Immuno-oncology

ATLANTA – Combination entinostat and pembrolizumab showed promising activity in a phase 2 study of non–small cell lung cancer patients who progressed on or after anti-programmed death-ligand 1 (PD-L1) therapy, and new analyses have identified gene signatures associated with treatment response.

Gene set analysis in tumors from 43 of the patients – 4 responders and 39 nonresponders – who participated in the open-label ENCORE-601 study revealed that Myc gene signaling was enriched in responders vs. nonresponders, Suresh S. Ramalingam, MD, said at the annual meeting of the American Association for Cancer Research.

High Myc gene activity is known from previous studies to be associated with response to immune checkpoint inhibition, and this has been attributed to high PD-L1 expression, decrease in interferon signatures, and exclusion of lymphocytes, he noted.

“And we know from other publications that entinostat is known to decrease Myc activity,” he said. “Therefore, our putative hypothesis at this time – albeit on a small set of patients – is that for patients with baseline high Myc activity, when they have developed resistance to PD-1 or PD-L1 inhibition ... giving them entinostat drives down the Myc activity and results in a change in the tumor microenvironment to one where immune checkpoint inhibition could be rendered effective.”


Patients from ENCORE-601 also were evaluated by baseline circulating classical monocyte levels as prior findings showed improved overall survival and progression-free survival (PFS) in melanoma patients with higher vs. lower counts, Dr. Ramalingam explained.

The overall response rate (ORR) in those with baseline levels above the median (MHi, 11 patients) was 21.1% vs. 6.5% in those with levels below the median (MLo, 32 patients); median PFS was 4.7 vs. 2.7 months in the MHi and MLo groups, respectively, said Dr. Ramalingam of Winship Cancer Institute, Emory University, Atlanta.

ENCORE-601 included 76 subjects who received entinostat at a dose of 5 mg per week plus intravenous pembrolizumab at 200 mg every 3 weeks. The confirmed ORR with treatment in 72 efficacy-evaluable patients was 10%, with an additional 50% of patients having stable disease. The median duration of response was 8 months, and median PFS was 2.8 months.

Top-line results from the study, which was undertaken based in part on preclinical data showing synergy between the oral class 1-selective histone deacetylase inhibitor entinostat and anti-PD-1 inhibition, were presented at the 2018 World Conference on Lung Cancer, and the current findings represent secondary outcome measures involving analyses in pretreatment tumor samples from patients with sufficient RNA yield for analysis.


The data may provide a mechanistic basis for the responses seen with entinostat and pembrolizumab in ENCORE-601, Dr. Ramalingam said.

“Now we acknowledge that this is a relatively small dataset, and therefore further studies are warranted using these biomarkers to further understand whether they can be used as predictive biomarkers for treatment,” he said, noting that one such clinical trial is currently in the discussion phase.

The ENCORE-601 findings are important given that “with the movement of checkpoint inhibitors to the front-line setting, there is now an unmet need in the second-line [setting] where patients have already received a checkpoint inhibitor and have developed disease progression,” he noted, adding that “while chemotherapy remains central to this group of patients, development of novel agents is an unmet need.”

Dr. Ramalingam disclosed ties to AbbVie, Advaxis, Amgen, Astra Zeneca, Bristol-Myers Squibb, Genentech/Roche, Loxo, Merck, Nektar, Takeda, and Syndax.

[email protected]

SOURCE: Ramalingam S et al. AACR 2019, Abstract CT041.

ATLANTA – Combination entinostat and pembrolizumab showed promising activity in a phase 2 study of non–small cell lung cancer patients who progressed on or after anti-programmed death-ligand 1 (PD-L1) therapy, and new analyses have identified gene signatures associated with treatment response.

Gene set analysis in tumors from 43 of the patients – 4 responders and 39 nonresponders – who participated in the open-label ENCORE-601 study revealed that Myc gene signaling was enriched in responders vs. nonresponders, Suresh S. Ramalingam, MD, said at the annual meeting of the American Association for Cancer Research.

