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DNA vaccine + PD-1 blockade shows promise in mCRPC
NATIONAL HARBOR, MD. – Combining programmed death (PD)-1 blockade with tumor-targeted T-cell activation by a novel DNA vaccine safely enhanced antitumor immune responses in metastatic castration-resistant prostate cancer (mCRPC) patients in a randomized clinical study.
Of 26 patients with mCRPC who were evaluable for response, 13 received treatment with an investigational DNA vaccine (pTVG-HP) that encodes prostatic acid phosphatase (PAP) and concurrent PD-1 blockade, and 13 received sequential vaccination and PD-1 blockade. No difference was seen between the groups with respect to progression-free survival at 6 months, but of eight patients in the concurrent therapy arm who had measurable disease, one experienced a partial response and two experienced a reduction in tumor volume, Douglas G. McNeel, MD, PhD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“We did not see objective responses in [six patients with measurable disease in the sequential treatment arm], said Dr. McNeel, a professor at the University of Wisconsin, Madison.
Prostate specific antigen (PSA) responses, which may be a more sensitive marker, were also more common in the concurrent treatment group; 8 of 13 patients in that group had a PSA decline from baseline, and 4 of those had a decline of greater than 25% from baseline, whereas only 1 of the 13 patients in the sequential treatment arm experienced any decline in PSA vs. baseline, Dr. McNeel said.
Responses to the vaccine’s target antigen, prostatic acid phosphatase, were seen in both arms, but only those who received the combined treatment and who had evidence of immune response experienced PSA decline, he added.
Pre- and postvaccination biopsies of metastatic sites showed that concurrent treatment, compared with sequential treatment, elicited tumor-infiltrating CD8+ T cells, PD-L1 expression in tumors, and changes associated with CD8+ T-cell activation, he said, adding that immunization with concurrent PD-1 blockade also elicits changes in proliferation detected by (18F) fluorothymidine PET/CT.
“We’ve been interested in vaccines for cancer, because we know that having the right kind of T cells in the tumor microenvironment is associated with better long-term outcomes,” Dr. McNeel said, noting that the ability of vaccines to activate T cells and augment cytolytic T cells, in particular, should have anticancer activity.
However, the clinical activity of single-agent tumor vaccines has been underwhelming, he noted.
PAP has been a focus in vaccine development, because it is essentially restricted to prostate tissue in humans. A nearly identical prostate-specific rat homologue was used in early studies, and PAP permits evaluation of serum PSA as an independent assessment of response in human trials, he explained.
“It’s the same target as the sipuleucel-T vaccine,” he said, referring to a Food and Drug Administration–approved vaccine for prostate cancer(Provenge).
Two prior phase 1/2 trials looking at DNA vaccine encoding PAP in patients with early biochemically recurrent prostate cancer showed that PAP-specific T-cell immune responses were elicited and that no significant adverse events occurred.
In both trials, the development of persistent PAP-specific, interferon-gamma–secreting T cells was associated with favorable change in PSA doubling time (suggesting a possible impact on the disease), and with PD-L1 expression in circulating tumor cells (suggesting a potential mechanism of resistance), he said.
Laboratory studies helped identify mechanisms of immune resistance following DNA immunization, he said, explaining that immunization elicits T cells secreting interferon-gamma, which leads to an increase in PD-L1 expression on tumor cells.
Encoding epitopes with increased major histocompatibility complex class 1 affinity elicited CD+ t cells with increased and persistent PD-1 expression, and blockade of PD-1 or PD-L1 with vaccination led to improved antitumor responses, he said.
The findings led to the new model focused on timing of PD-1 blockade with vaccine T-cell activation studied in the current trial.
It was hypothesized that PD-1 blockade at the time of T-cell activation with vaccination would be more effective than was blockade of PD-1-regulated T cells previously elicited with vaccination.
Study subjects had mCRPC and evidence of disease progression. Previous treatment with abiraterone(Zytiga), enzalutamide(Xtandi), or chemotherapy, was allowed, but patients with prior sipuleucel-T vaccine exposure were excluded.
Patients in the concurrent treatment arm received both the vaccine and PD-1 blockade with pembrolizumab (Keytruda)over 12 weeks, and those in the sequential therapy arm received vaccination first followed by PD-1 blockade, each for 12 weeks.
Both approaches were well tolerated.
“Essentially, we saw nothing that was unexpected,” Dr. McNeel said.
Adverse events greater than grade 2 included fatigue in one patient, diarrhea in one patient, and autoimmune hepatitis in one patient. No patients discontinued treatment from toxicity, he noted.
One death occurred during follow-up in a patient who had evidence of progression and refused further follow-up, therefore it could not be determined if the death was related to treatment.
The current findings, which are notable in part because PD-1 pathway inhibitors have demonstrated little clinical activity when used as single agents for prostate cancer and which expand upon data presented in a scientific poster at SITC 2016, demonstrate that combining this blockade with tumor-targeted T-cell activation by a DNA vaccine is safe and can augment tumor-specific T cells – as detectable within the peripheral blood and by imaging – and can result in objective antitumor changes.
“To summarize, plasmid DNA vaccines can elicit antigen-specific CD8+ T cells; immunization can increase PD-L1 expression on tumor cells – and we’ve demonstrated, in mice anyway, that this is mediated by the T cells elicited with immunization; PD-1 expression increases on CD8+ T cells following vaccination; and we think this is an opportunity to use checkpoint blockade at the point of vaccination to improve antitumor responses,” Dr. McNeel said.
“So we can look at this as PD-1 blockade to improve the effect of vaccination, but we can also look at it the other way around, and that is that anti-tumor vaccines can elicit the tumor-specific CD8+ T cells needed to enable PD-1 blockade to work,” he said. “ I think this has implications for the choice of vaccine approach, the antigen, and the timing of PD-1 blockade.”
Based on these results, an expansion arm has been opened to evaluate the safety and clinical efficacy of combination treatment beyond 12 weeks, and future studies will look at the combination of two different vaccines to improve antitumor response, he said.
Dr. McNeel disclosed financial relationships (intellectual property rights/patent holder, consultant, ownership interest) with Madison Vaccines Inc. The study is funded by a 2014 Movember PCF Challenge Award and Madison Vaccines.
SOURCE: McNeel D et al., J Immunother Cancer. 2017 5(Suppl 2):86 Abstract O11.
NATIONAL HARBOR, MD. – Combining programmed death (PD)-1 blockade with tumor-targeted T-cell activation by a novel DNA vaccine safely enhanced antitumor immune responses in metastatic castration-resistant prostate cancer (mCRPC) patients in a randomized clinical study.
Of 26 patients with mCRPC who were evaluable for response, 13 received treatment with an investigational DNA vaccine (pTVG-HP) that encodes prostatic acid phosphatase (PAP) and concurrent PD-1 blockade, and 13 received sequential vaccination and PD-1 blockade. No difference was seen between the groups with respect to progression-free survival at 6 months, but of eight patients in the concurrent therapy arm who had measurable disease, one experienced a partial response and two experienced a reduction in tumor volume, Douglas G. McNeel, MD, PhD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“We did not see objective responses in [six patients with measurable disease in the sequential treatment arm], said Dr. McNeel, a professor at the University of Wisconsin, Madison.
Prostate specific antigen (PSA) responses, which may be a more sensitive marker, were also more common in the concurrent treatment group; 8 of 13 patients in that group had a PSA decline from baseline, and 4 of those had a decline of greater than 25% from baseline, whereas only 1 of the 13 patients in the sequential treatment arm experienced any decline in PSA vs. baseline, Dr. McNeel said.
Responses to the vaccine’s target antigen, prostatic acid phosphatase, were seen in both arms, but only those who received the combined treatment and who had evidence of immune response experienced PSA decline, he added.
Pre- and postvaccination biopsies of metastatic sites showed that concurrent treatment, compared with sequential treatment, elicited tumor-infiltrating CD8+ T cells, PD-L1 expression in tumors, and changes associated with CD8+ T-cell activation, he said, adding that immunization with concurrent PD-1 blockade also elicits changes in proliferation detected by (18F) fluorothymidine PET/CT.
“We’ve been interested in vaccines for cancer, because we know that having the right kind of T cells in the tumor microenvironment is associated with better long-term outcomes,” Dr. McNeel said, noting that the ability of vaccines to activate T cells and augment cytolytic T cells, in particular, should have anticancer activity.
However, the clinical activity of single-agent tumor vaccines has been underwhelming, he noted.
PAP has been a focus in vaccine development, because it is essentially restricted to prostate tissue in humans. A nearly identical prostate-specific rat homologue was used in early studies, and PAP permits evaluation of serum PSA as an independent assessment of response in human trials, he explained.
“It’s the same target as the sipuleucel-T vaccine,” he said, referring to a Food and Drug Administration–approved vaccine for prostate cancer(Provenge).
Two prior phase 1/2 trials looking at DNA vaccine encoding PAP in patients with early biochemically recurrent prostate cancer showed that PAP-specific T-cell immune responses were elicited and that no significant adverse events occurred.
In both trials, the development of persistent PAP-specific, interferon-gamma–secreting T cells was associated with favorable change in PSA doubling time (suggesting a possible impact on the disease), and with PD-L1 expression in circulating tumor cells (suggesting a potential mechanism of resistance), he said.
Laboratory studies helped identify mechanisms of immune resistance following DNA immunization, he said, explaining that immunization elicits T cells secreting interferon-gamma, which leads to an increase in PD-L1 expression on tumor cells.
Encoding epitopes with increased major histocompatibility complex class 1 affinity elicited CD+ t cells with increased and persistent PD-1 expression, and blockade of PD-1 or PD-L1 with vaccination led to improved antitumor responses, he said.
The findings led to the new model focused on timing of PD-1 blockade with vaccine T-cell activation studied in the current trial.
It was hypothesized that PD-1 blockade at the time of T-cell activation with vaccination would be more effective than was blockade of PD-1-regulated T cells previously elicited with vaccination.
Study subjects had mCRPC and evidence of disease progression. Previous treatment with abiraterone(Zytiga), enzalutamide(Xtandi), or chemotherapy, was allowed, but patients with prior sipuleucel-T vaccine exposure were excluded.
Patients in the concurrent treatment arm received both the vaccine and PD-1 blockade with pembrolizumab (Keytruda)over 12 weeks, and those in the sequential therapy arm received vaccination first followed by PD-1 blockade, each for 12 weeks.
Both approaches were well tolerated.
“Essentially, we saw nothing that was unexpected,” Dr. McNeel said.
Adverse events greater than grade 2 included fatigue in one patient, diarrhea in one patient, and autoimmune hepatitis in one patient. No patients discontinued treatment from toxicity, he noted.
