials
The Centers for Medicare & Medicaid Services has proposed to cover chimeric antigen receptor (CAR) T-cell therapy for cancer patients participating in clinical trials that study the treatment’s effectiveness, according to a Feb. 15 announcement.
The proposed national coverage determination would require CMS to cover CAR T-cell therapies nationwide when the treatment is offered in CMS-approved registries or clinical studies in which patients are monitored for 2 or more years following treatment.
Results from the studies would help CMS identify which patients benefit most from CAR T-cell therapies and inform future coverage decisions, CMS Administrator Seema Verma said.
“CAR T-cell therapy was the first FDA-approved gene therapy, marking the beginning of an entirely new approach to treating serious and even life-threatening diseases,” Ms. Verma said in a statement. “Today’s proposed coverage decision would improve access to this therapy while deepening CMS’s understanding of how patients in Medicare respond to it, so the agency can ensure that it is paying for CAR T-cell therapy for cases in which the benefits outweigh the risks.”
As part of the proposal, CMS would cover autologous treatment with T cells expressing at least one chimeric antigen receptor (CAR) through coverage with evidence development when prescribed by a treating oncologist and performed in a hospital, according to a summary of the proposal.
The patient and hospital must meet specific criteria to be eligible for coverage, including that patients have relapsed or refractory cancer and do not have a comorbidity that would otherwise preclude patient benefit.
Hospitals, meanwhile, must have a cellular therapy program consisting of an integrated medical team that includes a clinical program director, a quality manager, and at least one physician experienced in cellular therapy, among other requirements.
CMS also would require that treatment is an FDA-approved biologic, providing targeted therapy for a known antigen expressed in the patient’s cancer according to an FDA indication. Repeat treatment would be covered only when a new primary cancer diagnosis is made by the treating oncologist and certain patient conditions are met.
Both inpatient and outpatient settings for the CAR T-cell therapy treatment are acceptable under the proposal. In either case, the patient and the hospital must be participating in a prospective, national, audited registry that consecutively enrolls patients, accepts all manufactured products, follows the patient for at least 2 years, and addresses a set of approved evidence-development questions. Additionally, all registries must be reviewed and approved by CMS.
The proposed national coverage determination was the result of an Aug. 22, 2018 meeting of the Medicare Evidence Development & Coverage Advisory Committee. The committee provides CMS with an external assessment of the appropriateness of therapies under review.
Public comments about the CAR T-cell therapy proposal will be accepted online here until March 15. A final decision on the proposal is expected by May 2019.
The agency’s proposal follows an Aug. 17 final rule by CMS that sets a new payment scheme for inpatient administration of two CAR T-cell therapies. The rule categorizes CAR T-cell therapies under the umbrella of the renamed Medicare Severity–Diagnosis Related Groups 016 – Autologous Bone Marrow Transplant with CC/MCC or T-cell Immunotherapy – and assigns ICD-10 PCS procedure codes XW033C3 and XW043C3 to the use of axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) in the inpatient setting for fiscal year 2019, which began in October 2018. CMS also approved a temporary New Technology Add-On Payment for use of the therapies with a maximum threshold of $186,500.
In April 2018, CMS announced payment rates for outpatient administration of the two drugs, settling on $395,380 for axicabtagene ciloleucel and $500,839 for tisagenlecleucel. The two medications have list prices of $373,000 and $475,000, respectively.
The Centers for Medicare & Medicaid Services has proposed to cover chimeric antigen receptor (CAR) T-cell therapy for cancer patients participating in clinical trials that study the treatment’s effectiveness, according to a Feb. 15 announcement.
The proposed national coverage determination would require CMS to cover CAR T-cell therapies nationwide when the treatment is offered in CMS-approved registries or clinical studies in which patients are monitored for 2 or more years following treatment.
Results from the studies would help CMS identify which patients benefit most from CAR T-cell therapies and inform future coverage decisions, CMS Administrator Seema Verma said.
“CAR T-cell therapy was the first FDA-approved gene therapy, marking the beginning of an entirely new approach to treating serious and even life-threatening diseases,” Ms. Verma said in a statement. “Today’s proposed coverage decision would improve access to this therapy while deepening CMS’s understanding of how patients in Medicare respond to it, so the agency can ensure that it is paying for CAR T-cell therapy for cases in which the benefits outweigh the risks.”
As part of the proposal, CMS would cover autologous treatment with T cells expressing at least one chimeric antigen receptor (CAR) through coverage with evidence development when prescribed by a treating oncologist and performed in a hospital, according to a summary of the proposal.
The patient and hospital must meet specific criteria to be eligible for coverage, including that patients have relapsed or refractory cancer and do not have a comorbidity that would otherwise preclude patient benefit.
Hospitals, meanwhile, must have a cellular therapy program consisting of an integrated medical team that includes a clinical program director, a quality manager, and at least one physician experienced in cellular therapy, among other requirements.
CMS also would require that treatment is an FDA-approved biologic, providing targeted therapy for a known antigen expressed in the patient’s cancer according to an FDA indication. Repeat treatment would be covered only when a new primary cancer diagnosis is made by the treating oncologist and certain patient conditions are met.
Both inpatient and outpatient settings for the CAR T-cell therapy treatment are acceptable under the proposal. In either case, the patient and the hospital must be participating in a prospective, national, audited registry that consecutively enrolls patients, accepts all manufactured products, follows the patient for at least 2 years, and addresses a set of approved evidence-development questions. Additionally, all registries must be reviewed and approved by CMS.
The proposed national coverage determination was the result of an Aug. 22, 2018 meeting of the Medicare Evidence Development & Coverage Advisory Committee. The committee provides CMS with an external assessment of the appropriateness of therapies under review.
Public comments about the CAR T-cell therapy proposal will be accepted online here until March 15. A final decision on the proposal is expected by May 2019.
The agency’s proposal follows an Aug. 17 final rule by CMS that sets a new payment scheme for inpatient administration of two CAR T-cell therapies. The rule categorizes CAR T-cell therapies under the umbrella of the renamed Medicare Severity–Diagnosis Related Groups 016 – Autologous Bone Marrow Transplant with CC/MCC or T-cell Immunotherapy – and assigns ICD-10 PCS procedure codes XW033C3 and XW043C3 to the use of axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) in the inpatient setting for fiscal year 2019, which began in October 2018. CMS also approved a temporary New Technology Add-On Payment for use of the therapies with a maximum threshold of $186,500.
In April 2018, CMS announced payment rates for outpatient administration of the two drugs, settling on $395,380 for axicabtagene ciloleucel and $500,839 for tisagenlecleucel. The two medications have list prices of $373,000 and $475,000, respectively.
The Centers for Medicare & Medicaid Services has proposed to cover chimeric antigen receptor (CAR) T-cell therapy for cancer patients participating in clinical trials that study the treatment’s effectiveness, according to a Feb. 15 announcement.
The proposed national coverage determination would require CMS to cover CAR T-cell therapies nationwide when the treatment is offered in CMS-approved registries or clinical studies in which patients are monitored for 2 or more years following treatment.
Results from the studies would help CMS identify which patients benefit most from CAR T-cell therapies and inform future coverage decisions, CMS Administrator Seema Verma said.
“CAR T-cell therapy was the first FDA-approved gene therapy, marking the beginning of an entirely new approach to treating serious and even life-threatening diseases,” Ms. Verma said in a statement. “Today’s proposed coverage decision would improve access to this therapy while deepening CMS’s understanding of how patients in Medicare respond to it, so the agency can ensure that it is paying for CAR T-cell therapy for cases in which the benefits outweigh the risks.”
As part of the proposal, CMS would cover autologous treatment with T cells expressing at least one chimeric antigen receptor (CAR) through coverage with evidence development when prescribed by a treating oncologist and performed in a hospital, according to a summary of the proposal.
The patient and hospital must meet specific criteria to be eligible for coverage, including that patients have relapsed or refractory cancer and do not have a comorbidity that would otherwise preclude patient benefit.
Hospitals, meanwhile, must have a cellular therapy program consisting of an integrated medical team that includes a clinical program director, a quality manager, and at least one physician experienced in cellular therapy, among other requirements.
CMS also would require that treatment is an FDA-approved biologic, providing targeted therapy for a known antigen expressed in the patient’s cancer according to an FDA indication. Repeat treatment would be covered only when a new primary cancer diagnosis is made by the treating oncologist and certain patient conditions are met.
Both inpatient and outpatient settings for the CAR T-cell therapy treatment are acceptable under the proposal. In either case, the patient and the hospital must be participating in a prospective, national, audited registry that consecutively enrolls patients, accepts all manufactured products, follows the patient for at least 2 years, and addresses a set of approved evidence-development questions. Additionally, all registries must be reviewed and approved by CMS.
The proposed national coverage determination was the result of an Aug. 22, 2018 meeting of the Medicare Evidence Development & Coverage Advisory Committee. The committee provides CMS with an external assessment of the appropriateness of therapies under review.
Public comments about the CAR T-cell therapy proposal will be accepted online here until March 15. A final decision on the proposal is expected by May 2019.