High Myc gene activity is known from previous studies to be associated with response to immune checkpoint inhibition, and this has been attributed to high PD-L1 expression, decrease in interferon signatures, and exclusion of lymphocytes, he noted.

“And we know from other publications that entinostat is known to decrease Myc activity,” he said. “Therefore, our putative hypothesis at this time – albeit on a small set of patients – is that for patients with baseline high Myc activity, when they have developed resistance to PD-1 or PD-L1 inhibition ... giving them entinostat drives down the Myc activity and results in a change in the tumor microenvironment to one where immune checkpoint inhibition could be rendered effective.”


Patients from ENCORE-601 also were evaluated by baseline circulating classical monocyte levels as prior findings showed improved overall survival and progression-free survival (PFS) in melanoma patients with higher vs. lower counts, Dr. Ramalingam explained.

The overall response rate (ORR) in those with baseline levels above the median (MHi, 11 patients) was 21.1% vs. 6.5% in those with levels below the median (MLo, 32 patients); median PFS was 4.7 vs. 2.7 months in the MHi and MLo groups, respectively, said Dr. Ramalingam of Winship Cancer Institute, Emory University, Atlanta.

ENCORE-601 included 76 subjects who received entinostat at a dose of 5 mg per week plus intravenous pembrolizumab at 200 mg every 3 weeks. The confirmed ORR with treatment in 72 efficacy-evaluable patients was 10%, with an additional 50% of patients having stable disease. The median duration of response was 8 months, and median PFS was 2.8 months.

Top-line results from the study, which was undertaken based in part on preclinical data showing synergy between the oral class 1-selective histone deacetylase inhibitor entinostat and anti-PD-1 inhibition, were presented at the 2018 World Conference on Lung Cancer, and the current findings represent secondary outcome measures involving analyses in pretreatment tumor samples from patients with sufficient RNA yield for analysis.


The data may provide a mechanistic basis for the responses seen with entinostat and pembrolizumab in ENCORE-601, Dr. Ramalingam said.

“Now we acknowledge that this is a relatively small dataset, and therefore further studies are warranted using these biomarkers to further understand whether they can be used as predictive biomarkers for treatment,” he said, noting that one such clinical trial is currently in the discussion phase.

The ENCORE-601 findings are important given that “with the movement of checkpoint inhibitors to the front-line setting, there is now an unmet need in the second-line [setting] where patients have already received a checkpoint inhibitor and have developed disease progression,” he noted, adding that “while chemotherapy remains central to this group of patients, development of novel agents is an unmet need.”

Dr. Ramalingam disclosed ties to AbbVie, Advaxis, Amgen, Astra Zeneca, Bristol-Myers Squibb, Genentech/Roche, Loxo, Merck, Nektar, Takeda, and Syndax.

[email protected]

SOURCE: Ramalingam S et al. AACR 2019, Abstract CT041.

ATLANTA – Combination entinostat and pembrolizumab showed promising activity in a phase 2 study of non–small cell lung cancer patients who progressed on or after anti-programmed death-ligand 1 (PD-L1) therapy, and new analyses have identified gene signatures associated with treatment response.

Gene set analysis in tumors from 43 of the patients – 4 responders and 39 nonresponders – who participated in the open-label ENCORE-601 study revealed that Myc gene signaling was enriched in responders vs. nonresponders, Suresh S. Ramalingam, MD, said at the annual meeting of the American Association for Cancer Research.

High Myc gene activity is known from previous studies to be associated with response to immune checkpoint inhibition, and this has been attributed to high PD-L1 expression, decrease in interferon signatures, and exclusion of lymphocytes, he noted.

“And we know from other publications that entinostat is known to decrease Myc activity,” he said. “Therefore, our putative hypothesis at this time – albeit on a small set of patients – is that for patients with baseline high Myc activity, when they have developed resistance to PD-1 or PD-L1 inhibition ... giving them entinostat drives down the Myc activity and results in a change in the tumor microenvironment to one where immune checkpoint inhibition could be rendered effective.”