One death occurred during follow-up in a patient who had evidence of progression and refused further follow-up, therefore it could not be determined if the death was related to treatment.
The current findings, which are notable in part because PD-1 pathway inhibitors have demonstrated little clinical activity when used as single agents for prostate cancer and which expand upon data presented in a scientific poster at SITC 2016, demonstrate that combining this blockade with tumor-targeted T-cell activation by a DNA vaccine is safe and can augment tumor-specific T cells – as detectable within the peripheral blood and by imaging – and can result in objective antitumor changes.
“To summarize, plasmid DNA vaccines can elicit antigen-specific CD8+ T cells; immunization can increase PD-L1 expression on tumor cells – and we’ve demonstrated, in mice anyway, that this is mediated by the T cells elicited with immunization; PD-1 expression increases on CD8+ T cells following vaccination; and we think this is an opportunity to use checkpoint blockade at the point of vaccination to improve antitumor responses,” Dr. McNeel said.
“So we can look at this as PD-1 blockade to improve the effect of vaccination, but we can also look at it the other way around, and that is that anti-tumor vaccines can elicit the tumor-specific CD8+ T cells needed to enable PD-1 blockade to work,” he said. “ I think this has implications for the choice of vaccine approach, the antigen, and the timing of PD-1 blockade.”
Based on these results, an expansion arm has been opened to evaluate the safety and clinical efficacy of combination treatment beyond 12 weeks, and future studies will look at the combination of two different vaccines to improve antitumor response, he said.
Dr. McNeel disclosed financial relationships (intellectual property rights/patent holder, consultant, ownership interest) with Madison Vaccines Inc. The study is funded by a 2014 Movember PCF Challenge Award and Madison Vaccines.
SOURCE: McNeel D et al., J Immunother Cancer. 2017 5(Suppl 2):86 Abstract O11.
NATIONAL HARBOR, MD. – Combining programmed death (PD)-1 blockade with tumor-targeted T-cell activation by a novel DNA vaccine safely enhanced antitumor immune responses in metastatic castration-resistant prostate cancer (mCRPC) patients in a randomized clinical study.
Of 26 patients with mCRPC who were evaluable for response, 13 received treatment with an investigational DNA vaccine (pTVG-HP) that encodes prostatic acid phosphatase (PAP) and concurrent PD-1 blockade, and 13 received sequential vaccination and PD-1 blockade. No difference was seen between the groups with respect to progression-free survival at 6 months, but of eight patients in the concurrent therapy arm who had measurable disease, one experienced a partial response and two experienced a reduction in tumor volume, Douglas G. McNeel, MD, PhD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“We did not see objective responses in [six patients with measurable disease in the sequential treatment arm], said Dr. McNeel, a professor at the University of Wisconsin, Madison.
Prostate specific antigen (PSA) responses, which may be a more sensitive marker, were also more common in the concurrent treatment group; 8 of 13 patients in that group had a PSA decline from baseline, and 4 of those had a decline of greater than 25% from baseline, whereas only 1 of the 13 patients in the sequential treatment arm experienced any decline in PSA vs. baseline, Dr. McNeel said.
Responses to the vaccine’s target antigen, prostatic acid phosphatase, were seen in both arms, but only those who received the combined treatment and who had evidence of immune response experienced PSA decline, he added.
Pre- and postvaccination biopsies of metastatic sites showed that concurrent treatment, compared with sequential treatment, elicited tumor-infiltrating CD8+ T cells, PD-L1 expression in tumors, and changes associated with CD8+ T-cell activation, he said, adding that immunization with concurrent PD-1 blockade also elicits changes in proliferation detected by (18F) fluorothymidine PET/CT.
“We’ve been interested in vaccines for cancer, because we know that having the right kind of T cells in the tumor microenvironment is associated with better long-term outcomes,” Dr. McNeel said, noting that the ability of vaccines to activate T cells and augment cytolytic T cells, in particular, should have anticancer activity.
However, the clinical activity of single-agent tumor vaccines has been underwhelming, he noted.
PAP has been a focus in vaccine development, because it is essentially restricted to prostate tissue in humans. A nearly identical prostate-specific rat homologue was used in early studies, and PAP permits evaluation of serum PSA as an independent assessment of response in human trials, he explained.
“It’s the same target as the sipuleucel-T vaccine,” he said, referring to a Food and Drug Administration–approved vaccine for prostate cancer(Provenge).
Two prior phase 1/2 trials looking at DNA vaccine encoding PAP in patients with early biochemically recurrent prostate cancer showed that PAP-specific T-cell immune responses were elicited and that no significant adverse events occurred.
In both trials, the development of persistent PAP-specific, interferon-gamma–secreting T cells was associated with favorable change in PSA doubling time (suggesting a possible impact on the disease), and with PD-L1 expression in circulating tumor cells (suggesting a potential mechanism of resistance), he said.
Laboratory studies helped identify mechanisms of immune resistance following DNA immunization, he said, explaining that immunization elicits T cells secreting interferon-gamma, which leads to an increase in PD-L1 expression on tumor cells.
Encoding epitopes with increased major histocompatibility complex class 1 affinity elicited CD+ t cells with increased and persistent PD-1 expression, and blockade of PD-1 or PD-L1 with vaccination led to improved antitumor responses, he said.
The findings led to the new model focused on timing of PD-1 blockade with vaccine T-cell activation studied in the current trial.
It was hypothesized that PD-1 blockade at the time of T-cell activation with vaccination would be more effective than was blockade of PD-1-regulated T cells previously elicited with vaccination.
Study subjects had mCRPC and evidence of disease progression. Previous treatment with abiraterone(Zytiga), enzalutamide(Xtandi), or chemotherapy, was allowed, but patients with prior sipuleucel-T vaccine exposure were excluded.
Patients in the concurrent treatment arm received both the vaccine and PD-1 blockade with pembrolizumab (Keytruda)over 12 weeks, and those in the sequential therapy arm received vaccination first followed by PD-1 blockade, each for 12 weeks.
Both approaches were well tolerated.
“Essentially, we saw nothing that was unexpected,” Dr. McNeel said.
Adverse events greater than grade 2 included fatigue in one patient, diarrhea in one patient, and autoimmune hepatitis in one patient. No patients discontinued treatment from toxicity, he noted.
One death occurred during follow-up in a patient who had evidence of progression and refused further follow-up, therefore it could not be determined if the death was related to treatment.
The current findings, which are notable in part because PD-1 pathway inhibitors have demonstrated little clinical activity when used as single agents for prostate cancer and which expand upon data presented in a scientific poster at SITC 2016, demonstrate that combining this blockade with tumor-targeted T-cell activation by a DNA vaccine is safe and can augment tumor-specific T cells – as detectable within the peripheral blood and by imaging – and can result in objective antitumor changes.
“To summarize, plasmid DNA vaccines can elicit antigen-specific CD8+ T cells; immunization can increase PD-L1 expression on tumor cells – and we’ve demonstrated, in mice anyway, that this is mediated by the T cells elicited with immunization; PD-1 expression increases on CD8+ T cells following vaccination; and we think this is an opportunity to use checkpoint blockade at the point of vaccination to improve antitumor responses,” Dr. McNeel said.
“So we can look at this as PD-1 blockade to improve the effect of vaccination, but we can also look at it the other way around, and that is that anti-tumor vaccines can elicit the tumor-specific CD8+ T cells needed to enable PD-1 blockade to work,” he said. “ I think this has implications for the choice of vaccine approach, the antigen, and the timing of PD-1 blockade.”
Based on these results, an expansion arm has been opened to evaluate the safety and clinical efficacy of combination treatment beyond 12 weeks, and future studies will look at the combination of two different vaccines to improve antitumor response, he said.
Dr. McNeel disclosed financial relationships (intellectual property rights/patent holder, consultant, ownership interest) with Madison Vaccines Inc. The study is funded by a 2014 Movember PCF Challenge Award and Madison Vaccines.
SOURCE: McNeel D et al., J Immunother Cancer. 2017 5(Suppl 2):86 Abstract O11.
REPORTING FROM SITC 2017
Key clinical point: Concurrent PD-1 blockade enhanced DNA vaccine activity in mCRPC.
Major finding: A partial response and tumor volume reduction occurred in one and two patients, respectively.
Study details: A randomized clinical study of 26 patients.
Disclosures: Dr. McNeel disclosed financial relationships (intellectual property rights/patent holder, consultant, ownership interest) with Madison Vaccines. The study is funded by a 2014 Movember PCF Challenge Award and Madison Vaccines.
Source: Douglas McNeel D et al. J Immunother Cancer. 2017 Nov; 5(Suppl 2):86 Abstract O11.
First-in-class glutaminase inhibitor combats anti-PD-1/PD-L1 resistance
NATIONAL HARBOR, MD. – Combination treatment with the first-in-class glutaminase inhibitor CB-839 and nivolumab is well-tolerated and shows clinical activity in patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer, including anti-PD-1/PD-L1 refractory patients, according to initial results from a phase 1/2 study.
Responses in melanoma patients who were progressing on nivolumab at study entry and who were refractory to multiple prior immunotherapy regimens are particularly notable, as they highlight the potential for CB-839, when added to nivolumab (Opdivo), to help overcome resistance to anti-PD-L1 therapy, Funda Meric‐Bernstam, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
CB‐839 is highly selective and targets tumor glutamine metabolism, said Dr. Meric-Bernstam of the University of Texas MD Anderson Cancer Center, Houston.
Competition between tumor cells and immune cells for nutrients such as glutamine in the tumor microenvironment can create a metabolic checkpoint that induces local immune suppression. CB‐839 inhibits tumor glutamine consumption, thereby increasing glutamine availability to support T‐cell activity, she explained, noting that in preclinical models, CB‐839 increased intra‐tumoral glutamine and enhanced antitumor activity of PD‐1/PD‐L1 inhibitors.
In the phase 1 dose escalation study, she and her colleagues evaluated the safety and efficacy of CB-839 in combination with the PD‐1 inhibitor nivolumab in patients with melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC). Phase 2 expansion cohorts include a melanoma rescue cohort of patients progressing on anti-PD-L1 therapy at study entry (22 patients), an NSCLC and RCC rescue cohort of patients who were progressing on anti-PD-L1 therapy at study entry or who had stable disease for 6 months or longer without a response (11 NSCLC and 11 RCC), an RCC cohort of patients with prior immunotherapy exposure and no response (10 patients), and an RCC cohort of patents who had no prior immunotherapy exposure (28 patients).
During dose escalation, patients received oral CB‐839 at 600 mg or 800 mg twice daily in combination with standard‐dose nivolumab. In the ongoing phase 2 expansion study, which continues to enroll, patients are receiving 800 mg of CB-839 twice daily with standard‐dose nivolumab, Dr. Meric-Bernstam said.