The agency’s proposal follows an Aug. 17 final rule by CMS that sets a new payment scheme for inpatient administration of two CAR T-cell therapies. The rule categorizes CAR T-cell therapies under the umbrella of the renamed Medicare Severity–Diagnosis Related Groups 016 – Autologous Bone Marrow Transplant with CC/MCC or T-cell Immunotherapy – and assigns ICD-10 PCS procedure codes XW033C3 and XW043C3 to the use of axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) in the inpatient setting for fiscal year 2019, which began in October 2018. CMS also approved a temporary New Technology Add-On Payment for use of the therapies with a maximum threshold of $186,500.
In April 2018, CMS announced payment rates for outpatient administration of the two drugs, settling on $395,380 for axicabtagene ciloleucel and $500,839 for tisagenlecleucel. The two medications have list prices of $373,000 and $475,000, respectively.
Pembrolizumab extends Merkel cell PFS, OS
Patients with the aggressive skin cancer Merkel cell carcinoma who were treated with the immune checkpoint inhibitor pembrolizumab (Keytruda) in the first line had higher complete response rates, better progression-free survival, and longer overall survival than historical controls treated with cytotoxic chemotherapy.
Among 50 adults with advanced Merkel cell carcinoma (MCC) with no prior systemic therapy who received pembrolizumab 2 mg/kg every 3 weeks for up to 2 years in a phase 2 clinical trial (NCT02267603), 24% had a complete response and 32% a partial response, for an overall response rate of 56%.
The 24-month overall survival rate was 68.7%, with median overall survival not reached after a median follow-up time of 14.9 months. In contrast, a retrospective study of 67 patients with MCC treated with first-line chemotherapy showed an ORR of 29.4%, a median OS of 10.5 months, and a 24-month OS of 24.5% (Future Oncol. 2017 Aug;13(19):1699-1710).
Similarly, a second retrospective study showed that, among 62 patients treated with first-line chemotherapy, the ORR was 55%, median OS was 9.5 months, and 24-month OS was 20% (Cancer Med. 2016 Sep;5(9):2294-2301), reported Paul Nghiem, MD, PhD, from the University of Washington and Fred Hutchinson Cancer Research Center in Seattle, and his colleagues.
The rationale for using a checkpoint inhibitor for advanced MCC is that “[m]ultiple lines of evidence support the notion that MCC is an immunogenic cancer, including the fact that MCC incidence is greater than 10-fold higher in chronically immunosuppressed persons,” they wrote in the Journal of Clinical Oncology.
The current National Comprehensive Cancer Network guideline on Merkel cell carcinoma recommends the use of the programmed death–1/programmed death–ligand 1 (PD-1/PD-L1) inhibitors pembrolizumab, avelumab (Bavencio), or nivolumab (Opdivo) as preferred first-line systemic therapy for patients with disseminated disease, Dr. Nghiem and his colleagues noted.
In the current report, they presented data on the longest follow-up to date of patients with advance MCC who received a PD-1 inhibitor in the first line.
In the multicenter, phase 2 trial, 50 patients with a median age of 70.5 years were treated. Of this group, 64% had tumors positive for the Merkel cell polyomavirus and 49% had PD-L1 expression on tumor cells.
Of the 50 total patients, 28 had an objective response according to Response Evaluation Criteria in Solid Tumors version 1.1, including 12 with a complete response and 16 with a partial response. A total of 5 patients had stable disease, 16 had progressive disease, and 1 patient died before the first on-treatment scan for assessment.
After a median follow-up of 4.9 months, the 24-month progression-free survival rate (PFS) was 48.3% months, with a median PFS of 16.8 months.
As noted before, the 24-month OS rate was 68.7% and the median OS had not been reached at the time of the analysis.
There were no significant differences in PFS or OS between patients with tumors positive or negative for the Merkel polyomavirus, and there was a nonsignificant trend toward better PFS and OS for patients whose tumors had PD-L1 expression greater than 1%.
In all, 48 of the 50 patients had a treatment-related adverse event of any kind, and 14 had grade 3 or greater events. Treatment-related events led to discontinuation of pembrolizumab for seven patients, and one patient, a 73-year-old man with metastatic MCC and atrial fibrillation, developed pericardial and pleural effusions 1 day after receiving a single pembrolizumab infusion. The patient died 10 days after receiving pembrolizumab, and his death was deemed to be related to the drug.
The investigators noted that the drug’s efficacy in patients with both polyomavirus- and UV-induced subtypes of MCC “provides compelling evidence that both the quality and quantity of tumor antigens are important factors driving antitumor immunity and tumor rejection.”
The study was supported by grants from the National Cancer Institute, the Merkel cell carcinoma (MCC) patient gift fund at University of Washington, the Kelsey Dickson MCC Challenge Grant from the Prostate Cancer Foundation, and Merck, which provided pembrolizumab and partial funding. Dr. Nghiem reported receiving honoraria, travel expenses, and a consulting or advisory role from/for Merck and others. Multiple coauthors reported similar relations with Merck and/or other companies.
SOURCE: Nghiem P et al. J Clin Oncol. 2019 Feb 6. doi: 10.1200/JCO.18.01896.
Patients with the aggressive skin cancer Merkel cell carcinoma who were treated with the immune checkpoint inhibitor pembrolizumab (Keytruda) in the first line had higher complete response rates, better progression-free survival, and longer overall survival than historical controls treated with cytotoxic chemotherapy.
Among 50 adults with advanced Merkel cell carcinoma (MCC) with no prior systemic therapy who received pembrolizumab 2 mg/kg every 3 weeks for up to 2 years in a phase 2 clinical trial (NCT02267603), 24% had a complete response and 32% a partial response, for an overall response rate of 56%.
The 24-month overall survival rate was 68.7%, with median overall survival not reached after a median follow-up time of 14.9 months. In contrast, a retrospective study of 67 patients with MCC treated with first-line chemotherapy showed an ORR of 29.4%, a median OS of 10.5 months, and a 24-month OS of 24.5% (Future Oncol. 2017 Aug;13(19):1699-1710).
Similarly, a second retrospective study showed that, among 62 patients treated with first-line chemotherapy, the ORR was 55%, median OS was 9.5 months, and 24-month OS was 20% (Cancer Med. 2016 Sep;5(9):2294-2301), reported Paul Nghiem, MD, PhD, from the University of Washington and Fred Hutchinson Cancer Research Center in Seattle, and his colleagues.
The rationale for using a checkpoint inhibitor for advanced MCC is that “[m]ultiple lines of evidence support the notion that MCC is an immunogenic cancer, including the fact that MCC incidence is greater than 10-fold higher in chronically immunosuppressed persons,” they wrote in the Journal of Clinical Oncology.
The current National Comprehensive Cancer Network guideline on Merkel cell carcinoma recommends the use of the programmed death–1/programmed death–ligand 1 (PD-1/PD-L1) inhibitors pembrolizumab, avelumab (Bavencio), or nivolumab (Opdivo) as preferred first-line systemic therapy for patients with disseminated disease, Dr. Nghiem and his colleagues noted.
In the current report, they presented data on the longest follow-up to date of patients with advance MCC who received a PD-1 inhibitor in the first line.
In the multicenter, phase 2 trial, 50 patients with a median age of 70.5 years were treated. Of this group, 64% had tumors positive for the Merkel cell polyomavirus and 49% had PD-L1 expression on tumor cells.
Of the 50 total patients, 28 had an objective response according to Response Evaluation Criteria in Solid Tumors version 1.1, including 12 with a complete response and 16 with a partial response. A total of 5 patients had stable disease, 16 had progressive disease, and 1 patient died before the first on-treatment scan for assessment.
After a median follow-up of 4.9 months, the 24-month progression-free survival rate (PFS) was 48.3% months, with a median PFS of 16.8 months.
As noted before, the 24-month OS rate was 68.7% and the median OS had not been reached at the time of the analysis.
There were no significant differences in PFS or OS between patients with tumors positive or negative for the Merkel polyomavirus, and there was a nonsignificant trend toward better PFS and OS for patients whose tumors had PD-L1 expression greater than 1%.
In all, 48 of the 50 patients had a treatment-related adverse event of any kind, and 14 had grade 3 or greater events. Treatment-related events led to discontinuation of pembrolizumab for seven patients, and one patient, a 73-year-old man with metastatic MCC and atrial fibrillation, developed pericardial and pleural effusions 1 day after receiving a single pembrolizumab infusion. The patient died 10 days after receiving pembrolizumab, and his death was deemed to be related to the drug.
The investigators noted that the drug’s efficacy in patients with both polyomavirus- and UV-induced subtypes of MCC “provides compelling evidence that both the quality and quantity of tumor antigens are important factors driving antitumor immunity and tumor rejection.”
The study was supported by grants from the National Cancer Institute, the Merkel cell carcinoma (MCC) patient gift fund at University of Washington, the Kelsey Dickson MCC Challenge Grant from the Prostate Cancer Foundation, and Merck, which provided pembrolizumab and partial funding. Dr. Nghiem reported receiving honoraria, travel expenses, and a consulting or advisory role from/for Merck and others. Multiple coauthors reported similar relations with Merck and/or other companies.