Patients from ENCORE-601 also were evaluated by baseline circulating classical monocyte levels as prior findings showed improved overall survival and progression-free survival (PFS) in melanoma patients with higher vs. lower counts, Dr. Ramalingam explained.

The overall response rate (ORR) in those with baseline levels above the median (MHi, 11 patients) was 21.1% vs. 6.5% in those with levels below the median (MLo, 32 patients); median PFS was 4.7 vs. 2.7 months in the MHi and MLo groups, respectively, said Dr. Ramalingam of Winship Cancer Institute, Emory University, Atlanta.

ENCORE-601 included 76 subjects who received entinostat at a dose of 5 mg per week plus intravenous pembrolizumab at 200 mg every 3 weeks. The confirmed ORR with treatment in 72 efficacy-evaluable patients was 10%, with an additional 50% of patients having stable disease. The median duration of response was 8 months, and median PFS was 2.8 months.

Top-line results from the study, which was undertaken based in part on preclinical data showing synergy between the oral class 1-selective histone deacetylase inhibitor entinostat and anti-PD-1 inhibition, were presented at the 2018 World Conference on Lung Cancer, and the current findings represent secondary outcome measures involving analyses in pretreatment tumor samples from patients with sufficient RNA yield for analysis.


The data may provide a mechanistic basis for the responses seen with entinostat and pembrolizumab in ENCORE-601, Dr. Ramalingam said.

“Now we acknowledge that this is a relatively small dataset, and therefore further studies are warranted using these biomarkers to further understand whether they can be used as predictive biomarkers for treatment,” he said, noting that one such clinical trial is currently in the discussion phase.

The ENCORE-601 findings are important given that “with the movement of checkpoint inhibitors to the front-line setting, there is now an unmet need in the second-line [setting] where patients have already received a checkpoint inhibitor and have developed disease progression,” he noted, adding that “while chemotherapy remains central to this group of patients, development of novel agents is an unmet need.”

Dr. Ramalingam disclosed ties to AbbVie, Advaxis, Amgen, Astra Zeneca, Bristol-Myers Squibb, Genentech/Roche, Loxo, Merck, Nektar, Takeda, and Syndax.

[email protected]

SOURCE: Ramalingam S et al. AACR 2019, Abstract CT041.

ATLANTA – Combined treatment with a programmed death-ligand 1 (PD-L1) inhibitor, the oral CHK1 inhibitor SRA737, and low-dose gemcitabine for small cell lung cancer (SCLC) resulted in dramatic antitumor activity and established a strong antitumor microenvironment in a preclinical model.

The findings provide a “strong rationale” for combining these agents in patients with SCLC, Triparna Sen, PhD, reported in a late-breaking abstract presentation at the annual meeting of the American Association for Cancer Research.

Dr. Sen and her colleagues assessed this triple regimen based on encouraging prior findings, including their own recent finding that DNA damage response (DDR) inhibition “actually increases antitumor immunity in this cancer type” by activating the STING/TBK1/RF3 innate immune pathway and increasing levels of chemokines-CXCL10 and CCL5 that induced activation of cytotoxic T lymphocytes.

“Based on this background and studies published in other cancer types, we hypothesized that ... SRA737... a very highly selective potent checkpoint inhibitor ... will upregulate the innate immune signaling, resulting in improved antitumor immune response in combination with anti–PD-L1,” she said, noting that bladder and colorectal cancer models were also studied.

The results varied by cancer type, but encouraging results in SCLC led to in vivo study, said Dr. Sen, who was a postdoctoral fellow, instructor, and member of the Byers Laboratory at MD Anderson Cancer Center, Houston, at the time the research was conducted.

She and her colleagues injected immunocompetent mice with Trp53, Rb1, and p130 triple-knockout SCLC cell lines that are “very highly representative of what we see in patients,” and resulting tumors were treated with SRA737 alone or in combination with an anti–PD-L1 agent.