Patients in each of the cohorts were high risk and/or had intermediate or poor prognostic status at study entry. For example, 50% of patients in the melanoma rescue cohort had liver metastases, 77% had other visceral metastases, and 18% had brain metastases, and the majority of patients in the lung cancer/RCC cohort had visceral metastases. Most had progressive disease as their best response on their last line of immunotherapy.
Of 16 response-evaluable melanoma patients, 1 experienced a complete response, 2 had partial responses, and 4 had stable disease.
“So overall in this patient population that was progressing on a PD-1/PD-L1 inhibitor at enrollment, 19% had an objective response. The disease control rate in this group was 44%,” she said.
In evaluable patients in the lung cancer rescue cohort (6 patients), RCC rescue cohort (8 patients), and RCC prior exposure cohort (7 patients), disease control rates ranged from 57% to 75%, and in the immunotherapy-naive RCC cohort (19 patients), the partial response rate was 21%, and 53% had stable disease, so the overall disease control rate was 74%. Half of the patients in that group remain on study, she noted.
A closer look at the melanoma rescue cohort showed dramatic and rapid responses in two patients who each achieved a partial response in about 8 weeks with response durations of 3.7 months and 5.4 months, respectively. Additionally, pre-treatment biopsies in this cohort showed an elevated T-cell inflamed signature associated with clinical benefit from the addition of CB-839, and in one patient who had both a pretreatment and on-treatment biopsy that was evaluable, the latter showed an increase in T-cell inflamed signature and T-cell effector genes.
In all cohorts, the combination therapy was generally well tolerated. A maximum tolerated dose was not reached. Dose-limiting toxicity – a grade 3 alanine aminotransferase (ALT) increase – occurred in one patient on the 800-mg dose. The most common grade 3 or greater adverse events were fatigue, nausea, photophobia, rash, and elevated ALT, she said, noting that two patients discontinued for treatment-related adverse events (one for a grade 3 rash and one for grade 2 pneumonitis).
“Overall there appeared to be no apparent increase in immune-related adverse events, either in rate or severity, compared with [nivolumab] monotherapy,” she said.
The combination of CB-839 and nivolumab was well tolerated, and in some patients – as seen in the melanoma cohort – adding CB-839 to checkpoint blockade can overcome checkpoint blockade resistance, Dr. Meric-Bernstam concluded, noting that the disease control rates seen in the majority of lung cancer and RCC patients who were progressing on checkpoint blockade is encouraging, as is the objective response rate seen thus far in the RCC therapy-naive patients, and the stable and deep responses seen in the melanoma rescue cohort.
“Based on our encouraging signal in the melanoma rescue cohort, this [cohort] has been expanded,” she said.
Calithera Biosciences sponsored the study. Bristol-Myers Squibb provided nivolumab for the study. Dr. Meric-Bernstam has received grant or research support from Calithera Biosciences and many other companies. She also reported being a paid consultant for several companies and serving on an advisory committee or review panel, or as a board member for multiple companies.
NATIONAL HARBOR, MD. – Combination treatment with the first-in-class glutaminase inhibitor CB-839 and nivolumab is well-tolerated and shows clinical activity in patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer, including anti-PD-1/PD-L1 refractory patients, according to initial results from a phase 1/2 study.
Responses in melanoma patients who were progressing on nivolumab at study entry and who were refractory to multiple prior immunotherapy regimens are particularly notable, as they highlight the potential for CB-839, when added to nivolumab (Opdivo), to help overcome resistance to anti-PD-L1 therapy, Funda Meric‐Bernstam, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
CB‐839 is highly selective and targets tumor glutamine metabolism, said Dr. Meric-Bernstam of the University of Texas MD Anderson Cancer Center, Houston.
Competition between tumor cells and immune cells for nutrients such as glutamine in the tumor microenvironment can create a metabolic checkpoint that induces local immune suppression. CB‐839 inhibits tumor glutamine consumption, thereby increasing glutamine availability to support T‐cell activity, she explained, noting that in preclinical models, CB‐839 increased intra‐tumoral glutamine and enhanced antitumor activity of PD‐1/PD‐L1 inhibitors.
In the phase 1 dose escalation study, she and her colleagues evaluated the safety and efficacy of CB-839 in combination with the PD‐1 inhibitor nivolumab in patients with melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC). Phase 2 expansion cohorts include a melanoma rescue cohort of patients progressing on anti-PD-L1 therapy at study entry (22 patients), an NSCLC and RCC rescue cohort of patients who were progressing on anti-PD-L1 therapy at study entry or who had stable disease for 6 months or longer without a response (11 NSCLC and 11 RCC), an RCC cohort of patients with prior immunotherapy exposure and no response (10 patients), and an RCC cohort of patents who had no prior immunotherapy exposure (28 patients).
During dose escalation, patients received oral CB‐839 at 600 mg or 800 mg twice daily in combination with standard‐dose nivolumab. In the ongoing phase 2 expansion study, which continues to enroll, patients are receiving 800 mg of CB-839 twice daily with standard‐dose nivolumab, Dr. Meric-Bernstam said.
Patients in each of the cohorts were high risk and/or had intermediate or poor prognostic status at study entry. For example, 50% of patients in the melanoma rescue cohort had liver metastases, 77% had other visceral metastases, and 18% had brain metastases, and the majority of patients in the lung cancer/RCC cohort had visceral metastases. Most had progressive disease as their best response on their last line of immunotherapy.
Of 16 response-evaluable melanoma patients, 1 experienced a complete response, 2 had partial responses, and 4 had stable disease.
“So overall in this patient population that was progressing on a PD-1/PD-L1 inhibitor at enrollment, 19% had an objective response. The disease control rate in this group was 44%,” she said.
In evaluable patients in the lung cancer rescue cohort (6 patients), RCC rescue cohort (8 patients), and RCC prior exposure cohort (7 patients), disease control rates ranged from 57% to 75%, and in the immunotherapy-naive RCC cohort (19 patients), the partial response rate was 21%, and 53% had stable disease, so the overall disease control rate was 74%. Half of the patients in that group remain on study, she noted.
A closer look at the melanoma rescue cohort showed dramatic and rapid responses in two patients who each achieved a partial response in about 8 weeks with response durations of 3.7 months and 5.4 months, respectively. Additionally, pre-treatment biopsies in this cohort showed an elevated T-cell inflamed signature associated with clinical benefit from the addition of CB-839, and in one patient who had both a pretreatment and on-treatment biopsy that was evaluable, the latter showed an increase in T-cell inflamed signature and T-cell effector genes.
In all cohorts, the combination therapy was generally well tolerated. A maximum tolerated dose was not reached. Dose-limiting toxicity – a grade 3 alanine aminotransferase (ALT) increase – occurred in one patient on the 800-mg dose. The most common grade 3 or greater adverse events were fatigue, nausea, photophobia, rash, and elevated ALT, she said, noting that two patients discontinued for treatment-related adverse events (one for a grade 3 rash and one for grade 2 pneumonitis).
“Overall there appeared to be no apparent increase in immune-related adverse events, either in rate or severity, compared with [nivolumab] monotherapy,” she said.
The combination of CB-839 and nivolumab was well tolerated, and in some patients – as seen in the melanoma cohort – adding CB-839 to checkpoint blockade can overcome checkpoint blockade resistance, Dr. Meric-Bernstam concluded, noting that the disease control rates seen in the majority of lung cancer and RCC patients who were progressing on checkpoint blockade is encouraging, as is the objective response rate seen thus far in the RCC therapy-naive patients, and the stable and deep responses seen in the melanoma rescue cohort.
“Based on our encouraging signal in the melanoma rescue cohort, this [cohort] has been expanded,” she said.
Calithera Biosciences sponsored the study. Bristol-Myers Squibb provided nivolumab for the study. Dr. Meric-Bernstam has received grant or research support from Calithera Biosciences and many other companies. She also reported being a paid consultant for several companies and serving on an advisory committee or review panel, or as a board member for multiple companies.
NATIONAL HARBOR, MD. – Combination treatment with the first-in-class glutaminase inhibitor CB-839 and nivolumab is well-tolerated and shows clinical activity in patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer, including anti-PD-1/PD-L1 refractory patients, according to initial results from a phase 1/2 study.
Responses in melanoma patients who were progressing on nivolumab at study entry and who were refractory to multiple prior immunotherapy regimens are particularly notable, as they highlight the potential for CB-839, when added to nivolumab (Opdivo), to help overcome resistance to anti-PD-L1 therapy, Funda Meric‐Bernstam, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
CB‐839 is highly selective and targets tumor glutamine metabolism, said Dr. Meric-Bernstam of the University of Texas MD Anderson Cancer Center, Houston.
Competition between tumor cells and immune cells for nutrients such as glutamine in the tumor microenvironment can create a metabolic checkpoint that induces local immune suppression. CB‐839 inhibits tumor glutamine consumption, thereby increasing glutamine availability to support T‐cell activity, she explained, noting that in preclinical models, CB‐839 increased intra‐tumoral glutamine and enhanced antitumor activity of PD‐1/PD‐L1 inhibitors.
In the phase 1 dose escalation study, she and her colleagues evaluated the safety and efficacy of CB-839 in combination with the PD‐1 inhibitor nivolumab in patients with melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC). Phase 2 expansion cohorts include a melanoma rescue cohort of patients progressing on anti-PD-L1 therapy at study entry (22 patients), an NSCLC and RCC rescue cohort of patients who were progressing on anti-PD-L1 therapy at study entry or who had stable disease for 6 months or longer without a response (11 NSCLC and 11 RCC), an RCC cohort of patients with prior immunotherapy exposure and no response (10 patients), and an RCC cohort of patents who had no prior immunotherapy exposure (28 patients).
During dose escalation, patients received oral CB‐839 at 600 mg or 800 mg twice daily in combination with standard‐dose nivolumab. In the ongoing phase 2 expansion study, which continues to enroll, patients are receiving 800 mg of CB-839 twice daily with standard‐dose nivolumab, Dr. Meric-Bernstam said.
Patients in each of the cohorts were high risk and/or had intermediate or poor prognostic status at study entry. For example, 50% of patients in the melanoma rescue cohort had liver metastases, 77% had other visceral metastases, and 18% had brain metastases, and the majority of patients in the lung cancer/RCC cohort had visceral metastases. Most had progressive disease as their best response on their last line of immunotherapy.
Of 16 response-evaluable melanoma patients, 1 experienced a complete response, 2 had partial responses, and 4 had stable disease.
“So overall in this patient population that was progressing on a PD-1/PD-L1 inhibitor at enrollment, 19% had an objective response. The disease control rate in this group was 44%,” she said.