SOURCE: Nghiem P et al. J Clin Oncol. 2019 Feb 6. doi: 10.1200/JCO.18.01896.
Patients with the aggressive skin cancer Merkel cell carcinoma who were treated with the immune checkpoint inhibitor pembrolizumab (Keytruda) in the first line had higher complete response rates, better progression-free survival, and longer overall survival than historical controls treated with cytotoxic chemotherapy.
Among 50 adults with advanced Merkel cell carcinoma (MCC) with no prior systemic therapy who received pembrolizumab 2 mg/kg every 3 weeks for up to 2 years in a phase 2 clinical trial (NCT02267603), 24% had a complete response and 32% a partial response, for an overall response rate of 56%.
The 24-month overall survival rate was 68.7%, with median overall survival not reached after a median follow-up time of 14.9 months. In contrast, a retrospective study of 67 patients with MCC treated with first-line chemotherapy showed an ORR of 29.4%, a median OS of 10.5 months, and a 24-month OS of 24.5% (Future Oncol. 2017 Aug;13(19):1699-1710).
Similarly, a second retrospective study showed that, among 62 patients treated with first-line chemotherapy, the ORR was 55%, median OS was 9.5 months, and 24-month OS was 20% (Cancer Med. 2016 Sep;5(9):2294-2301), reported Paul Nghiem, MD, PhD, from the University of Washington and Fred Hutchinson Cancer Research Center in Seattle, and his colleagues.
The rationale for using a checkpoint inhibitor for advanced MCC is that “[m]ultiple lines of evidence support the notion that MCC is an immunogenic cancer, including the fact that MCC incidence is greater than 10-fold higher in chronically immunosuppressed persons,” they wrote in the Journal of Clinical Oncology.
The current National Comprehensive Cancer Network guideline on Merkel cell carcinoma recommends the use of the programmed death–1/programmed death–ligand 1 (PD-1/PD-L1) inhibitors pembrolizumab, avelumab (Bavencio), or nivolumab (Opdivo) as preferred first-line systemic therapy for patients with disseminated disease, Dr. Nghiem and his colleagues noted.
In the current report, they presented data on the longest follow-up to date of patients with advance MCC who received a PD-1 inhibitor in the first line.
In the multicenter, phase 2 trial, 50 patients with a median age of 70.5 years were treated. Of this group, 64% had tumors positive for the Merkel cell polyomavirus and 49% had PD-L1 expression on tumor cells.
Of the 50 total patients, 28 had an objective response according to Response Evaluation Criteria in Solid Tumors version 1.1, including 12 with a complete response and 16 with a partial response. A total of 5 patients had stable disease, 16 had progressive disease, and 1 patient died before the first on-treatment scan for assessment.
After a median follow-up of 4.9 months, the 24-month progression-free survival rate (PFS) was 48.3% months, with a median PFS of 16.8 months.
As noted before, the 24-month OS rate was 68.7% and the median OS had not been reached at the time of the analysis.
There were no significant differences in PFS or OS between patients with tumors positive or negative for the Merkel polyomavirus, and there was a nonsignificant trend toward better PFS and OS for patients whose tumors had PD-L1 expression greater than 1%.
In all, 48 of the 50 patients had a treatment-related adverse event of any kind, and 14 had grade 3 or greater events. Treatment-related events led to discontinuation of pembrolizumab for seven patients, and one patient, a 73-year-old man with metastatic MCC and atrial fibrillation, developed pericardial and pleural effusions 1 day after receiving a single pembrolizumab infusion. The patient died 10 days after receiving pembrolizumab, and his death was deemed to be related to the drug.
The investigators noted that the drug’s efficacy in patients with both polyomavirus- and UV-induced subtypes of MCC “provides compelling evidence that both the quality and quantity of tumor antigens are important factors driving antitumor immunity and tumor rejection.”
The study was supported by grants from the National Cancer Institute, the Merkel cell carcinoma (MCC) patient gift fund at University of Washington, the Kelsey Dickson MCC Challenge Grant from the Prostate Cancer Foundation, and Merck, which provided pembrolizumab and partial funding. Dr. Nghiem reported receiving honoraria, travel expenses, and a consulting or advisory role from/for Merck and others. Multiple coauthors reported similar relations with Merck and/or other companies.
SOURCE: Nghiem P et al. J Clin Oncol. 2019 Feb 6. doi: 10.1200/JCO.18.01896.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: A programmed death–1/programmed death–ligand 1 inhibitor is preferred in the first line for disseminated Merkel cell carcinoma.
Major finding: Overall survival after 24 months was 68.7%, with the median overall survival not reached.
Study details: A follow-up of a phase 2, open-label trial in 50 patients with advanced Merkel cell carcinoma.
Disclosures: The study was supported by supported by grants from the National Cancer Institute, the Merkel cell carcinoma (MCC) patient gift fund at University of Washington, the Kelsey Dickson MCC Challenge Grant from the Prostate Cancer Foundation, and Merck, which provided pembrolizumab and partial funding. Dr. Nghiem reported receiving honoraria, travel expenses, and a consulting or advisory role from/for Merck and others. Multiple coauthors reported similar relations with Merck and/or other companies.
Source: Nghiem P et al. J Clin Oncol. 2019 Feb 6. doi: 10.1200/JCO.18.01896.
Pembrolizumab-axitinib nearly halves risk of death in RCC
SAN FRANCISCO – When used as first-line therapy for renal cell carcinoma (RCC), the combination of pembrolizumab and axitinib has similar safety and better efficacy than single-agent sunitinib, the current standard of care, according to findings of the KEYNOTE-426 trial that will be reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.
“Axitinib is usually licensed and usually used in sunitinib-refractory disease. However, there is data for both pembrolizumab and axitinib in the frontline setting,” said lead author Thomas Powles, MBBS, MRCP, MD, of Barts Health and the Royal Free NHS Trusts, Barts Cancer Institute, and Queen Mary University of London. A phase 1b trial testing the combination showed an impressive 73% objective response rate and acceptable toxicity (Lancet Oncol. 2018;19:405-15), prompting further investigation.
The 861 patients in KEYNOTE-426, a phase 3, randomized, controlled trial, were evenly assigned to combination therapy with the immune checkpoint inhibitor pembrolizumab (Keytruda), which targets programmed death–1, plus the tyrosine kinase inhibitor axitinib (Inlyta), which targets vascular endothelial growth factor and platelet-derived growth factor, or to monotherapy with the tyrosine kinase inhibitor sunitinib (Sutent), which also targets those growth factors.
Main results reported in a presscast held before the symposium showed that, with a median follow-up of 12.8 months, pembrolizumab-axitinib reduced the risk of progression-free survival events by a relative 31% and the risk of death by a relative 47%, compared with sunitinib. The combination had a rate of grade 3-5 treatment-related adverse events similar to the rate with sunitinib alone.
“The benefit of pembrolizumab plus axitinib was seen irrespective of IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] risk group or PD-L1 [programmed death–ligand 1] status,” Dr. Powles noted. “Pembrolizumab and axitinib should be a standard of care in this setting, in my opinion.”
“This is a very significant trial, and it’s going to impact on patient management going forward, as it works through the regulatory process,” commented ASCO Expert and presscast moderator Robert Dreicer, MD, MS, MACP, FASCO, who is also deputy director and associate director of clinical research at the University of Virginia Cancer Center and a professor of medicine and urology at the University of Virginia, Charlottesville.
Study details
Patients in KEYNOTE-426 had newly diagnosed or recurrent stage IV clear cell RCC and had not received any previous systemic treatment for their advanced disease. They were randomized to pembrolizumab (200 mg intravenously every 3 weeks up to 35 cycles) plus axitinib (5 mg orally twice daily), or to sunitinib (50 mg orally once daily for first 4 weeks of each 6-week cycle).
Median overall survival was not reached in either group, but the 12-month rate was 89.9% with pembrolizumab-axitinib versus 78.3% with sunitinib, Dr. Powles reported in the presscast. The difference corresponded to a near halving of the risk of death with the combination (hazard ratio, 0.53; P less than .0001).
Median progression-free survival was 15.1 months with pembrolizumab-axitinib and 11.1 months with sunitinib. The difference corresponded to a nearly one-third reduction in the risk of events with the combination (HR, 0.69; P = .0001). “The 11.1 months is quite long for a control arm, so there’s nothing from these data to suggest that sunitinib underperformed in this trial,” he noted.
Pembrolizumab-axitinib was also associated with a higher objective response rate (59.3% vs. 35.7%; P less than .0001). The median duration of response was not reached with the former, compared with 15.2 months with the latter.
“Pembrolizumab and axitinib had a manageable safety profile,” Dr. Powles said. The rate of grade 3-5 treatment-related adverse events was 62.9% with the combination and 58.1% with sunitinib monotherapy.
The rate of events leading to death was similar at 0.9% and 1.6%, respectively. The rate of events leading to discontinuation of any treatment was 25.9% for pembrolizumab-axitinib and 10.1% for sunitinib, and the rate of events leading to discontinuation of both drugs in the combination was 8.2%.