PD-L1 alone did not work, and SRA737 with 5- out of 7-day dosing was associated with a significant delay in tumor growth.

“However, the combination does much better than either of the single agents alone. ... we never had tumor growth beyond baseline and there was regression as early as 12 days,” she said, noting that the combination activates the STING pathway.

Similar findings were seen for bladder and colorectal cancer models, she noted.

The next question is how chemotherapy plus immune checkpoint blockade – the currently approved first-line therapy in SCLC – can be improved, and how chemotherapy modulates the immune microenvironment in SCLC, she said.

To explore this, she and her colleagues treated the mice with subtherapeutic doses of SRA737 on 2 out of 7 days with low-dose gemcitabine, followed by anti–PD-L1 therapy, or with single-agent therapy and various double-agent combinations.

Again, none of the agents worked on their own.

“Even with the double combinations you see very, very modest benefit,” she said. “With the triple combination we wipe out the tumors; as early as 14 days we have 8 out of 10 complete responses, and we have followed the tumors up to 2 months and they stay gone.”

“In a nutshell, this works,” she added.

Additional analyses showed that the CD3+ T cells increase with the gemcitabine/SRA737 combination, and even more so with the triple-combination therapy.

“So we not only increase the CD3+ total T cells, we do increase CD8+ cytotoxic T cells,” she said. “Interestingly, we also decrease exhausted T-cell populations, and also [regulatory T] cells.”

Additionally, the M1 macrophage population was significantly higher with the triple regimen, there was a trend toward a decrease in the antimacrophage population, and there was a higher population of dendritic cells and myeloid-derived suppressor cells.

“What I believe is we are still scratching the surface, and we need to go deeper into the tumor microenvironment and see how these combinations really work,” she said, concluding that SRA737 is cytotoxic and induces micro-nuclei formation in a subset of SCLC and other cancer models in vitro, that in combination with anti–PD-L1 it activates innate immune signaling and causes tumor regression in SCLC, and that with low-dose gemcitabine it results in durable tumor regression in combination with SRA737 and anti–PD-L1.

“What is the most interesting is that this triple combination enhances antitumor immunity by increasing cytotoxic T-cell infiltration, decreasing T-cell exhaustion, and a favorable modulation of antigen presenting cells,” she said. “Why do we care? The anti–PD-L1 drug ... atezolizumab ... is right now FDA approved as a first-line treatment in combination with chemotherapy, and we already have DDR inhibitors in the clinic, we have PARP inhibitors in the clinic, we have checkpoint inhibitors in the clinic, SRA737 is in the clinic.

“So our preclinical data provides a strong rationale for combining low-dose gemcitabine with checkpoint inhibition and with anti–PD-L1 to enhance the clinical efficacy of these drugs,” she concluded.

Dr. Sen reported having no disclosures.

[email protected]

SOURCE: Sen T et al. AACR 2019, Abstract LB-148.

ATLANTA – Combined treatment with a programmed death-ligand 1 (PD-L1) inhibitor, the oral CHK1 inhibitor SRA737, and low-dose gemcitabine for small cell lung cancer (SCLC) resulted in dramatic antitumor activity and established a strong antitumor microenvironment in a preclinical model.

The findings provide a “strong rationale” for combining these agents in patients with SCLC, Triparna Sen, PhD, reported in a late-breaking abstract presentation at the annual meeting of the American Association for Cancer Research.

Dr. Sen and her colleagues assessed this triple regimen based on encouraging prior findings, including their own recent finding that DNA damage response (DDR) inhibition “actually increases antitumor immunity in this cancer type” by activating the STING/TBK1/RF3 innate immune pathway and increasing levels of chemokines-CXCL10 and CCL5 that induced activation of cytotoxic T lymphocytes.

“Based on this background and studies published in other cancer types, we hypothesized that ... SRA737... a very highly selective potent checkpoint inhibitor ... will upregulate the innate immune signaling, resulting in improved antitumor immune response in combination with anti–PD-L1,” she said, noting that bladder and colorectal cancer models were also studied.