In evaluable patients in the lung cancer rescue cohort (6 patients), RCC rescue cohort (8 patients), and RCC prior exposure cohort (7 patients), disease control rates ranged from 57% to 75%, and in the immunotherapy-naive RCC cohort (19 patients), the partial response rate was 21%, and 53% had stable disease, so the overall disease control rate was 74%. Half of the patients in that group remain on study, she noted.
A closer look at the melanoma rescue cohort showed dramatic and rapid responses in two patients who each achieved a partial response in about 8 weeks with response durations of 3.7 months and 5.4 months, respectively. Additionally, pre-treatment biopsies in this cohort showed an elevated T-cell inflamed signature associated with clinical benefit from the addition of CB-839, and in one patient who had both a pretreatment and on-treatment biopsy that was evaluable, the latter showed an increase in T-cell inflamed signature and T-cell effector genes.
In all cohorts, the combination therapy was generally well tolerated. A maximum tolerated dose was not reached. Dose-limiting toxicity – a grade 3 alanine aminotransferase (ALT) increase – occurred in one patient on the 800-mg dose. The most common grade 3 or greater adverse events were fatigue, nausea, photophobia, rash, and elevated ALT, she said, noting that two patients discontinued for treatment-related adverse events (one for a grade 3 rash and one for grade 2 pneumonitis).
“Overall there appeared to be no apparent increase in immune-related adverse events, either in rate or severity, compared with [nivolumab] monotherapy,” she said.
The combination of CB-839 and nivolumab was well tolerated, and in some patients – as seen in the melanoma cohort – adding CB-839 to checkpoint blockade can overcome checkpoint blockade resistance, Dr. Meric-Bernstam concluded, noting that the disease control rates seen in the majority of lung cancer and RCC patients who were progressing on checkpoint blockade is encouraging, as is the objective response rate seen thus far in the RCC therapy-naive patients, and the stable and deep responses seen in the melanoma rescue cohort.
“Based on our encouraging signal in the melanoma rescue cohort, this [cohort] has been expanded,” she said.
Calithera Biosciences sponsored the study. Bristol-Myers Squibb provided nivolumab for the study. Dr. Meric-Bernstam has received grant or research support from Calithera Biosciences and many other companies. She also reported being a paid consultant for several companies and serving on an advisory committee or review panel, or as a board member for multiple companies.
AT SITC 2017
Key clinical point:
Major finding: The objective response rate in advanced melanoma patients refractory to anti-PD-1/PD-L1 therapy was 19%.
Data source: A phase 1/2 study of 82 patients.
Disclosures: Calithera Biosciences sponsored the study. Bristol-Myers Squibb provided nivolumab for the study. Dr. Meric-Bernstam has received grant or research support from Calithera Biosciences and many other companies. She also reported being a paid consultant for several companies and serving on an advisory committee or review panel or as a board member for multiple companies.
ENCORE 601 study: Entinostat shows promise in NSCLC
NATIONAL HARBOR, MD. – The oral, class I selective histone deacetylase (HDAC) inhibitor entinostat given in combination with pembrolizumab demonstrated antitumor activity and acceptable safety in patients with non–small cell lung cancer in the phase 1b/2 ENCORE 601 study.
Entinostat, which has been shown in preclinical models to enhance suppressor cells in the tumor microenvironment, was evaluated in ENCORE 601 as a treatment for non–small cell lung cancer (NSCLC), melanoma, and colorectal cancer. Previously reported phase 1 results showed that an oral dose of 5 mg weekly plus 200 mg of pembrolizumab given intravenously every 3 weeks deserved further exploration for these indications, according to Leena Gandhi, MD, who reported phase 2, stage 1 results from the lung cancer arm of the Simon two-stage study at the annual meeting of the Society for Immunotherapy of Cancer.
Treatment at that dose was studied in both anti-PD-L1–naive patients with advanced NSCLC, and in NSCLC patients who progressed on anti-PD-L1 treatment, said Dr. Gandhi of New York University Langone Medical Center.
The primary objective of stage 1 was objective response rate, and criteria for advancement were 4 or more responses out of 17 evaluable anti-PD-L1–naive patients (cohort 1), and at least 3 responses out of 31 patients who progressed on anti-PD-L1 therapy (cohort 2).
Both cohorts met the endpoint, with 4 of 17 evaluable cohort 1 patients (24%) achieving a partial response, and 3 of 31 evaluable cohort 2 patients (10%) achieving a partial response.
In cohort 1, two responses were confirmed and two were unconfirmed. One of the unconfirmed patients had malignant pericardial effusion, but remains on study with continued clinical benefit, Dr. Gandhi said, noting that three patients remain on study in all.
“The other notable thing I’d like to point out here … is that the majority of these were patients who did not have high levels of expression of PD-L1,” she said.
In cohort 2 patients, two responses were confirmed and one was unconfirmed. Three patients remain on study.
“In both of these cohorts there are a couple of patients who’ve had quite durable responses,” she said.
The best response to prior anti-PD-1therapy in the cohort 2 patients who had a response was stable disease (two patients). The response to prior therapy was unknown in one patient, she noted.
“All of them had clear regressions, after that initial PD-1 therapy, with this combination,” she said, noting that two had “essentially negative PD-L1 expression, and none had high levels of expression.”
Treatment was associated with grade 3/4 adverse events deemed drug related in 31% of patients; the most common of these events, occurring in at least 10% of patients in cohort 1, were hypophosphatemia and neutropenia, and in cohort 2 were fatigue, anemia, anorexia, and pneumonitis; 13% of patients discontinued treatment due to an adverse event, Dr. Gandhi said.
Of note, there were reductions in circulating myeloid derived suppressor cells in both cohorts following treatment.
Based on the responses seen in this first stage of the study, cohort 2 has advanced to stage 2 and has completed enrollment. Additional patients have not been enrolled in cohort 1, but that is still under consideration, she said.
Dr. Gandhi reported having no disclosures.
NATIONAL HARBOR, MD. – The oral, class I selective histone deacetylase (HDAC) inhibitor entinostat given in combination with pembrolizumab demonstrated antitumor activity and acceptable safety in patients with non–small cell lung cancer in the phase 1b/2 ENCORE 601 study.
Entinostat, which has been shown in preclinical models to enhance suppressor cells in the tumor microenvironment, was evaluated in ENCORE 601 as a treatment for non–small cell lung cancer (NSCLC), melanoma, and colorectal cancer. Previously reported phase 1 results showed that an oral dose of 5 mg weekly plus 200 mg of pembrolizumab given intravenously every 3 weeks deserved further exploration for these indications, according to Leena Gandhi, MD, who reported phase 2, stage 1 results from the lung cancer arm of the Simon two-stage study at the annual meeting of the Society for Immunotherapy of Cancer.
Treatment at that dose was studied in both anti-PD-L1–naive patients with advanced NSCLC, and in NSCLC patients who progressed on anti-PD-L1 treatment, said Dr. Gandhi of New York University Langone Medical Center.
The primary objective of stage 1 was objective response rate, and criteria for advancement were 4 or more responses out of 17 evaluable anti-PD-L1–naive patients (cohort 1), and at least 3 responses out of 31 patients who progressed on anti-PD-L1 therapy (cohort 2).
Both cohorts met the endpoint, with 4 of 17 evaluable cohort 1 patients (24%) achieving a partial response, and 3 of 31 evaluable cohort 2 patients (10%) achieving a partial response.
In cohort 1, two responses were confirmed and two were unconfirmed. One of the unconfirmed patients had malignant pericardial effusion, but remains on study with continued clinical benefit, Dr. Gandhi said, noting that three patients remain on study in all.
“The other notable thing I’d like to point out here … is that the majority of these were patients who did not have high levels of expression of PD-L1,” she said.
In cohort 2 patients, two responses were confirmed and one was unconfirmed. Three patients remain on study.
“In both of these cohorts there are a couple of patients who’ve had quite durable responses,” she said.
The best response to prior anti-PD-1therapy in the cohort 2 patients who had a response was stable disease (two patients). The response to prior therapy was unknown in one patient, she noted.
“All of them had clear regressions, after that initial PD-1 therapy, with this combination,” she said, noting that two had “essentially negative PD-L1 expression, and none had high levels of expression.”
Treatment was associated with grade 3/4 adverse events deemed drug related in 31% of patients; the most common of these events, occurring in at least 10% of patients in cohort 1, were hypophosphatemia and neutropenia, and in cohort 2 were fatigue, anemia, anorexia, and pneumonitis; 13% of patients discontinued treatment due to an adverse event, Dr. Gandhi said.
Of note, there were reductions in circulating myeloid derived suppressor cells in both cohorts following treatment.
Based on the responses seen in this first stage of the study, cohort 2 has advanced to stage 2 and has completed enrollment. Additional patients have not been enrolled in cohort 1, but that is still under consideration, she said.
Dr. Gandhi reported having no disclosures.
NATIONAL HARBOR, MD. – The oral, class I selective histone deacetylase (HDAC) inhibitor entinostat given in combination with pembrolizumab demonstrated antitumor activity and acceptable safety in patients with non–small cell lung cancer in the phase 1b/2 ENCORE 601 study.
Entinostat, which has been shown in preclinical models to enhance suppressor cells in the tumor microenvironment, was evaluated in ENCORE 601 as a treatment for non–small cell lung cancer (NSCLC), melanoma, and colorectal cancer. Previously reported phase 1 results showed that an oral dose of 5 mg weekly plus 200 mg of pembrolizumab given intravenously every 3 weeks deserved further exploration for these indications, according to Leena Gandhi, MD, who reported phase 2, stage 1 results from the lung cancer arm of the Simon two-stage study at the annual meeting of the Society for Immunotherapy of Cancer.
Treatment at that dose was studied in both anti-PD-L1–naive patients with advanced NSCLC, and in NSCLC patients who progressed on anti-PD-L1 treatment, said Dr. Gandhi of New York University Langone Medical Center.
The primary objective of stage 1 was objective response rate, and criteria for advancement were 4 or more responses out of 17 evaluable anti-PD-L1–naive patients (cohort 1), and at least 3 responses out of 31 patients who progressed on anti-PD-L1 therapy (cohort 2).
Both cohorts met the endpoint, with 4 of 17 evaluable cohort 1 patients (24%) achieving a partial response, and 3 of 31 evaluable cohort 2 patients (10%) achieving a partial response.
In cohort 1, two responses were confirmed and two were unconfirmed. One of the unconfirmed patients had malignant pericardial effusion, but remains on study with continued clinical benefit, Dr. Gandhi said, noting that three patients remain on study in all.
“The other notable thing I’d like to point out here … is that the majority of these were patients who did not have high levels of expression of PD-L1,” she said.