Dr. Powles reported that he has a consulting or advisory role with Genentech/Roche, Bristol-Myers Squibb, Merck, Novartis, and AstraZeneca; has a nonspecified relationship with Ipsen and Bristol-Myers Squibb; receives honoraria from Roche/Genentech, Bristol-Myers Squibb, and Merck; and receives research funding from Astra-Zeneca/MedImmune and Roche/Genentech. The study was funded by Merck.
SOURCE: Powles T et al. GUCS 2019, Abstract 543.
SAN FRANCISCO – When used as first-line therapy for renal cell carcinoma (RCC), the combination of pembrolizumab and axitinib has similar safety and better efficacy than single-agent sunitinib, the current standard of care, according to findings of the KEYNOTE-426 trial that will be reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.
“Axitinib is usually licensed and usually used in sunitinib-refractory disease. However, there is data for both pembrolizumab and axitinib in the frontline setting,” said lead author Thomas Powles, MBBS, MRCP, MD, of Barts Health and the Royal Free NHS Trusts, Barts Cancer Institute, and Queen Mary University of London. A phase 1b trial testing the combination showed an impressive 73% objective response rate and acceptable toxicity (Lancet Oncol. 2018;19:405-15), prompting further investigation.
The 861 patients in KEYNOTE-426, a phase 3, randomized, controlled trial, were evenly assigned to combination therapy with the immune checkpoint inhibitor pembrolizumab (Keytruda), which targets programmed death–1, plus the tyrosine kinase inhibitor axitinib (Inlyta), which targets vascular endothelial growth factor and platelet-derived growth factor, or to monotherapy with the tyrosine kinase inhibitor sunitinib (Sutent), which also targets those growth factors.
Main results reported in a presscast held before the symposium showed that, with a median follow-up of 12.8 months, pembrolizumab-axitinib reduced the risk of progression-free survival events by a relative 31% and the risk of death by a relative 47%, compared with sunitinib. The combination had a rate of grade 3-5 treatment-related adverse events similar to the rate with sunitinib alone.
“The benefit of pembrolizumab plus axitinib was seen irrespective of IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] risk group or PD-L1 [programmed death–ligand 1] status,” Dr. Powles noted. “Pembrolizumab and axitinib should be a standard of care in this setting, in my opinion.”
“This is a very significant trial, and it’s going to impact on patient management going forward, as it works through the regulatory process,” commented ASCO Expert and presscast moderator Robert Dreicer, MD, MS, MACP, FASCO, who is also deputy director and associate director of clinical research at the University of Virginia Cancer Center and a professor of medicine and urology at the University of Virginia, Charlottesville.
Study details
Patients in KEYNOTE-426 had newly diagnosed or recurrent stage IV clear cell RCC and had not received any previous systemic treatment for their advanced disease. They were randomized to pembrolizumab (200 mg intravenously every 3 weeks up to 35 cycles) plus axitinib (5 mg orally twice daily), or to sunitinib (50 mg orally once daily for first 4 weeks of each 6-week cycle).
Median overall survival was not reached in either group, but the 12-month rate was 89.9% with pembrolizumab-axitinib versus 78.3% with sunitinib, Dr. Powles reported in the presscast. The difference corresponded to a near halving of the risk of death with the combination (hazard ratio, 0.53; P less than .0001).
Median progression-free survival was 15.1 months with pembrolizumab-axitinib and 11.1 months with sunitinib. The difference corresponded to a nearly one-third reduction in the risk of events with the combination (HR, 0.69; P = .0001). “The 11.1 months is quite long for a control arm, so there’s nothing from these data to suggest that sunitinib underperformed in this trial,” he noted.
Pembrolizumab-axitinib was also associated with a higher objective response rate (59.3% vs. 35.7%; P less than .0001). The median duration of response was not reached with the former, compared with 15.2 months with the latter.
“Pembrolizumab and axitinib had a manageable safety profile,” Dr. Powles said. The rate of grade 3-5 treatment-related adverse events was 62.9% with the combination and 58.1% with sunitinib monotherapy.
The rate of events leading to death was similar at 0.9% and 1.6%, respectively. The rate of events leading to discontinuation of any treatment was 25.9% for pembrolizumab-axitinib and 10.1% for sunitinib, and the rate of events leading to discontinuation of both drugs in the combination was 8.2%.
Dr. Powles reported that he has a consulting or advisory role with Genentech/Roche, Bristol-Myers Squibb, Merck, Novartis, and AstraZeneca; has a nonspecified relationship with Ipsen and Bristol-Myers Squibb; receives honoraria from Roche/Genentech, Bristol-Myers Squibb, and Merck; and receives research funding from Astra-Zeneca/MedImmune and Roche/Genentech. The study was funded by Merck.
SOURCE: Powles T et al. GUCS 2019, Abstract 543.
SAN FRANCISCO – When used as first-line therapy for renal cell carcinoma (RCC), the combination of pembrolizumab and axitinib has similar safety and better efficacy than single-agent sunitinib, the current standard of care, according to findings of the KEYNOTE-426 trial that will be reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.
“Axitinib is usually licensed and usually used in sunitinib-refractory disease. However, there is data for both pembrolizumab and axitinib in the frontline setting,” said lead author Thomas Powles, MBBS, MRCP, MD, of Barts Health and the Royal Free NHS Trusts, Barts Cancer Institute, and Queen Mary University of London. A phase 1b trial testing the combination showed an impressive 73% objective response rate and acceptable toxicity (Lancet Oncol. 2018;19:405-15), prompting further investigation.
The 861 patients in KEYNOTE-426, a phase 3, randomized, controlled trial, were evenly assigned to combination therapy with the immune checkpoint inhibitor pembrolizumab (Keytruda), which targets programmed death–1, plus the tyrosine kinase inhibitor axitinib (Inlyta), which targets vascular endothelial growth factor and platelet-derived growth factor, or to monotherapy with the tyrosine kinase inhibitor sunitinib (Sutent), which also targets those growth factors.
Main results reported in a presscast held before the symposium showed that, with a median follow-up of 12.8 months, pembrolizumab-axitinib reduced the risk of progression-free survival events by a relative 31% and the risk of death by a relative 47%, compared with sunitinib. The combination had a rate of grade 3-5 treatment-related adverse events similar to the rate with sunitinib alone.
“The benefit of pembrolizumab plus axitinib was seen irrespective of IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] risk group or PD-L1 [programmed death–ligand 1] status,” Dr. Powles noted. “Pembrolizumab and axitinib should be a standard of care in this setting, in my opinion.”
“This is a very significant trial, and it’s going to impact on patient management going forward, as it works through the regulatory process,” commented ASCO Expert and presscast moderator Robert Dreicer, MD, MS, MACP, FASCO, who is also deputy director and associate director of clinical research at the University of Virginia Cancer Center and a professor of medicine and urology at the University of Virginia, Charlottesville.
Study details
Patients in KEYNOTE-426 had newly diagnosed or recurrent stage IV clear cell RCC and had not received any previous systemic treatment for their advanced disease. They were randomized to pembrolizumab (200 mg intravenously every 3 weeks up to 35 cycles) plus axitinib (5 mg orally twice daily), or to sunitinib (50 mg orally once daily for first 4 weeks of each 6-week cycle).
Median overall survival was not reached in either group, but the 12-month rate was 89.9% with pembrolizumab-axitinib versus 78.3% with sunitinib, Dr. Powles reported in the presscast. The difference corresponded to a near halving of the risk of death with the combination (hazard ratio, 0.53; P less than .0001).
Median progression-free survival was 15.1 months with pembrolizumab-axitinib and 11.1 months with sunitinib. The difference corresponded to a nearly one-third reduction in the risk of events with the combination (HR, 0.69; P = .0001). “The 11.1 months is quite long for a control arm, so there’s nothing from these data to suggest that sunitinib underperformed in this trial,” he noted.
Pembrolizumab-axitinib was also associated with a higher objective response rate (59.3% vs. 35.7%; P less than .0001). The median duration of response was not reached with the former, compared with 15.2 months with the latter.
“Pembrolizumab and axitinib had a manageable safety profile,” Dr. Powles said. The rate of grade 3-5 treatment-related adverse events was 62.9% with the combination and 58.1% with sunitinib monotherapy.
The rate of events leading to death was similar at 0.9% and 1.6%, respectively. The rate of events leading to discontinuation of any treatment was 25.9% for pembrolizumab-axitinib and 10.1% for sunitinib, and the rate of events leading to discontinuation of both drugs in the combination was 8.2%.
Dr. Powles reported that he has a consulting or advisory role with Genentech/Roche, Bristol-Myers Squibb, Merck, Novartis, and AstraZeneca; has a nonspecified relationship with Ipsen and Bristol-Myers Squibb; receives honoraria from Roche/Genentech, Bristol-Myers Squibb, and Merck; and receives research funding from Astra-Zeneca/MedImmune and Roche/Genentech. The study was funded by Merck.
SOURCE: Powles T et al. GUCS 2019, Abstract 543.