The results varied by cancer type, but encouraging results in SCLC led to in vivo study, said Dr. Sen, who was a postdoctoral fellow, instructor, and member of the Byers Laboratory at MD Anderson Cancer Center, Houston, at the time the research was conducted.

She and her colleagues injected immunocompetent mice with Trp53, Rb1, and p130 triple-knockout SCLC cell lines that are “very highly representative of what we see in patients,” and resulting tumors were treated with SRA737 alone or in combination with an anti–PD-L1 agent.

PD-L1 alone did not work, and SRA737 with 5- out of 7-day dosing was associated with a significant delay in tumor growth.

“However, the combination does much better than either of the single agents alone. ... we never had tumor growth beyond baseline and there was regression as early as 12 days,” she said, noting that the combination activates the STING pathway.

Similar findings were seen for bladder and colorectal cancer models, she noted.

The next question is how chemotherapy plus immune checkpoint blockade – the currently approved first-line therapy in SCLC – can be improved, and how chemotherapy modulates the immune microenvironment in SCLC, she said.

To explore this, she and her colleagues treated the mice with subtherapeutic doses of SRA737 on 2 out of 7 days with low-dose gemcitabine, followed by anti–PD-L1 therapy, or with single-agent therapy and various double-agent combinations.

Again, none of the agents worked on their own.

“Even with the double combinations you see very, very modest benefit,” she said. “With the triple combination we wipe out the tumors; as early as 14 days we have 8 out of 10 complete responses, and we have followed the tumors up to 2 months and they stay gone.”

“In a nutshell, this works,” she added.

Additional analyses showed that the CD3+ T cells increase with the gemcitabine/SRA737 combination, and even more so with the triple-combination therapy.

“So we not only increase the CD3+ total T cells, we do increase CD8+ cytotoxic T cells,” she said. “Interestingly, we also decrease exhausted T-cell populations, and also [regulatory T] cells.”

Additionally, the M1 macrophage population was significantly higher with the triple regimen, there was a trend toward a decrease in the antimacrophage population, and there was a higher population of dendritic cells and myeloid-derived suppressor cells.

“What I believe is we are still scratching the surface, and we need to go deeper into the tumor microenvironment and see how these combinations really work,” she said, concluding that SRA737 is cytotoxic and induces micro-nuclei formation in a subset of SCLC and other cancer models in vitro, that in combination with anti–PD-L1 it activates innate immune signaling and causes tumor regression in SCLC, and that with low-dose gemcitabine it results in durable tumor regression in combination with SRA737 and anti–PD-L1.

“What is the most interesting is that this triple combination enhances antitumor immunity by increasing cytotoxic T-cell infiltration, decreasing T-cell exhaustion, and a favorable modulation of antigen presenting cells,” she said. “Why do we care? The anti–PD-L1 drug ... atezolizumab ... is right now FDA approved as a first-line treatment in combination with chemotherapy, and we already have DDR inhibitors in the clinic, we have PARP inhibitors in the clinic, we have checkpoint inhibitors in the clinic, SRA737 is in the clinic.

“So our preclinical data provides a strong rationale for combining low-dose gemcitabine with checkpoint inhibition and with anti–PD-L1 to enhance the clinical efficacy of these drugs,” she concluded.

Dr. Sen reported having no disclosures.

[email protected]

SOURCE: Sen T et al. AACR 2019, Abstract LB-148.

ATLANTA – Combined treatment with a programmed death-ligand 1 (PD-L1) inhibitor, the oral CHK1 inhibitor SRA737, and low-dose gemcitabine for small cell lung cancer (SCLC) resulted in dramatic antitumor activity and established a strong antitumor microenvironment in a preclinical model.

The findings provide a “strong rationale” for combining these agents in patients with SCLC, Triparna Sen, PhD, reported in a late-breaking abstract presentation at the annual meeting of the American Association for Cancer Research.