In cohort 2 patients, two responses were confirmed and one was unconfirmed. Three patients remain on study.
“In both of these cohorts there are a couple of patients who’ve had quite durable responses,” she said.
The best response to prior anti-PD-1therapy in the cohort 2 patients who had a response was stable disease (two patients). The response to prior therapy was unknown in one patient, she noted.
“All of them had clear regressions, after that initial PD-1 therapy, with this combination,” she said, noting that two had “essentially negative PD-L1 expression, and none had high levels of expression.”
Treatment was associated with grade 3/4 adverse events deemed drug related in 31% of patients; the most common of these events, occurring in at least 10% of patients in cohort 1, were hypophosphatemia and neutropenia, and in cohort 2 were fatigue, anemia, anorexia, and pneumonitis; 13% of patients discontinued treatment due to an adverse event, Dr. Gandhi said.
Of note, there were reductions in circulating myeloid derived suppressor cells in both cohorts following treatment.
Based on the responses seen in this first stage of the study, cohort 2 has advanced to stage 2 and has completed enrollment. Additional patients have not been enrolled in cohort 1, but that is still under consideration, she said.
Dr. Gandhi reported having no disclosures.
AT SITC 2017
Key clinical point:
Major finding: Partial responses were seen in 24% of cohort 1 patients and 10% of cohort 2 patients.
Data source: Stage 1 of a phase 2 Simon two-stage study (48 evaluable patients).
Disclosures: Dr. Gandhi reported having no disclosures.
GSI may boost BCMA CAR T-cell therapy efficacy in myeloma
NATIONAL HARBOR, MD. – Gamma secretase inhibition may lead to improved outcomes in multiple myeloma patients treated with B-cell maturation antigen (BCMA)–specific CAR T-cell therapy, according to Margot J. Pont, PhD.
In a preclinical myeloma model, gamma secretase inhibition (GSI) increased antitumor efficacy of BCMA-specific chimeric antigen receptor modified T-cells (BCMA CAR T), Dr. Pont of Fred Hutchinson Cancer Research Center, Seattle, reported at the annual meeting of the Society for Immunotherapy of Cancer.
BCMA is expressed in most multiple myeloma patients, and can be targeted by T cells that have been transduced with an anti-BCMA CAR. Other studies have shown efficacy of BCMA CAR T cells, and Dr. Pont and her colleagues have developed and optimized a CAR, based on a previously described single-chain variable fragment (scFv), that performs at least as well as a similar CAR developed previously by another group.
Previous studies have found that antigen down-regulation and escape can be an important escape mechanism by the tumor, so low-to-negative antigen expression could lead to failure in CAR T-cell recognition, resulting in relapse, she explained.
“We need the antigen density to be high enough,” she said, noting that BCMA, specifically, can be susceptible to antigen down-regulation, because its extracellular component is cleaved off the cell membrane by the enzyme gamma-secretase.
“That leads to two things: It reduces the surface expression of BCMA and it sheds soluble BCMA into the circulation, so you get high concentrations of soluble BCMA in the tumor microenvironment,” she said.
Inhibiting BCMA shedding with GSI can increase surface expression and reduce levels of soluble BCMA, thereby potentially enhancing the CAR activity.
First, soluble BCMA levels were measured in bone marrow sera from myeloma patients.
“We indeed saw high levels of soluble BCMA in these patients, and they roughly correlated with tumor burden. When culturing myeloma cell lines in vitro, we detected sBCMA in the culture supernatant within 24 hours,” Dr. Pont said, adding that the introduction of recombinant BCMA to the cultures showed that increasing levels of recombinant BCMA reduced staining of the CAR, demonstrating binding to the receptor.
Next, GSI was used to increase BCMA levels, and with increasing concentrations of the drug, BCMA surface expression was increased, she said, noting that this coincided with a reduction of soluble BCMA in the culture supernatant.
This also worked in patient samples, and was achieved with low doses of GSI, which upregulated surface BCMA levels on primary multiple myeloma by up to tenfold, she said.
In vivo testing of CAR T-cell efficacy was performed in tumor-bearing mice, which were treated with either BCMA-specific CAR T cells alone or in combination with GSI.
In this preclinical model of myeloma, RO4929097 increased BCMA on tumor cells in bone marrow and decreased soluble BCMA in peripheral blood. The myeloma-bearing mice treated with both BCMA CAR T cells and intermittent doses of RO4929097 experienced improved antitumor effects of the BCMA CAR T-cell therapy, as well as increased survival versus mice that did not receive RO4929097, she said.
“We’re currently optimizing these dosing regimens,” she said, concluding that “combining GSI and BCMA CAR T is an attractive option to improve the level of efficacy and prevent the outgrowth of BCMA-low tumor cells.”
Dr. Pont reported having no relevant financial disclosures.
NATIONAL HARBOR, MD. – Gamma secretase inhibition may lead to improved outcomes in multiple myeloma patients treated with B-cell maturation antigen (BCMA)–specific CAR T-cell therapy, according to Margot J. Pont, PhD.
In a preclinical myeloma model, gamma secretase inhibition (GSI) increased antitumor efficacy of BCMA-specific chimeric antigen receptor modified T-cells (BCMA CAR T), Dr. Pont of Fred Hutchinson Cancer Research Center, Seattle, reported at the annual meeting of the Society for Immunotherapy of Cancer.
BCMA is expressed in most multiple myeloma patients, and can be targeted by T cells that have been transduced with an anti-BCMA CAR. Other studies have shown efficacy of BCMA CAR T cells, and Dr. Pont and her colleagues have developed and optimized a CAR, based on a previously described single-chain variable fragment (scFv), that performs at least as well as a similar CAR developed previously by another group.
Previous studies have found that antigen down-regulation and escape can be an important escape mechanism by the tumor, so low-to-negative antigen expression could lead to failure in CAR T-cell recognition, resulting in relapse, she explained.
“We need the antigen density to be high enough,” she said, noting that BCMA, specifically, can be susceptible to antigen down-regulation, because its extracellular component is cleaved off the cell membrane by the enzyme gamma-secretase.
“That leads to two things: It reduces the surface expression of BCMA and it sheds soluble BCMA into the circulation, so you get high concentrations of soluble BCMA in the tumor microenvironment,” she said.
Inhibiting BCMA shedding with GSI can increase surface expression and reduce levels of soluble BCMA, thereby potentially enhancing the CAR activity.
First, soluble BCMA levels were measured in bone marrow sera from myeloma patients.
“We indeed saw high levels of soluble BCMA in these patients, and they roughly correlated with tumor burden. When culturing myeloma cell lines in vitro, we detected sBCMA in the culture supernatant within 24 hours,” Dr. Pont said, adding that the introduction of recombinant BCMA to the cultures showed that increasing levels of recombinant BCMA reduced staining of the CAR, demonstrating binding to the receptor.
Next, GSI was used to increase BCMA levels, and with increasing concentrations of the drug, BCMA surface expression was increased, she said, noting that this coincided with a reduction of soluble BCMA in the culture supernatant.
This also worked in patient samples, and was achieved with low doses of GSI, which upregulated surface BCMA levels on primary multiple myeloma by up to tenfold, she said.
In vivo testing of CAR T-cell efficacy was performed in tumor-bearing mice, which were treated with either BCMA-specific CAR T cells alone or in combination with GSI.
In this preclinical model of myeloma, RO4929097 increased BCMA on tumor cells in bone marrow and decreased soluble BCMA in peripheral blood. The myeloma-bearing mice treated with both BCMA CAR T cells and intermittent doses of RO4929097 experienced improved antitumor effects of the BCMA CAR T-cell therapy, as well as increased survival versus mice that did not receive RO4929097, she said.
“We’re currently optimizing these dosing regimens,” she said, concluding that “combining GSI and BCMA CAR T is an attractive option to improve the level of efficacy and prevent the outgrowth of BCMA-low tumor cells.”
Dr. Pont reported having no relevant financial disclosures.
NATIONAL HARBOR, MD. – Gamma secretase inhibition may lead to improved outcomes in multiple myeloma patients treated with B-cell maturation antigen (BCMA)–specific CAR T-cell therapy, according to Margot J. Pont, PhD.
In a preclinical myeloma model, gamma secretase inhibition (GSI) increased antitumor efficacy of BCMA-specific chimeric antigen receptor modified T-cells (BCMA CAR T), Dr. Pont of Fred Hutchinson Cancer Research Center, Seattle, reported at the annual meeting of the Society for Immunotherapy of Cancer.
BCMA is expressed in most multiple myeloma patients, and can be targeted by T cells that have been transduced with an anti-BCMA CAR. Other studies have shown efficacy of BCMA CAR T cells, and Dr. Pont and her colleagues have developed and optimized a CAR, based on a previously described single-chain variable fragment (scFv), that performs at least as well as a similar CAR developed previously by another group.
Previous studies have found that antigen down-regulation and escape can be an important escape mechanism by the tumor, so low-to-negative antigen expression could lead to failure in CAR T-cell recognition, resulting in relapse, she explained.
“We need the antigen density to be high enough,” she said, noting that BCMA, specifically, can be susceptible to antigen down-regulation, because its extracellular component is cleaved off the cell membrane by the enzyme gamma-secretase.
“That leads to two things: It reduces the surface expression of BCMA and it sheds soluble BCMA into the circulation, so you get high concentrations of soluble BCMA in the tumor microenvironment,” she said.
Inhibiting BCMA shedding with GSI can increase surface expression and reduce levels of soluble BCMA, thereby potentially enhancing the CAR activity.
First, soluble BCMA levels were measured in bone marrow sera from myeloma patients.
“We indeed saw high levels of soluble BCMA in these patients, and they roughly correlated with tumor burden. When culturing myeloma cell lines in vitro, we detected sBCMA in the culture supernatant within 24 hours,” Dr. Pont said, adding that the introduction of recombinant BCMA to the cultures showed that increasing levels of recombinant BCMA reduced staining of the CAR, demonstrating binding to the receptor.
Next, GSI was used to increase BCMA levels, and with increasing concentrations of the drug, BCMA surface expression was increased, she said, noting that this coincided with a reduction of soluble BCMA in the culture supernatant.
This also worked in patient samples, and was achieved with low doses of GSI, which upregulated surface BCMA levels on primary multiple myeloma by up to tenfold, she said.
In vivo testing of CAR T-cell efficacy was performed in tumor-bearing mice, which were treated with either BCMA-specific CAR T cells alone or in combination with GSI.
In this preclinical model of myeloma, RO4929097 increased BCMA on tumor cells in bone marrow and decreased soluble BCMA in peripheral blood. The myeloma-bearing mice treated with both BCMA CAR T cells and intermittent doses of RO4929097 experienced improved antitumor effects of the BCMA CAR T-cell therapy, as well as increased survival versus mice that did not receive RO4929097, she said.