REPORTING FROM GUCS 2019
Key clinical point: The combination of pembrolizumab and axitinib may become a new first-line standard of care in advanced renal cell carcinoma.
Major finding: Compared with sunitinib monotherapy, pembrolizumab and axitinib combination therapy prolonged progression-free survival (hazard ratio, 0.69; P = .0001) and overall survival (HR, 0.53; P less than .0001).
Study details: A phase 3, randomized, controlled trial among 861 patients with untreated locally advanced or metastatic renal cell carcinoma (KEYNOTE-426).
Disclosures: Dr. Powles reported that he has a consulting or advisory role with Genentech/Roche, Bristol-Myers Squibb, Merck, Novartis, and AstraZeneca; has a nonspecified relationship with Ipsen and Bristol-Myers Squibb; receives honoraria from Roche/Genentech, Bristol-Myers Squibb, and Merck; and receives research funding from AstraZeneca/MedImmune and Roche/Genentech. The study was funded by Merck.
Source: Powles T et al. GUCS 2019, Abstract 543.
PD-1 blockade plus CD19 CAR T boosts CAR T-cell persistence
SAN DIEGO – Checkpoint inhibition can be used safely and effectively with CD19-directed chimeric antigen receptor (CAR) T-cell therapy in children with relapsed B-cell acute lymphoblastic leukemia (ALL), and it may bolster CAR T-cell effects and persistence, suggest the findings in a series of 14 patients at the Children’s Hospital of Philadelphia.
Combined programmed death-1 (PD-1) blockade and CAR T-cell therapy appeared to have particular benefit in patients with early B-cell recovery and in those with bulky extramedullary disease, Shannon Maude, MD, PhD, reported during a press conference at the annual meeting of the American Society of Hematology.
The patients, aged 4-17 years with heavily pretreated relapsed B-ALL (13 patients) or B lymphoblastic lymphoma (1 patient), were treated with CD19-directed CAR T-cell therapy, including CTL019 in 4 patients and CTL119 in 10 patients, followed by pembrolizumab (in 13 patients) or nivolumab (in 1 patient).
Six patients received the combination therapy because of early B-cell recovery after initial CAR T-cell infusion, four patients had relapsed or refractory (R/R) bulky extramedullary disease, and four patients had failed to respond or relapsed after initial CAR T-cell therapy.
Three of the six with poor persistence of response reestablished B-cell aplasia (a reflection of CAR T-cell function) after reinfusion of the CAR T-cell product followed by infusion with PD-1 blockade, and they have “sustained CR [complete response] with B-cell aplasia, showing continued persistence of their CAR T cells,” said Dr. Maude, an attending physician in the Cancer Center at Children’s Hospital of Philadelphia.
Of the four patients with R/R bulky extramedullary disease, two patients had a partial response and two patients had CR, she said, explaining that it was hypothesized that the “PD-1 checkpoint pathway may be activated through the microenvironment in that extramedullary situation.”
However, all four patients who had partial or no response to initial CAR T-cell therapy progressed after PD-1 administration, she said, noting that “in one patient, this progression was marked by reduced CD19 expression, which was probably the mode of escape from CD19 CAR T cells.”
Prior studies have shown that patients who respond to CAR T-cell therapy have persistence of CD19 CAR T cells, whereas those with loss of CD19 CAR T cells within 6 months of infusion have a higher rate of relapse, Dr. Maude explained.
“Our hypothesis was that T cells, upon activation, may become exhausted through activation of immune checkpoint pathways, that one such pathway – PD-1 – may be involved in early loss of CD19 CAR T cells and therefore that the combination [of CD19 CAR T-cell therapy] with PD-1 checkpoint blockade may improve the function of the CAR T cells and their persistence,” she said.
The combined approach was well tolerated in this study, she said, noting that mild cytokine release syndrome symptoms and fever typical of CAR T-cell proliferative responses were observed in three patients within 2 days of starting pembrolizumab.
Other adverse effects associated with PD-1 inhibition, including acute pancreatitis, hypothyroidism, arthralgias, and urticaria, occurred in one patient each. There were four cases of grade 3-4 cytopenias that were deemed tolerable or reversible upon discontinuation.
“We show that PD-1 checkpoint inhibitors can be safely combined with CD19 CAR T-cell therapy and that this mechanism may be useful to improve CAR T-cell persistence,” Dr. Maude said.
These findings, which showed particular benefit in patients with poor persistence marked by early B-cell recovery and in those with R/R bulky extramedullary disease, should help inform future use of checkpoint inhibitors after CAR T-cell therapy, she added.
Dr. Maude reported financial ties to Novartis.
SOURCE: Li AM et al. ASH 2018, Abstract 556.
SAN DIEGO – Checkpoint inhibition can be used safely and effectively with CD19-directed chimeric antigen receptor (CAR) T-cell therapy in children with relapsed B-cell acute lymphoblastic leukemia (ALL), and it may bolster CAR T-cell effects and persistence, suggest the findings in a series of 14 patients at the Children’s Hospital of Philadelphia.
Combined programmed death-1 (PD-1) blockade and CAR T-cell therapy appeared to have particular benefit in patients with early B-cell recovery and in those with bulky extramedullary disease, Shannon Maude, MD, PhD, reported during a press conference at the annual meeting of the American Society of Hematology.
The patients, aged 4-17 years with heavily pretreated relapsed B-ALL (13 patients) or B lymphoblastic lymphoma (1 patient), were treated with CD19-directed CAR T-cell therapy, including CTL019 in 4 patients and CTL119 in 10 patients, followed by pembrolizumab (in 13 patients) or nivolumab (in 1 patient).
Six patients received the combination therapy because of early B-cell recovery after initial CAR T-cell infusion, four patients had relapsed or refractory (R/R) bulky extramedullary disease, and four patients had failed to respond or relapsed after initial CAR T-cell therapy.
Three of the six with poor persistence of response reestablished B-cell aplasia (a reflection of CAR T-cell function) after reinfusion of the CAR T-cell product followed by infusion with PD-1 blockade, and they have “sustained CR [complete response] with B-cell aplasia, showing continued persistence of their CAR T cells,” said Dr. Maude, an attending physician in the Cancer Center at Children’s Hospital of Philadelphia.
Of the four patients with R/R bulky extramedullary disease, two patients had a partial response and two patients had CR, she said, explaining that it was hypothesized that the “PD-1 checkpoint pathway may be activated through the microenvironment in that extramedullary situation.”
However, all four patients who had partial or no response to initial CAR T-cell therapy progressed after PD-1 administration, she said, noting that “in one patient, this progression was marked by reduced CD19 expression, which was probably the mode of escape from CD19 CAR T cells.”
Prior studies have shown that patients who respond to CAR T-cell therapy have persistence of CD19 CAR T cells, whereas those with loss of CD19 CAR T cells within 6 months of infusion have a higher rate of relapse, Dr. Maude explained.
“Our hypothesis was that T cells, upon activation, may become exhausted through activation of immune checkpoint pathways, that one such pathway – PD-1 – may be involved in early loss of CD19 CAR T cells and therefore that the combination [of CD19 CAR T-cell therapy] with PD-1 checkpoint blockade may improve the function of the CAR T cells and their persistence,” she said.
The combined approach was well tolerated in this study, she said, noting that mild cytokine release syndrome symptoms and fever typical of CAR T-cell proliferative responses were observed in three patients within 2 days of starting pembrolizumab.
Other adverse effects associated with PD-1 inhibition, including acute pancreatitis, hypothyroidism, arthralgias, and urticaria, occurred in one patient each. There were four cases of grade 3-4 cytopenias that were deemed tolerable or reversible upon discontinuation.
“We show that PD-1 checkpoint inhibitors can be safely combined with CD19 CAR T-cell therapy and that this mechanism may be useful to improve CAR T-cell persistence,” Dr. Maude said.
These findings, which showed particular benefit in patients with poor persistence marked by early B-cell recovery and in those with R/R bulky extramedullary disease, should help inform future use of checkpoint inhibitors after CAR T-cell therapy, she added.
Dr. Maude reported financial ties to Novartis.
SOURCE: Li AM et al. ASH 2018, Abstract 556.
SAN DIEGO – Checkpoint inhibition can be used safely and effectively with CD19-directed chimeric antigen receptor (CAR) T-cell therapy in children with relapsed B-cell acute lymphoblastic leukemia (ALL), and it may bolster CAR T-cell effects and persistence, suggest the findings in a series of 14 patients at the Children’s Hospital of Philadelphia.
Combined programmed death-1 (PD-1) blockade and CAR T-cell therapy appeared to have particular benefit in patients with early B-cell recovery and in those with bulky extramedullary disease, Shannon Maude, MD, PhD, reported during a press conference at the annual meeting of the American Society of Hematology.
The patients, aged 4-17 years with heavily pretreated relapsed B-ALL (13 patients) or B lymphoblastic lymphoma (1 patient), were treated with CD19-directed CAR T-cell therapy, including CTL019 in 4 patients and CTL119 in 10 patients, followed by pembrolizumab (in 13 patients) or nivolumab (in 1 patient).