Dr. Sen and her colleagues assessed this triple regimen based on encouraging prior findings, including their own recent finding that DNA damage response (DDR) inhibition “actually increases antitumor immunity in this cancer type” by activating the STING/TBK1/RF3 innate immune pathway and increasing levels of chemokines-CXCL10 and CCL5 that induced activation of cytotoxic T lymphocytes.

“Based on this background and studies published in other cancer types, we hypothesized that ... SRA737... a very highly selective potent checkpoint inhibitor ... will upregulate the innate immune signaling, resulting in improved antitumor immune response in combination with anti–PD-L1,” she said, noting that bladder and colorectal cancer models were also studied.

The results varied by cancer type, but encouraging results in SCLC led to in vivo study, said Dr. Sen, who was a postdoctoral fellow, instructor, and member of the Byers Laboratory at MD Anderson Cancer Center, Houston, at the time the research was conducted.

She and her colleagues injected immunocompetent mice with Trp53, Rb1, and p130 triple-knockout SCLC cell lines that are “very highly representative of what we see in patients,” and resulting tumors were treated with SRA737 alone or in combination with an anti–PD-L1 agent.

PD-L1 alone did not work, and SRA737 with 5- out of 7-day dosing was associated with a significant delay in tumor growth.

“However, the combination does much better than either of the single agents alone. ... we never had tumor growth beyond baseline and there was regression as early as 12 days,” she said, noting that the combination activates the STING pathway.

Similar findings were seen for bladder and colorectal cancer models, she noted.

The next question is how chemotherapy plus immune checkpoint blockade – the currently approved first-line therapy in SCLC – can be improved, and how chemotherapy modulates the immune microenvironment in SCLC, she said.

To explore this, she and her colleagues treated the mice with subtherapeutic doses of SRA737 on 2 out of 7 days with low-dose gemcitabine, followed by anti–PD-L1 therapy, or with single-agent therapy and various double-agent combinations.

Again, none of the agents worked on their own.

“Even with the double combinations you see very, very modest benefit,” she said. “With the triple combination we wipe out the tumors; as early as 14 days we have 8 out of 10 complete responses, and we have followed the tumors up to 2 months and they stay gone.”

“In a nutshell, this works,” she added.

Additional analyses showed that the CD3+ T cells increase with the gemcitabine/SRA737 combination, and even more so with the triple-combination therapy.

“So we not only increase the CD3+ total T cells, we do increase CD8+ cytotoxic T cells,” she said. “Interestingly, we also decrease exhausted T-cell populations, and also [regulatory T] cells.”

Additionally, the M1 macrophage population was significantly higher with the triple regimen, there was a trend toward a decrease in the antimacrophage population, and there was a higher population of dendritic cells and myeloid-derived suppressor cells.

“What I believe is we are still scratching the surface, and we need to go deeper into the tumor microenvironment and see how these combinations really work,” she said, concluding that SRA737 is cytotoxic and induces micro-nuclei formation in a subset of SCLC and other cancer models in vitro, that in combination with anti–PD-L1 it activates innate immune signaling and causes tumor regression in SCLC, and that with low-dose gemcitabine it results in durable tumor regression in combination with SRA737 and anti–PD-L1.

“What is the most interesting is that this triple combination enhances antitumor immunity by increasing cytotoxic T-cell infiltration, decreasing T-cell exhaustion, and a favorable modulation of antigen presenting cells,” she said. “Why do we care? The anti–PD-L1 drug ... atezolizumab ... is right now FDA approved as a first-line treatment in combination with chemotherapy, and we already have DDR inhibitors in the clinic, we have PARP inhibitors in the clinic, we have checkpoint inhibitors in the clinic, SRA737 is in the clinic.

“So our preclinical data provides a strong rationale for combining low-dose gemcitabine with checkpoint inhibition and with anti–PD-L1 to enhance the clinical efficacy of these drugs,” she concluded.

Dr. Sen reported having no disclosures.

[email protected]

SOURCE: Sen T et al. AACR 2019, Abstract LB-148.