“We’re currently optimizing these dosing regimens,” she said, concluding that “combining GSI and BCMA CAR T is an attractive option to improve the level of efficacy and prevent the outgrowth of BCMA-low tumor cells.”
Dr. Pont reported having no relevant financial disclosures.
AT SITC 2017
CD22 CAR activity in B-ALL highlights promise of multispecific CARs
NATIONAL HARBOR, MD. – A new CD22-targeted chimeric antigen receptor (CAR) demonstrated clinical activity in a phase 1 study of adults and children with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), including several who were previously treated with CD19-directed immunotherapy.
In 21 children and adults with B-ALL who were treated with the CD22 CAR, dose-dependent antileukemic activity was observed; complete remission occurred in 11 of 15 (73%) who received bioactive doses (at least 1 x 106 CD22 CAR T-cells per kg of body weight), including 5 of 5 patients with CD19dim or CD19neg B-ALL, Terry J. Fry, MD, of the National Institutes of Health, Bethesda, Md., and colleagues reported in Nature Medicine (2017 Nov 20. doi: 10.1038.nm.4441).
This study is the first to establish the clinical activity of a CD22 CAR in B-ALL. The investigators developed the CAR in an effort to counter the resistance sometimes seen in patients who receive CD19 CAR T-cell therapy. CD22 is also expressed in most B-ALL cases – and usually is retained following CD19 loss, they explained.
The findings, when considered in light of efficacy demonstrated in leukemia that is resistant to anti-CD19 immunotherapy, highlights the potential for – and importance of – developing multispecific CARs, Crystal L. Mackall, MD, the senior author of the study, said during an update on CAR T-cell research at the annual meeting of the Society for Immunotherapy of Cancer.
“All in all, once we got to the dose that was appropriate ... this CAR had really impressive activity,” said Dr. Mackall, director of the Parker Institute for Cancer Immunotherapy at Stanford (Calif.) University. “In some patients, this was all the patient needed for a prolonged disease-free interval.”
Three patients had ongoing responses, at 21 months, 9 months, and 6 months, she said. There was a high rate of relapse among the study participants, but all patients had previously received at least one bone marrow transplant, and 17 had received CD19-based immunotherapy.
“But nonetheless, the interrogation of these relapses was really essential to understand more about the Achilles heels of these CAR T-cells,” she said. “What we saw is that it was all about the antigen.”
Unlike CD19, which tends to disappear after relapse, CD22-expressing tumors that relapse tend to come back with “simply lower expression of CD22,” she said. The CD22 CAR was unable to control the CD22lo leukemias. This is not unique to the CD22 CAR, she said.
“Every CAR we’ve looked at so far has this exquisite dependence on antigen density for functionality,” she explained, noting that heterogeneity in antigen expression will pose major challenges for the development of therapies, and “maybe has been one of the main reasons we haven’t yet seen the effectiveness of CAR T-cells in solid tumors that we have for hematological malignancies where we’ve typically had targets that are expressed homogenously and at high levels.”
“So we believe very strongly that multispecific CARS are going to be essential for progress, especially as we move into solid tumors,” she added.
Early attempts at developing multispecific CARS suggest that coadministration is not ideal, but two other approaches – coexpression using two vectors or a bicistronic vector, or by creation of a bivalent-bispecific CAR (also known as a tandem CAR) – are both still on the table, she said.
Two clinical first-in-human trials evaluating a CD19/22-bispecific CAR (one in children and one in adults) for relapsed/refractory B-cell malignancies are underway at Stanford.
“We predict that this is going to be the beginning of a wave of bispecific, trispecific, and maybe even quad CARs,” she said. “There’s a lot of work to do, but this is an area that’s going to be very active in the coming years.”
Dr. Mackall has received consulting fees from Adaptimmune, GSK, Roche, Unum Therapeutics, and Vore Pharmaceuticals; has conducted research for Bluebird Bio; and has ownership interest from Juno Therapeutics.
NATIONAL HARBOR, MD. – A new CD22-targeted chimeric antigen receptor (CAR) demonstrated clinical activity in a phase 1 study of adults and children with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), including several who were previously treated with CD19-directed immunotherapy.
In 21 children and adults with B-ALL who were treated with the CD22 CAR, dose-dependent antileukemic activity was observed; complete remission occurred in 11 of 15 (73%) who received bioactive doses (at least 1 x 106 CD22 CAR T-cells per kg of body weight), including 5 of 5 patients with CD19dim or CD19neg B-ALL, Terry J. Fry, MD, of the National Institutes of Health, Bethesda, Md., and colleagues reported in Nature Medicine (2017 Nov 20. doi: 10.1038.nm.4441).
This study is the first to establish the clinical activity of a CD22 CAR in B-ALL. The investigators developed the CAR in an effort to counter the resistance sometimes seen in patients who receive CD19 CAR T-cell therapy. CD22 is also expressed in most B-ALL cases – and usually is retained following CD19 loss, they explained.
The findings, when considered in light of efficacy demonstrated in leukemia that is resistant to anti-CD19 immunotherapy, highlights the potential for – and importance of – developing multispecific CARs, Crystal L. Mackall, MD, the senior author of the study, said during an update on CAR T-cell research at the annual meeting of the Society for Immunotherapy of Cancer.
“All in all, once we got to the dose that was appropriate ... this CAR had really impressive activity,” said Dr. Mackall, director of the Parker Institute for Cancer Immunotherapy at Stanford (Calif.) University. “In some patients, this was all the patient needed for a prolonged disease-free interval.”
Three patients had ongoing responses, at 21 months, 9 months, and 6 months, she said. There was a high rate of relapse among the study participants, but all patients had previously received at least one bone marrow transplant, and 17 had received CD19-based immunotherapy.
“But nonetheless, the interrogation of these relapses was really essential to understand more about the Achilles heels of these CAR T-cells,” she said. “What we saw is that it was all about the antigen.”
Unlike CD19, which tends to disappear after relapse, CD22-expressing tumors that relapse tend to come back with “simply lower expression of CD22,” she said. The CD22 CAR was unable to control the CD22lo leukemias. This is not unique to the CD22 CAR, she said.
“Every CAR we’ve looked at so far has this exquisite dependence on antigen density for functionality,” she explained, noting that heterogeneity in antigen expression will pose major challenges for the development of therapies, and “maybe has been one of the main reasons we haven’t yet seen the effectiveness of CAR T-cells in solid tumors that we have for hematological malignancies where we’ve typically had targets that are expressed homogenously and at high levels.”
“So we believe very strongly that multispecific CARS are going to be essential for progress, especially as we move into solid tumors,” she added.
Early attempts at developing multispecific CARS suggest that coadministration is not ideal, but two other approaches – coexpression using two vectors or a bicistronic vector, or by creation of a bivalent-bispecific CAR (also known as a tandem CAR) – are both still on the table, she said.
Two clinical first-in-human trials evaluating a CD19/22-bispecific CAR (one in children and one in adults) for relapsed/refractory B-cell malignancies are underway at Stanford.
“We predict that this is going to be the beginning of a wave of bispecific, trispecific, and maybe even quad CARs,” she said. “There’s a lot of work to do, but this is an area that’s going to be very active in the coming years.”
Dr. Mackall has received consulting fees from Adaptimmune, GSK, Roche, Unum Therapeutics, and Vore Pharmaceuticals; has conducted research for Bluebird Bio; and has ownership interest from Juno Therapeutics.
NATIONAL HARBOR, MD. – A new CD22-targeted chimeric antigen receptor (CAR) demonstrated clinical activity in a phase 1 study of adults and children with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), including several who were previously treated with CD19-directed immunotherapy.
In 21 children and adults with B-ALL who were treated with the CD22 CAR, dose-dependent antileukemic activity was observed; complete remission occurred in 11 of 15 (73%) who received bioactive doses (at least 1 x 106 CD22 CAR T-cells per kg of body weight), including 5 of 5 patients with CD19dim or CD19neg B-ALL, Terry J. Fry, MD, of the National Institutes of Health, Bethesda, Md., and colleagues reported in Nature Medicine (2017 Nov 20. doi: 10.1038.nm.4441).
This study is the first to establish the clinical activity of a CD22 CAR in B-ALL. The investigators developed the CAR in an effort to counter the resistance sometimes seen in patients who receive CD19 CAR T-cell therapy. CD22 is also expressed in most B-ALL cases – and usually is retained following CD19 loss, they explained.
The findings, when considered in light of efficacy demonstrated in leukemia that is resistant to anti-CD19 immunotherapy, highlights the potential for – and importance of – developing multispecific CARs, Crystal L. Mackall, MD, the senior author of the study, said during an update on CAR T-cell research at the annual meeting of the Society for Immunotherapy of Cancer.
“All in all, once we got to the dose that was appropriate ... this CAR had really impressive activity,” said Dr. Mackall, director of the Parker Institute for Cancer Immunotherapy at Stanford (Calif.) University. “In some patients, this was all the patient needed for a prolonged disease-free interval.”
Three patients had ongoing responses, at 21 months, 9 months, and 6 months, she said. There was a high rate of relapse among the study participants, but all patients had previously received at least one bone marrow transplant, and 17 had received CD19-based immunotherapy.
“But nonetheless, the interrogation of these relapses was really essential to understand more about the Achilles heels of these CAR T-cells,” she said. “What we saw is that it was all about the antigen.”
Unlike CD19, which tends to disappear after relapse, CD22-expressing tumors that relapse tend to come back with “simply lower expression of CD22,” she said. The CD22 CAR was unable to control the CD22lo leukemias. This is not unique to the CD22 CAR, she said.
“Every CAR we’ve looked at so far has this exquisite dependence on antigen density for functionality,” she explained, noting that heterogeneity in antigen expression will pose major challenges for the development of therapies, and “maybe has been one of the main reasons we haven’t yet seen the effectiveness of CAR T-cells in solid tumors that we have for hematological malignancies where we’ve typically had targets that are expressed homogenously and at high levels.”
“So we believe very strongly that multispecific CARS are going to be essential for progress, especially as we move into solid tumors,” she added.
Early attempts at developing multispecific CARS suggest that coadministration is not ideal, but two other approaches – coexpression using two vectors or a bicistronic vector, or by creation of a bivalent-bispecific CAR (also known as a tandem CAR) – are both still on the table, she said.
Two clinical first-in-human trials evaluating a CD19/22-bispecific CAR (one in children and one in adults) for relapsed/refractory B-cell malignancies are underway at Stanford.
“We predict that this is going to be the beginning of a wave of bispecific, trispecific, and maybe even quad CARs,” she said. “There’s a lot of work to do, but this is an area that’s going to be very active in the coming years.”