Six patients received the combination therapy because of early B-cell recovery after initial CAR T-cell infusion, four patients had relapsed or refractory (R/R) bulky extramedullary disease, and four patients had failed to respond or relapsed after initial CAR T-cell therapy.
Three of the six with poor persistence of response reestablished B-cell aplasia (a reflection of CAR T-cell function) after reinfusion of the CAR T-cell product followed by infusion with PD-1 blockade, and they have “sustained CR [complete response] with B-cell aplasia, showing continued persistence of their CAR T cells,” said Dr. Maude, an attending physician in the Cancer Center at Children’s Hospital of Philadelphia.
Of the four patients with R/R bulky extramedullary disease, two patients had a partial response and two patients had CR, she said, explaining that it was hypothesized that the “PD-1 checkpoint pathway may be activated through the microenvironment in that extramedullary situation.”
However, all four patients who had partial or no response to initial CAR T-cell therapy progressed after PD-1 administration, she said, noting that “in one patient, this progression was marked by reduced CD19 expression, which was probably the mode of escape from CD19 CAR T cells.”
Prior studies have shown that patients who respond to CAR T-cell therapy have persistence of CD19 CAR T cells, whereas those with loss of CD19 CAR T cells within 6 months of infusion have a higher rate of relapse, Dr. Maude explained.
“Our hypothesis was that T cells, upon activation, may become exhausted through activation of immune checkpoint pathways, that one such pathway – PD-1 – may be involved in early loss of CD19 CAR T cells and therefore that the combination [of CD19 CAR T-cell therapy] with PD-1 checkpoint blockade may improve the function of the CAR T cells and their persistence,” she said.
The combined approach was well tolerated in this study, she said, noting that mild cytokine release syndrome symptoms and fever typical of CAR T-cell proliferative responses were observed in three patients within 2 days of starting pembrolizumab.
Other adverse effects associated with PD-1 inhibition, including acute pancreatitis, hypothyroidism, arthralgias, and urticaria, occurred in one patient each. There were four cases of grade 3-4 cytopenias that were deemed tolerable or reversible upon discontinuation.
“We show that PD-1 checkpoint inhibitors can be safely combined with CD19 CAR T-cell therapy and that this mechanism may be useful to improve CAR T-cell persistence,” Dr. Maude said.
These findings, which showed particular benefit in patients with poor persistence marked by early B-cell recovery and in those with R/R bulky extramedullary disease, should help inform future use of checkpoint inhibitors after CAR T-cell therapy, she added.
Dr. Maude reported financial ties to Novartis.
SOURCE: Li AM et al. ASH 2018, Abstract 556.
REPORTING FROM ASH 2018
Key clinical point: Major finding: Three of six patients with poor CAR T-cell persistence had a complete response after treatment with the combination therapy. Study details: A clinical study of 14 patients with relapsed B-ALL.
Disclosures: Dr. Maude reported financial relationships with Novartis.
Source: Li AM et al. ASH 2018, Abstract 556.
Checkpoint inhibitors ‘viable treatment option’ in HIV-infected individuals
Immune checkpoint inhibitors are safe and effective in HIV-infected patients with advanced cancers, according to authors of a recently published systematic review.
The treatment was well tolerated and associated with a 9% rate of grade 3 or higher immune-related adverse events, according to results of the review of 73 patient cases.
There were no adverse impacts on HIV load or CD4 cell count detected in the patients, according to researchers Michael R. Cook, MD, and Chul Kim, MD, MPH, of Georgetown University, Washington.
Antitumor activity of the checkpoint inhibitors in lung cancer patients was comparable to what has been seen in previous randomized clinical trials that excluded HIV-infected individuals, Dr. Cook and Dr. Kim reported in JAMA Oncology.
“Based on the results of the present systematic review, and in the absence of definitive prospective data suggesting an unfavorable risk-to-benefit ratio, immune checkpoint inhibitor therapy may be considered as a viable treatment option for HIV-infected patients with advanced cancer,” they said.
There are preclinical data suggesting that immune checkpoint modulation could improve function of HIV-specific T cells, the investigators added.
“Prospective trials of immune checkpoint inhibitors are necessary to elucidate the antiviral efficacy of immune checkpoint inhibitor therapy in patients with HIV infection and cancer,” they said.
Several such trials are underway to evaluate the role of the pembrolizumab, nivolumab, nivolumab plus ipilimumab, and durvalumab in HIV-infected patients with advanced-stage cancers, according to the review authors.
In the present systematic review, Dr. Cook and Dr. Kim conducted a literature search and reviewed presentations from major annual medical conferences.
Of the 73 HIV-infected patients they identified, most had non–small cell lung cancer (34.2%), melanoma (21.9%), or Kaposi sarcoma (12.3%), while the rest had anal cancer, head and neck cancer, or other malignancies. Most patients had received either nivolumab (39.7%) or pembrolizumab (35.6%).
There were “no concerning findings” among these patients with regard to immune-mediated toxicities or changes in HIV-related parameters.
Six of 70 patients had immune-related adverse events of grade 3 or greater.
Thirty-four patients had documented HIV loads before and after receiving an immune checkpoint inhibitor. Of those, 28 had undetectable HIV loads at baseline, and all but 2 (7%) maintained undetectable loads in the posttreatment evaluation.
Of the remaining six with detectable HIV loads before treatment, five had a decrease in viral load, to the point that four had undetectable HIV viral load in the posttreatment evaluation, the investigators reported.
The overall response rate was 30% for the lung cancer patients, 27% for melanoma, and 63% for Kaposi sarcoma.
In the non–small cell lung cancer subset, response rates were 26% for those who had received previous systemic treatment, and 50% for those who had not, which was similar to findings from major checkpoint inhibitor trials that excluded HIV-infected individuals, the investigators said.
The American Society of Clinical Oncology Conquer Cancer Foundation and Georgetown University supported the study. Dr. Kim reported disclosures related to CARIS Life Science and AstraZeneca.
SOURCE: Cook MR and Kim C. JAMA Oncol. 2019 Feb 7. doi: 10.1001/jamaoncol.2018.6737.
Immune checkpoint inhibitors are safe and effective in HIV-infected patients with advanced cancers, according to authors of a recently published systematic review.
The treatment was well tolerated and associated with a 9% rate of grade 3 or higher immune-related adverse events, according to results of the review of 73 patient cases.
There were no adverse impacts on HIV load or CD4 cell count detected in the patients, according to researchers Michael R. Cook, MD, and Chul Kim, MD, MPH, of Georgetown University, Washington.
Antitumor activity of the checkpoint inhibitors in lung cancer patients was comparable to what has been seen in previous randomized clinical trials that excluded HIV-infected individuals, Dr. Cook and Dr. Kim reported in JAMA Oncology.
“Based on the results of the present systematic review, and in the absence of definitive prospective data suggesting an unfavorable risk-to-benefit ratio, immune checkpoint inhibitor therapy may be considered as a viable treatment option for HIV-infected patients with advanced cancer,” they said.
There are preclinical data suggesting that immune checkpoint modulation could improve function of HIV-specific T cells, the investigators added.
“Prospective trials of immune checkpoint inhibitors are necessary to elucidate the antiviral efficacy of immune checkpoint inhibitor therapy in patients with HIV infection and cancer,” they said.
Several such trials are underway to evaluate the role of the pembrolizumab, nivolumab, nivolumab plus ipilimumab, and durvalumab in HIV-infected patients with advanced-stage cancers, according to the review authors.
In the present systematic review, Dr. Cook and Dr. Kim conducted a literature search and reviewed presentations from major annual medical conferences.
Of the 73 HIV-infected patients they identified, most had non–small cell lung cancer (34.2%), melanoma (21.9%), or Kaposi sarcoma (12.3%), while the rest had anal cancer, head and neck cancer, or other malignancies. Most patients had received either nivolumab (39.7%) or pembrolizumab (35.6%).
There were “no concerning findings” among these patients with regard to immune-mediated toxicities or changes in HIV-related parameters.
Six of 70 patients had immune-related adverse events of grade 3 or greater.
Thirty-four patients had documented HIV loads before and after receiving an immune checkpoint inhibitor. Of those, 28 had undetectable HIV loads at baseline, and all but 2 (7%) maintained undetectable loads in the posttreatment evaluation.
Of the remaining six with detectable HIV loads before treatment, five had a decrease in viral load, to the point that four had undetectable HIV viral load in the posttreatment evaluation, the investigators reported.
The overall response rate was 30% for the lung cancer patients, 27% for melanoma, and 63% for Kaposi sarcoma.
In the non–small cell lung cancer subset, response rates were 26% for those who had received previous systemic treatment, and 50% for those who had not, which was similar to findings from major checkpoint inhibitor trials that excluded HIV-infected individuals, the investigators said.
The American Society of Clinical Oncology Conquer Cancer Foundation and Georgetown University supported the study. Dr. Kim reported disclosures related to CARIS Life Science and AstraZeneca.
SOURCE: Cook MR and Kim C. JAMA Oncol. 2019 Feb 7. doi: 10.1001/jamaoncol.2018.6737.
Immune checkpoint inhibitors are safe and effective in HIV-infected patients with advanced cancers, according to authors of a recently published systematic review.