ATLANTA – For patients with locally advanced head and neck squamous cell carcinomas positive for human papillomavirus type 16, neoadjuvant therapy with the immune checkpoint inhibitor nivolumab combined with stereotactic body radiation therapy (SBRT) was associated with high response rates and a lower toxicity profile compared with the current standard of care, results of a phase 1/1b study suggest.

Neil Osterweil/MDedge News

All of five patients treated with SBRT doses of 8 Gy per day for 5 days (40 Gy total) had pathologic complete responses (pCR), as did four of five patients treated at a deescalated SBRT dose of 8 Gy on alternating days for 3 days (24 Gy total), reported Rom S. Leidner, MD, of Providence Cancer Center in Portland, Ore.

“We’ve met the primary endpoint. This approach certainly was safe as far as not preventing definitive surgery. The potency was much greater than expected, with a pCR rate of 90% and a major response in 100% of patients,” he said at the annual meeting of the American Association for Cancer Research.

Dr. Leidner and colleagues are investigating therapies for locally advanced HPV-associated head and neck squamous cell carcinoma (HNSCC) that are as effective as but less toxic than the current standard of care: definitive chemoradiotherapy or surgery followed by risk-adapted adjuvant radiotherapy with or without chemotherapy.

They enrolled 10 patients, all men, with a mean age of 64.5 years. Seven patients had HPV16-positive oropharyngeal HNSCC, and three had unknown primary HNSCC (HPV-positive lymph nodes in the neck without an identifiable mucosal primary site). All patients had clinical indications for adjuvant radiotherapy or upfront transoral robotic surgery (TORS) but were ineligible because of tumor size.

The patients were assigned to one of two dose-finding cohorts in groups of five each to receive nivolumab (Opdivo) 240 mg intravenously every other week for three cycles prior to surgery, with SBRT to gross tumor volume plus 3 mm delivered between the first and second doses of nivolumab.

One cohort of patients received SBRT 8 Gy daily for 5 consecutive days (Monday-Friday), and the other received deescalated SBRT 8 Gy delivered on alternating days (Monday, Wednesday, Friday).

Patients underwent surgery 5 weeks after SBRT, and 4 weeks after surgery were started on adjuvant nivolumab 480 mg IV every 4 weeks for three cycles.

The trial met its primary endpoint of fewer than one-third of patients having an unplanned surgical delay. None of the 10 patients required a surgical delay, in fact.

Although all patients had radiologic evidence of tumor shrinkage prior to surgery, there were no complete responses according to Response Criteria in Solid Tumors (RECIST, version 1.1). Seven patients had a partial response (PR), and three had stable disease.

Dr. Leidner noted that when a patient with stable disease according to RECIST went to surgery “we found a [pCR] in the primary site, and residual cancer in the neck nodes with less than 10% viable tumor cells and evidence of immune eradication.”

As noted, all five patients in the 40-Gy dose group had complete pathologic responses, as did four of the five patients in the deescalated dose group. The remaining patient in this group had a major pathologic response, with less than 10% residual tumor.

“The secondary tissue endpoint far exceeded our expectations on this trial,” Dr. Leidner said.

There were no reports of acute toxicity in the neoadjuvant phase, but delayed mucositis (grade 1 or 2) and immune-related grade 1 dermatologic and rhinitis events were seen. Mucositis resolved by week 4 in all patients, at least 2 weeks before surgery.

Postoperative delayed toxicities up to grade 3 were seen, with delays in mucosal healing in patients who underwent mucosal resections; there were no cases of delayed healing among patients who underwent neck dissection only.

Grade 3 oropharyngeal pain requiring opiates for more than 4 weeks after surgery was seen in both cohorts, but lasted longer among patients in the 8-Gy-times-5 cohort.

Half of all patients were found to have adrenal insufficiency, a rate higher than that previously reported with the use of anti-PD-1 immune checkpoint inhibitors in HNSCC, Dr. Leidner said.

“Clinically we’re seeing, as one might expect, substantially reduced xerostomia and ageusia, but that was not formally measured,” he said.