Dr. Mackall has received consulting fees from Adaptimmune, GSK, Roche, Unum Therapeutics, and Vore Pharmaceuticals; has conducted research for Bluebird Bio; and has ownership interest from Juno Therapeutics.
AT SITC 2017
Key clinical point:
Major finding: Complete remission occurred in 73% of patients who received bioactive doses of the CD22 CAR.
Data source: A phase 1 study of 21 patients.
Disclosures: Dr. Mackall has received consulting fees from Adaptimmune, GSK, Roche, Unum Therapeutics, and Vore Pharmaceuticals; has conducted research for Bluebird Bio; and has ownership interest from Juno Therapeutics.
NCI-MATCH: Nivolumab shows promising activity in noncolorectal cancers
NATIONAL HARBOR, MD. – The immune checkpoint inhibitor nivolumab has promising activity in mismatch repair–deficient noncolorectal cancers, according to preliminary findings from the first sub-arm of the National Cancer Institute’s landmark Molecular Analysis for Therapy Choice (NCI-MATCH) trial.
NCI-MATCH is a 1,173-site precision medicine trial launched in 2015 to study targeted therapies for patients with relapsed/refractory solid tumors, lymphomas, and myelomas. In the first substudy (arm Z1D), the investigators identified 4,900 subjects with samples that could be tested for “actionable molecular abnormalities,” and from among those, they identified 77 with loss of mismatch repair proteins MLH1 or MSH2. Ultimately 47 patients were treated with nivolumab in the substudy.
The confirmed overall response rate was 24%, and an additional 27% of patients had stable disease, said Dr. Azad of Johns Hopkins University, Baltimore.
The patients had a median age of 60 years and were heavily pretreated with a median of three prior therapies. The most common histologies among them were endometrioid endometrial cancer (10 patients), prostate cancer (6 patients), and breast cancer (3 patients).
The safety and tolerability of treatment was as expected for single-agent nivolumab treatment. Toxicity was predominantly low-grade fatigue. Anemia was the most common grade 3 toxicity.
“DNA repair defects due to mismatch repair–deficiency are most commonly caused by silencing of mismatch repair proteins MLH1 or MSH2 and, a little less commonly, MSH6 or PMS2. This can happen through DNA mutation, as well as promoter methylation,” Dr. Azad explained. “In fact, nivolumab has already been tested in patients with mismatch repair–deficient colorectal cancer, both alone and in combination with anti-CTLA-4 ipilimumab ... in addition, pembrolizumab was approved earlier this year for pretreated mismatch repair–deficient cancer.”
“So this formed the nidus for our interest and hypothesis that nivolumab would also have activity in mismatch repair–deficient noncolorectal cancer,” she said.
Study subjects had relapsed/refractory cancers, good end-organ function, and good performance status. They were screened for molecular alterations by centralized testing on fresh biopsy tissue, and mismatch repair deficiency was defined through immunohistochemistry as loss of nuclear expression of MLH1 or MSH2. Patients with mismatch repair–deficient colorectal cancer were excluded.
Those in the nivolumab arm received 3 mg/kg every 2 weeks, and after cycle 4, they could be switched to receive treatment every 4 weeks. Imaging was performed every 2 weeks, and patients were allowed to remain in the study as long as their disease had not progressed. A caveat was that patients with progression within the first 24 weeks, but with no more than four new lesions or 40% increase in tumor index lesions, could remain in the study as long as they were clinically stable.
The overall response rate was compared against a null value of 5%.
“We enrolled 35 patients so that we could have 31 evaluable patients, looking for a signal of 5 or greater responses in that patient group to conclude that the arm was promising and worth further testing,” Dr. Azad said. “This gave us 91.8% power to conclude that an agent was promising if the overall response was truly 25%.”
The study met its primary endpoint, with 8 responses out of 34 evaluable patients, she reported.
“Of note, we had five more patients that had unconfirmed responses. Two of those remained on study at the time of data cutoff, so these response numbers may change as the study matures,” she said.
The disease control rate was 56%, and benefit was seen across tumor histologies, she noted.
“The duration of benefit was compelling for these patients,” she said. “The median time to response was 2.1 cycles, and the 6-month progression-free survival was 49%.”
The median duration of response has not been reached.
Follow-up is ongoing, and 12 patients are enrolled in an expansion cohort; results should be reported within the next year.
“Future work includes interrogating tumor tissue and blood to identify possible predictive markers of response and resistance,” Dr. Azad concluded.
Dr. Azad reported having no disclosures.
NATIONAL HARBOR, MD. – The immune checkpoint inhibitor nivolumab has promising activity in mismatch repair–deficient noncolorectal cancers, according to preliminary findings from the first sub-arm of the National Cancer Institute’s landmark Molecular Analysis for Therapy Choice (NCI-MATCH) trial.
NCI-MATCH is a 1,173-site precision medicine trial launched in 2015 to study targeted therapies for patients with relapsed/refractory solid tumors, lymphomas, and myelomas. In the first substudy (arm Z1D), the investigators identified 4,900 subjects with samples that could be tested for “actionable molecular abnormalities,” and from among those, they identified 77 with loss of mismatch repair proteins MLH1 or MSH2. Ultimately 47 patients were treated with nivolumab in the substudy.
The confirmed overall response rate was 24%, and an additional 27% of patients had stable disease, said Dr. Azad of Johns Hopkins University, Baltimore.
The patients had a median age of 60 years and were heavily pretreated with a median of three prior therapies. The most common histologies among them were endometrioid endometrial cancer (10 patients), prostate cancer (6 patients), and breast cancer (3 patients).
The safety and tolerability of treatment was as expected for single-agent nivolumab treatment. Toxicity was predominantly low-grade fatigue. Anemia was the most common grade 3 toxicity.
“DNA repair defects due to mismatch repair–deficiency are most commonly caused by silencing of mismatch repair proteins MLH1 or MSH2 and, a little less commonly, MSH6 or PMS2. This can happen through DNA mutation, as well as promoter methylation,” Dr. Azad explained. “In fact, nivolumab has already been tested in patients with mismatch repair–deficient colorectal cancer, both alone and in combination with anti-CTLA-4 ipilimumab ... in addition, pembrolizumab was approved earlier this year for pretreated mismatch repair–deficient cancer.”
“So this formed the nidus for our interest and hypothesis that nivolumab would also have activity in mismatch repair–deficient noncolorectal cancer,” she said.
Study subjects had relapsed/refractory cancers, good end-organ function, and good performance status. They were screened for molecular alterations by centralized testing on fresh biopsy tissue, and mismatch repair deficiency was defined through immunohistochemistry as loss of nuclear expression of MLH1 or MSH2. Patients with mismatch repair–deficient colorectal cancer were excluded.
Those in the nivolumab arm received 3 mg/kg every 2 weeks, and after cycle 4, they could be switched to receive treatment every 4 weeks. Imaging was performed every 2 weeks, and patients were allowed to remain in the study as long as their disease had not progressed. A caveat was that patients with progression within the first 24 weeks, but with no more than four new lesions or 40% increase in tumor index lesions, could remain in the study as long as they were clinically stable.
The overall response rate was compared against a null value of 5%.
“We enrolled 35 patients so that we could have 31 evaluable patients, looking for a signal of 5 or greater responses in that patient group to conclude that the arm was promising and worth further testing,” Dr. Azad said. “This gave us 91.8% power to conclude that an agent was promising if the overall response was truly 25%.”
The study met its primary endpoint, with 8 responses out of 34 evaluable patients, she reported.
“Of note, we had five more patients that had unconfirmed responses. Two of those remained on study at the time of data cutoff, so these response numbers may change as the study matures,” she said.
The disease control rate was 56%, and benefit was seen across tumor histologies, she noted.
“The duration of benefit was compelling for these patients,” she said. “The median time to response was 2.1 cycles, and the 6-month progression-free survival was 49%.”
The median duration of response has not been reached.
Follow-up is ongoing, and 12 patients are enrolled in an expansion cohort; results should be reported within the next year.
“Future work includes interrogating tumor tissue and blood to identify possible predictive markers of response and resistance,” Dr. Azad concluded.
Dr. Azad reported having no disclosures.
NATIONAL HARBOR, MD. – The immune checkpoint inhibitor nivolumab has promising activity in mismatch repair–deficient noncolorectal cancers, according to preliminary findings from the first sub-arm of the National Cancer Institute’s landmark Molecular Analysis for Therapy Choice (NCI-MATCH) trial.
NCI-MATCH is a 1,173-site precision medicine trial launched in 2015 to study targeted therapies for patients with relapsed/refractory solid tumors, lymphomas, and myelomas. In the first substudy (arm Z1D), the investigators identified 4,900 subjects with samples that could be tested for “actionable molecular abnormalities,” and from among those, they identified 77 with loss of mismatch repair proteins MLH1 or MSH2. Ultimately 47 patients were treated with nivolumab in the substudy.
The confirmed overall response rate was 24%, and an additional 27% of patients had stable disease, said Dr. Azad of Johns Hopkins University, Baltimore.
The patients had a median age of 60 years and were heavily pretreated with a median of three prior therapies. The most common histologies among them were endometrioid endometrial cancer (10 patients), prostate cancer (6 patients), and breast cancer (3 patients).
The safety and tolerability of treatment was as expected for single-agent nivolumab treatment. Toxicity was predominantly low-grade fatigue. Anemia was the most common grade 3 toxicity.
“DNA repair defects due to mismatch repair–deficiency are most commonly caused by silencing of mismatch repair proteins MLH1 or MSH2 and, a little less commonly, MSH6 or PMS2. This can happen through DNA mutation, as well as promoter methylation,” Dr. Azad explained. “In fact, nivolumab has already been tested in patients with mismatch repair–deficient colorectal cancer, both alone and in combination with anti-CTLA-4 ipilimumab ... in addition, pembrolizumab was approved earlier this year for pretreated mismatch repair–deficient cancer.”
“So this formed the nidus for our interest and hypothesis that nivolumab would also have activity in mismatch repair–deficient noncolorectal cancer,” she said.
Study subjects had relapsed/refractory cancers, good end-organ function, and good performance status. They were screened for molecular alterations by centralized testing on fresh biopsy tissue, and mismatch repair deficiency was defined through immunohistochemistry as loss of nuclear expression of MLH1 or MSH2. Patients with mismatch repair–deficient colorectal cancer were excluded.
Those in the nivolumab arm received 3 mg/kg every 2 weeks, and after cycle 4, they could be switched to receive treatment every 4 weeks. Imaging was performed every 2 weeks, and patients were allowed to remain in the study as long as their disease had not progressed. A caveat was that patients with progression within the first 24 weeks, but with no more than four new lesions or 40% increase in tumor index lesions, could remain in the study as long as they were clinically stable.