The treatment was well tolerated and associated with a 9% rate of grade 3 or higher immune-related adverse events, according to results of the review of 73 patient cases.
There were no adverse impacts on HIV load or CD4 cell count detected in the patients, according to researchers Michael R. Cook, MD, and Chul Kim, MD, MPH, of Georgetown University, Washington.
Antitumor activity of the checkpoint inhibitors in lung cancer patients was comparable to what has been seen in previous randomized clinical trials that excluded HIV-infected individuals, Dr. Cook and Dr. Kim reported in JAMA Oncology.
“Based on the results of the present systematic review, and in the absence of definitive prospective data suggesting an unfavorable risk-to-benefit ratio, immune checkpoint inhibitor therapy may be considered as a viable treatment option for HIV-infected patients with advanced cancer,” they said.
There are preclinical data suggesting that immune checkpoint modulation could improve function of HIV-specific T cells, the investigators added.
“Prospective trials of immune checkpoint inhibitors are necessary to elucidate the antiviral efficacy of immune checkpoint inhibitor therapy in patients with HIV infection and cancer,” they said.
Several such trials are underway to evaluate the role of the pembrolizumab, nivolumab, nivolumab plus ipilimumab, and durvalumab in HIV-infected patients with advanced-stage cancers, according to the review authors.
In the present systematic review, Dr. Cook and Dr. Kim conducted a literature search and reviewed presentations from major annual medical conferences.
Of the 73 HIV-infected patients they identified, most had non–small cell lung cancer (34.2%), melanoma (21.9%), or Kaposi sarcoma (12.3%), while the rest had anal cancer, head and neck cancer, or other malignancies. Most patients had received either nivolumab (39.7%) or pembrolizumab (35.6%).
There were “no concerning findings” among these patients with regard to immune-mediated toxicities or changes in HIV-related parameters.
Six of 70 patients had immune-related adverse events of grade 3 or greater.
Thirty-four patients had documented HIV loads before and after receiving an immune checkpoint inhibitor. Of those, 28 had undetectable HIV loads at baseline, and all but 2 (7%) maintained undetectable loads in the posttreatment evaluation.
Of the remaining six with detectable HIV loads before treatment, five had a decrease in viral load, to the point that four had undetectable HIV viral load in the posttreatment evaluation, the investigators reported.
The overall response rate was 30% for the lung cancer patients, 27% for melanoma, and 63% for Kaposi sarcoma.
In the non–small cell lung cancer subset, response rates were 26% for those who had received previous systemic treatment, and 50% for those who had not, which was similar to findings from major checkpoint inhibitor trials that excluded HIV-infected individuals, the investigators said.
The American Society of Clinical Oncology Conquer Cancer Foundation and Georgetown University supported the study. Dr. Kim reported disclosures related to CARIS Life Science and AstraZeneca.
SOURCE: Cook MR and Kim C. JAMA Oncol. 2019 Feb 7. doi: 10.1001/jamaoncol.2018.6737.
FROM JAMA ONCOLOGY
Key clinical point: Immune checkpoint inhibitors are a viable treatment option for HIV-infected patients, according to data supporting their safety and efficacy in this patient population.
Major finding: The treatment was well tolerated, with an 8.6% rate of grade 3 or greater immune-related adverse events, and no impact on HIV-related parameters.
Study details: A systematic review of 73 patients with HIV infection who had received treatment with a checkpoint inhibitor.
Disclosures: The American Society of Clinical Oncology Conquer Cancer Foundation and Georgetown University supported the study. One study author reported disclosures related to CARIS Life Science and AstraZeneca.
Source: Cook MR and Kim C. JAMA Oncol. 2019 Feb 7. doi: 10.1001/jamaoncol.2018.6737.
Enoblituzumab plus pembrolizumab shows promise for select solid tumors
WASHINGTON – Combination enoblituzumab and pembrolizumab showed acceptable safety and encouraging antitumor activity in select patients with B7-H3-expressing non–small-cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), and other solid tumors in a phase 1 dose-escalation and expansion study.
Of note, the combination showed activity in patients anticipated to be poorly responsive to checkpoint inhibitor therapy alone, Charu Aggarwal, MD, of the University of Pennsylvania, Philadelphia, reported at the annual meeting of the Society for Immunotherapy of Cancer.
In all, 133 patients were treated weekly with 3, 10 or 15 mg/kg intravenous doses of the investigational anti-B7-H3 monoclonal antibody enoblituzumab plus 2 mg/kg intravenous doses of the programmed death-1 (PD-1) inhibitor pembrolizumab every 3 weeks (the standard dose at the time) for up to 1 year in the open-label dose-escalation study. Of those, 85% experienced treatment-related adverse events (AEs), and 27.1% experienced grade 3 or higher AEs, Dr. Aggarwal said.
These AEs were mostly infusion-related reactions typically seen with the first dose, and they were not usually cumulative, she said, noting that the rates of immune-related adverse events were less than 5%, about 7% of patients discontinued treatment because of a drug-related AE, and 1 treatment-related death due to pneumonitis occurred.
“No maximum tolerated dose was reached,” she added. “What I want to emphasize is that this is a combination immunotherapy approach, and what we found was that despite a combination approach, the nature, rate, and incidence of immune-related adverse events was not different than what is expected compared to single-agent [therapy] alone.”
Patients were then divided into disease-specific dose-expansion cohorts and the SCCHN and NSCLC cohorts were further stratified based on whether or not they had prior exposure to PD-1 inhibitor therapy.
Antitumor activity was noted in anti-PD-1-naive SCCHN patients, and objective responses were also seen in NSCLC patient with tumor programmed death-ligand 1 (PD-L1) expression of less than 1% and patients with checkpoint inhibitor–refractory urothelial carcinoma.
“We saw a 33.3% response rate in IO [immunotherapy]-naive head and neck cancer patients, and a 35.7% response rate in patients with PD-L1-negative immunotherapy-naive non–small-cell lung cancer patients,” she said.
No objective radiographic responses were seen in the IO-exposed SCCHN patients, but a few were seen in the other tumor cohorts, she noted.
“What was more interesting is this prolonged and high level of stable disease that we found in patients who had been previously treated with IO and had actually experienced significant clinical and radiographic progression then experienced stability with this combination,” she said, noting that “a fair amount of stable disease” was also seen in the IO-naive SCCHN and NSCLC patients.
In the immunotherapy-naive SCCHN patients, responses were seen regardless of human papillomavirus status, and four are still on treatment. One had a confirmed complete response.
“The majority of our patients on our trial and in this cohort were B7-H3-positive, she said, adding that the responses that were seen, including in those with stable disease, were “sustained and durable.”
Responses were similar in the immunotherapy-naive NSCLC patients who were PD-L1 negative, she said.
“Responses were seen irrespective of histology ... and many of these patients are still on treatment,” she added, noting that most were B7-H3-positive, which “seems to select our patients who have an even higher response rate of about 45%.”
The responses in that cohort also occurred early, were durable, and are sustained, and some patients remain on treatment and “are enjoying the clinical benefit afforded by this combination,” she said.
The findings are notable, because B7-H3 is highly expressed in many solid tumors, and monotherapy with enoblituzumab, which targets B7-H3 and is engineered to enhance antibody-dependent cell-mediated cytotoxicity, has demonstrated antitumor activity with an acceptable safety profile in patients with selected solid tumors.
In this study it was combined with pembrolizumab to test the hypothesis that coordinated engagement of both innate and adaptive immunity via the targeting of two distinct members of the B7 family could achieve greater antitumor activity than either agent alone, she explained.
The results “benchmark favorably” versus prior experience with PD-1 agents; pembrolizumab and nivolumab each lead to activity of about 13%-16%, she said.
“We acknowledge that our study has very small numbers. Nevertheless, these are encouraging data ... in this very tough-to-treat population,” Dr. Aggarwal said, adding that “further investigation of enoblituzumab with an anti-PD-1 molecule is warranted in both head and neck and lung cancer patients, perhaps including in combination with chemotherapy.”
Further, given the expression patterns of B7-H3 on a wide variety of solid tumors, further investigation of this combination ... is warranted in other tumor types, including in both checkpoint-naive and -treated populations, she concluded.
This study was sponsored by MacroGenics. Dr. Aggarwal reported receiving consulting fees from BMS.
SOURCE: Aggarwal C et al., SITC 2018 Abstract O24.
WASHINGTON – Combination enoblituzumab and pembrolizumab showed acceptable safety and encouraging antitumor activity in select patients with B7-H3-expressing non–small-cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), and other solid tumors in a phase 1 dose-escalation and expansion study.
Of note, the combination showed activity in patients anticipated to be poorly responsive to checkpoint inhibitor therapy alone, Charu Aggarwal, MD, of the University of Pennsylvania, Philadelphia, reported at the annual meeting of the Society for Immunotherapy of Cancer.
In all, 133 patients were treated weekly with 3, 10 or 15 mg/kg intravenous doses of the investigational anti-B7-H3 monoclonal antibody enoblituzumab plus 2 mg/kg intravenous doses of the programmed death-1 (PD-1) inhibitor pembrolizumab every 3 weeks (the standard dose at the time) for up to 1 year in the open-label dose-escalation study. Of those, 85% experienced treatment-related adverse events (AEs), and 27.1% experienced grade 3 or higher AEs, Dr. Aggarwal said.
These AEs were mostly infusion-related reactions typically seen with the first dose, and they were not usually cumulative, she said, noting that the rates of immune-related adverse events were less than 5%, about 7% of patients discontinued treatment because of a drug-related AE, and 1 treatment-related death due to pneumonitis occurred.
“No maximum tolerated dose was reached,” she added. “What I want to emphasize is that this is a combination immunotherapy approach, and what we found was that despite a combination approach, the nature, rate, and incidence of immune-related adverse events was not different than what is expected compared to single-agent [therapy] alone.”
Patients were then divided into disease-specific dose-expansion cohorts and the SCCHN and NSCLC cohorts were further stratified based on whether or not they had prior exposure to PD-1 inhibitor therapy.
Antitumor activity was noted in anti-PD-1-naive SCCHN patients, and objective responses were also seen in NSCLC patient with tumor programmed death-ligand 1 (PD-L1) expression of less than 1% and patients with checkpoint inhibitor–refractory urothelial carcinoma.
“We saw a 33.3% response rate in IO [immunotherapy]-naive head and neck cancer patients, and a 35.7% response rate in patients with PD-L1-negative immunotherapy-naive non–small-cell lung cancer patients,” she said.
No objective radiographic responses were seen in the IO-exposed SCCHN patients, but a few were seen in the other tumor cohorts, she noted.
“What was more interesting is this prolonged and high level of stable disease that we found in patients who had been previously treated with IO and had actually experienced significant clinical and radiographic progression then experienced stability with this combination,” she said, noting that “a fair amount of stable disease” was also seen in the IO-naive SCCHN and NSCLC patients.
In the immunotherapy-naive SCCHN patients, responses were seen regardless of human papillomavirus status, and four are still on treatment. One had a confirmed complete response.
“The majority of our patients on our trial and in this cohort were B7-H3-positive, she said, adding that the responses that were seen, including in those with stable disease, were “sustained and durable.”
Responses were similar in the immunotherapy-naive NSCLC patients who were PD-L1 negative, she said.
“Responses were seen irrespective of histology ... and many of these patients are still on treatment,” she added, noting that most were B7-H3-positive, which “seems to select our patients who have an even higher response rate of about 45%.”
The responses in that cohort also occurred early, were durable, and are sustained, and some patients remain on treatment and “are enjoying the clinical benefit afforded by this combination,” she said.
The findings are notable, because B7-H3 is highly expressed in many solid tumors, and monotherapy with enoblituzumab, which targets B7-H3 and is engineered to enhance antibody-dependent cell-mediated cytotoxicity, has demonstrated antitumor activity with an acceptable safety profile in patients with selected solid tumors.
In this study it was combined with pembrolizumab to test the hypothesis that coordinated engagement of both innate and adaptive immunity via the targeting of two distinct members of the B7 family could achieve greater antitumor activity than either agent alone, she explained.
The results “benchmark favorably” versus prior experience with PD-1 agents; pembrolizumab and nivolumab each lead to activity of about 13%-16%, she said.
“We acknowledge that our study has very small numbers. Nevertheless, these are encouraging data ... in this very tough-to-treat population,” Dr. Aggarwal said, adding that “further investigation of enoblituzumab with an anti-PD-1 molecule is warranted in both head and neck and lung cancer patients, perhaps including in combination with chemotherapy.”
Further, given the expression patterns of B7-H3 on a wide variety of solid tumors, further investigation of this combination ... is warranted in other tumor types, including in both checkpoint-naive and -treated populations, she concluded.
This study was sponsored by MacroGenics. Dr. Aggarwal reported receiving consulting fees from BMS.
SOURCE: Aggarwal C et al., SITC 2018 Abstract O24.
WASHINGTON – Combination enoblituzumab and pembrolizumab showed acceptable safety and encouraging antitumor activity in select patients with B7-H3-expressing non–small-cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), and other solid tumors in a phase 1 dose-escalation and expansion study.
Of note, the combination showed activity in patients anticipated to be poorly responsive to checkpoint inhibitor therapy alone, Charu Aggarwal, MD, of the University of Pennsylvania, Philadelphia, reported at the annual meeting of the Society for Immunotherapy of Cancer.
In all, 133 patients were treated weekly with 3, 10 or 15 mg/kg intravenous doses of the investigational anti-B7-H3 monoclonal antibody enoblituzumab plus 2 mg/kg intravenous doses of the programmed death-1 (PD-1) inhibitor pembrolizumab every 3 weeks (the standard dose at the time) for up to 1 year in the open-label dose-escalation study. Of those, 85% experienced treatment-related adverse events (AEs), and 27.1% experienced grade 3 or higher AEs, Dr. Aggarwal said.
These AEs were mostly infusion-related reactions typically seen with the first dose, and they were not usually cumulative, she said, noting that the rates of immune-related adverse events were less than 5%, about 7% of patients discontinued treatment because of a drug-related AE, and 1 treatment-related death due to pneumonitis occurred.
“No maximum tolerated dose was reached,” she added. “What I want to emphasize is that this is a combination immunotherapy approach, and what we found was that despite a combination approach, the nature, rate, and incidence of immune-related adverse events was not different than what is expected compared to single-agent [therapy] alone.”
Patients were then divided into disease-specific dose-expansion cohorts and the SCCHN and NSCLC cohorts were further stratified based on whether or not they had prior exposure to PD-1 inhibitor therapy.
Antitumor activity was noted in anti-PD-1-naive SCCHN patients, and objective responses were also seen in NSCLC patient with tumor programmed death-ligand 1 (PD-L1) expression of less than 1% and patients with checkpoint inhibitor–refractory urothelial carcinoma.
“We saw a 33.3% response rate in IO [immunotherapy]-naive head and neck cancer patients, and a 35.7% response rate in patients with PD-L1-negative immunotherapy-naive non–small-cell lung cancer patients,” she said.
No objective radiographic responses were seen in the IO-exposed SCCHN patients, but a few were seen in the other tumor cohorts, she noted.
“What was more interesting is this prolonged and high level of stable disease that we found in patients who had been previously treated with IO and had actually experienced significant clinical and radiographic progression then experienced stability with this combination,” she said, noting that “a fair amount of stable disease” was also seen in the IO-naive SCCHN and NSCLC patients.
In the immunotherapy-naive SCCHN patients, responses were seen regardless of human papillomavirus status, and four are still on treatment. One had a confirmed complete response.
“The majority of our patients on our trial and in this cohort were B7-H3-positive, she said, adding that the responses that were seen, including in those with stable disease, were “sustained and durable.”
Responses were similar in the immunotherapy-naive NSCLC patients who were PD-L1 negative, she said.
“Responses were seen irrespective of histology ... and many of these patients are still on treatment,” she added, noting that most were B7-H3-positive, which “seems to select our patients who have an even higher response rate of about 45%.”
The responses in that cohort also occurred early, were durable, and are sustained, and some patients remain on treatment and “are enjoying the clinical benefit afforded by this combination,” she said.
The findings are notable, because B7-H3 is highly expressed in many solid tumors, and monotherapy with enoblituzumab, which targets B7-H3 and is engineered to enhance antibody-dependent cell-mediated cytotoxicity, has demonstrated antitumor activity with an acceptable safety profile in patients with selected solid tumors.
In this study it was combined with pembrolizumab to test the hypothesis that coordinated engagement of both innate and adaptive immunity via the targeting of two distinct members of the B7 family could achieve greater antitumor activity than either agent alone, she explained.
The results “benchmark favorably” versus prior experience with PD-1 agents; pembrolizumab and nivolumab each lead to activity of about 13%-16%, she said.
“We acknowledge that our study has very small numbers. Nevertheless, these are encouraging data ... in this very tough-to-treat population,” Dr. Aggarwal said, adding that “further investigation of enoblituzumab with an anti-PD-1 molecule is warranted in both head and neck and lung cancer patients, perhaps including in combination with chemotherapy.”
Further, given the expression patterns of B7-H3 on a wide variety of solid tumors, further investigation of this combination ... is warranted in other tumor types, including in both checkpoint-naive and -treated populations, she concluded.
This study was sponsored by MacroGenics. Dr. Aggarwal reported receiving consulting fees from BMS.
SOURCE: Aggarwal C et al., SITC 2018 Abstract O24.
REPORTING FROM SITC 2018
Key clinical point: Enoblituzumab plus pembrolizumab shows promise in select patients with B7-H3-expressing solid tumors.
Major finding: The ORRs were 33.3% in IO-naive SCCHN patients and 35.7% in PD-L1-negative IO-naive NSCLC patients.
Study details: A phase 1 dose-escalation and expansion study of 133 patients.
Disclosures: This study was sponsored by MacroGenics. Dr. Aggarwal reported receiving consulting fees from BMS.
Source: Aggarwal C et al. SITC 2018 Abstract O24.