The overall response rate was compared against a null value of 5%.
“We enrolled 35 patients so that we could have 31 evaluable patients, looking for a signal of 5 or greater responses in that patient group to conclude that the arm was promising and worth further testing,” Dr. Azad said. “This gave us 91.8% power to conclude that an agent was promising if the overall response was truly 25%.”
The study met its primary endpoint, with 8 responses out of 34 evaluable patients, she reported.
“Of note, we had five more patients that had unconfirmed responses. Two of those remained on study at the time of data cutoff, so these response numbers may change as the study matures,” she said.
The disease control rate was 56%, and benefit was seen across tumor histologies, she noted.
“The duration of benefit was compelling for these patients,” she said. “The median time to response was 2.1 cycles, and the 6-month progression-free survival was 49%.”
The median duration of response has not been reached.
Follow-up is ongoing, and 12 patients are enrolled in an expansion cohort; results should be reported within the next year.
“Future work includes interrogating tumor tissue and blood to identify possible predictive markers of response and resistance,” Dr. Azad concluded.
Dr. Azad reported having no disclosures.
AT SITC 2017
Key clinical point:
Major finding: The confirmed overall response rate was 24%, and an additional 27% of patients had stable disease.
Data source: Arm Z1D (35 patients) of the NCI-MATCH trial.
Disclosures: Dr. Azad reported having no disclosures.
CheckMate 214: Updated results for RCC focus on PD-L1 expression, QOL
NATIONAL HARBOR, MD. – The benefits of combined treatment with the immune checkpoint inhibitors nivolumab and ipilimumab (nivo/ipi) vs. the tyrosine kinase inhibitor sunitinib as demonstrated in intermediate- to poor-risk renal cell carcinoma patients in the CheckMate 214 trial were observed across baseline programmed death–ligand 1 (PD-L1) expression levels, according to subgroup analyses from the open-label phase 3 trial.
However, those with PD-L1–positive tumors – defined as tumors with PD-L1 expression in 1% or more of cells – had improved outcomes, compared with those with PD-L1–negative tumors. This was true for all three co-primary endpoints of the study: overall response rate, progression-free survival, and overall survival, Robert J. Motzer, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“For progression-free survival ... [there was] a strong signal in patients who were PD-L1 expression–positive, but not so in those with PD-L1–negative tumors,” he said (P = .003 and .9670, respectively). “In the overall survival endpoint ... patients benefited with longer survival with nivo/ipi, regardless of PD-L1 expression, but the relative benefit seemed higher in patients expressing PD-L1 (P less than .0001 and .0249, respectively).”
The primary efficacy results of CheckMate 214 were reported in September at the European Society of Medical Oncology. The study enrolled 1,096 patients with treatment-naive advanced or metastatic clear-cell renal cell carcinoma with measurable disease and adequate performance status who were stratified by prognostic score and geographical region and randomly assigned to receive either 3 mg/kg nivolumab and 1 mg/kg ipilimumab every 3 weeks for four doses, then 3 mg/kg nivolumab monotherapy every other week, or 50 mg oral sunitinib once daily for 4 weeks in a 6-week cycle. Treatment continued until patients progressed or experienced unacceptable toxicity.
Most of the patients in the study (847 of 1,096) had intermediate- to poor-risk disease and most of those (about 70%) were PD-L1 negative.
Overall, the study met two of the primary endpoints, demonstrating superior overall survival and overall response rates with nivo/ipi vs. sunitinib in intermediate/poor-risk patients with treatment-naive advanced renal cell carcinoma, Dr. Motzer said.
In addition to presenting the subgroup data regarding outcomes across PD-L1 expression levels at the meeting, he also presented new data showing improved self-reported quality of life among patients treated with nivo/ipi vs. sunitinib. Quality of life was measured using the National Comprehensive Cancer Network/ Functional Assessment Of Cancer Therapy–Kidney Symptom Index 19 questionnaire, which “looks at questions particularly relevant to renal cell carcinoma patients,” he said.
The mean change in questionnaire scores from baseline was consistently better in the nivo/ipi arm. At 104 weeks the mean change was about +5 points with nivo/ipi vs. about –7 points with sunitinib.
“These results support the use of nivo/ipi as a new first-line standard of care option for patients with intermediate/poor-risk advanced [renal cell carcinoma],” he concluded.
CheckMate 214 was funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Motzer reported ownership interest in Armo Biosciences.
NATIONAL HARBOR, MD. – The benefits of combined treatment with the immune checkpoint inhibitors nivolumab and ipilimumab (nivo/ipi) vs. the tyrosine kinase inhibitor sunitinib as demonstrated in intermediate- to poor-risk renal cell carcinoma patients in the CheckMate 214 trial were observed across baseline programmed death–ligand 1 (PD-L1) expression levels, according to subgroup analyses from the open-label phase 3 trial.
However, those with PD-L1–positive tumors – defined as tumors with PD-L1 expression in 1% or more of cells – had improved outcomes, compared with those with PD-L1–negative tumors. This was true for all three co-primary endpoints of the study: overall response rate, progression-free survival, and overall survival, Robert J. Motzer, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“For progression-free survival ... [there was] a strong signal in patients who were PD-L1 expression–positive, but not so in those with PD-L1–negative tumors,” he said (P = .003 and .9670, respectively). “In the overall survival endpoint ... patients benefited with longer survival with nivo/ipi, regardless of PD-L1 expression, but the relative benefit seemed higher in patients expressing PD-L1 (P less than .0001 and .0249, respectively).”
The primary efficacy results of CheckMate 214 were reported in September at the European Society of Medical Oncology. The study enrolled 1,096 patients with treatment-naive advanced or metastatic clear-cell renal cell carcinoma with measurable disease and adequate performance status who were stratified by prognostic score and geographical region and randomly assigned to receive either 3 mg/kg nivolumab and 1 mg/kg ipilimumab every 3 weeks for four doses, then 3 mg/kg nivolumab monotherapy every other week, or 50 mg oral sunitinib once daily for 4 weeks in a 6-week cycle. Treatment continued until patients progressed or experienced unacceptable toxicity.
Most of the patients in the study (847 of 1,096) had intermediate- to poor-risk disease and most of those (about 70%) were PD-L1 negative.
Overall, the study met two of the primary endpoints, demonstrating superior overall survival and overall response rates with nivo/ipi vs. sunitinib in intermediate/poor-risk patients with treatment-naive advanced renal cell carcinoma, Dr. Motzer said.
In addition to presenting the subgroup data regarding outcomes across PD-L1 expression levels at the meeting, he also presented new data showing improved self-reported quality of life among patients treated with nivo/ipi vs. sunitinib. Quality of life was measured using the National Comprehensive Cancer Network/ Functional Assessment Of Cancer Therapy–Kidney Symptom Index 19 questionnaire, which “looks at questions particularly relevant to renal cell carcinoma patients,” he said.
The mean change in questionnaire scores from baseline was consistently better in the nivo/ipi arm. At 104 weeks the mean change was about +5 points with nivo/ipi vs. about –7 points with sunitinib.
“These results support the use of nivo/ipi as a new first-line standard of care option for patients with intermediate/poor-risk advanced [renal cell carcinoma],” he concluded.
CheckMate 214 was funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Motzer reported ownership interest in Armo Biosciences.
NATIONAL HARBOR, MD. – The benefits of combined treatment with the immune checkpoint inhibitors nivolumab and ipilimumab (nivo/ipi) vs. the tyrosine kinase inhibitor sunitinib as demonstrated in intermediate- to poor-risk renal cell carcinoma patients in the CheckMate 214 trial were observed across baseline programmed death–ligand 1 (PD-L1) expression levels, according to subgroup analyses from the open-label phase 3 trial.
However, those with PD-L1–positive tumors – defined as tumors with PD-L1 expression in 1% or more of cells – had improved outcomes, compared with those with PD-L1–negative tumors. This was true for all three co-primary endpoints of the study: overall response rate, progression-free survival, and overall survival, Robert J. Motzer, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“For progression-free survival ... [there was] a strong signal in patients who were PD-L1 expression–positive, but not so in those with PD-L1–negative tumors,” he said (P = .003 and .9670, respectively). “In the overall survival endpoint ... patients benefited with longer survival with nivo/ipi, regardless of PD-L1 expression, but the relative benefit seemed higher in patients expressing PD-L1 (P less than .0001 and .0249, respectively).”
The primary efficacy results of CheckMate 214 were reported in September at the European Society of Medical Oncology. The study enrolled 1,096 patients with treatment-naive advanced or metastatic clear-cell renal cell carcinoma with measurable disease and adequate performance status who were stratified by prognostic score and geographical region and randomly assigned to receive either 3 mg/kg nivolumab and 1 mg/kg ipilimumab every 3 weeks for four doses, then 3 mg/kg nivolumab monotherapy every other week, or 50 mg oral sunitinib once daily for 4 weeks in a 6-week cycle. Treatment continued until patients progressed or experienced unacceptable toxicity.
Most of the patients in the study (847 of 1,096) had intermediate- to poor-risk disease and most of those (about 70%) were PD-L1 negative.
Overall, the study met two of the primary endpoints, demonstrating superior overall survival and overall response rates with nivo/ipi vs. sunitinib in intermediate/poor-risk patients with treatment-naive advanced renal cell carcinoma, Dr. Motzer said.
In addition to presenting the subgroup data regarding outcomes across PD-L1 expression levels at the meeting, he also presented new data showing improved self-reported quality of life among patients treated with nivo/ipi vs. sunitinib. Quality of life was measured using the National Comprehensive Cancer Network/ Functional Assessment Of Cancer Therapy–Kidney Symptom Index 19 questionnaire, which “looks at questions particularly relevant to renal cell carcinoma patients,” he said.
The mean change in questionnaire scores from baseline was consistently better in the nivo/ipi arm. At 104 weeks the mean change was about +5 points with nivo/ipi vs. about –7 points with sunitinib.
“These results support the use of nivo/ipi as a new first-line standard of care option for patients with intermediate/poor-risk advanced [renal cell carcinoma],” he concluded.
CheckMate 214 was funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Motzer reported ownership interest in Armo Biosciences.
AT SITC 2017
Key clinical point:
Major finding: Overall response outcomes favored nivo/ipi vs. sunitinib for both PD-L1–positive tumors and PD-L1–negative tumors, but more so for PD-L1–positive tumors (P less than .0001 and P = .252, respectively).
Data source: The 1,096-patient open-label, phase 3 CheckMate 214 trial.
Disclosures: CheckMate 214 was funded by Bristol-Myers Squibb and Ono Pharmaceutical.