Based on the study findings, investigations are proceeding at the deescalated dose.

Neil Osterweil/MDedge News

Invited discussant Christine H. Chung, MD, of H. Lee Moffitt Cancer Center and Research Institute in Tampa, did not appear to share Dr. Leidner’s enthusiasm for the approach, saying that “overall, path CR in already resectable patients with an extremely high cure rate may not be clinically meaningful.”

She said that the role of adjuvant nivolumab following neoadjuvant nivolumab, radiotherapy, and surgery in HPV-positive patients is unclear, and that “the approach may be more suitable for HPV-negative patients with poor prognosis and in need of treatment intensification.”

Providence Cancer Center sponsored the study. Dr. Leidner reported having no relevant disclosures. Dr. Chung reported research funding from Lilly Oncology, and advisory board honoraria from BMS, CUE, and Ignyta.

SOURCE: Leidner RS et al. AACR 2019, Abstract CT182.

ATLANTA – For patients with locally advanced head and neck squamous cell carcinomas positive for human papillomavirus type 16, neoadjuvant therapy with the immune checkpoint inhibitor nivolumab combined with stereotactic body radiation therapy (SBRT) was associated with high response rates and a lower toxicity profile compared with the current standard of care, results of a phase 1/1b study suggest.

Neil Osterweil/MDedge News

All of five patients treated with SBRT doses of 8 Gy per day for 5 days (40 Gy total) had pathologic complete responses (pCR), as did four of five patients treated at a deescalated SBRT dose of 8 Gy on alternating days for 3 days (24 Gy total), reported Rom S. Leidner, MD, of Providence Cancer Center in Portland, Ore.

“We’ve met the primary endpoint. This approach certainly was safe as far as not preventing definitive surgery. The potency was much greater than expected, with a pCR rate of 90% and a major response in 100% of patients,” he said at the annual meeting of the American Association for Cancer Research.

Dr. Leidner and colleagues are investigating therapies for locally advanced HPV-associated head and neck squamous cell carcinoma (HNSCC) that are as effective as but less toxic than the current standard of care: definitive chemoradiotherapy or surgery followed by risk-adapted adjuvant radiotherapy with or without chemotherapy.

They enrolled 10 patients, all men, with a mean age of 64.5 years. Seven patients had HPV16-positive oropharyngeal HNSCC, and three had unknown primary HNSCC (HPV-positive lymph nodes in the neck without an identifiable mucosal primary site). All patients had clinical indications for adjuvant radiotherapy or upfront transoral robotic surgery (TORS) but were ineligible because of tumor size.

The patients were assigned to one of two dose-finding cohorts in groups of five each to receive nivolumab (Opdivo) 240 mg intravenously every other week for three cycles prior to surgery, with SBRT to gross tumor volume plus 3 mm delivered between the first and second doses of nivolumab.

One cohort of patients received SBRT 8 Gy daily for 5 consecutive days (Monday-Friday), and the other received deescalated SBRT 8 Gy delivered on alternating days (Monday, Wednesday, Friday).

Patients underwent surgery 5 weeks after SBRT, and 4 weeks after surgery were started on adjuvant nivolumab 480 mg IV every 4 weeks for three cycles.

The trial met its primary endpoint of fewer than one-third of patients having an unplanned surgical delay. None of the 10 patients required a surgical delay, in fact.

Although all patients had radiologic evidence of tumor shrinkage prior to surgery, there were no complete responses according to Response Criteria in Solid Tumors (RECIST, version 1.1). Seven patients had a partial response (PR), and three had stable disease.

Dr. Leidner noted that when a patient with stable disease according to RECIST went to surgery “we found a [pCR] in the primary site, and residual cancer in the neck nodes with less than 10% viable tumor cells and evidence of immune eradication.”

As noted, all five patients in the 40-Gy dose group had complete pathologic responses, as did four of the five patients in the deescalated dose group. The remaining patient in this group had a major pathologic response, with less than 10% residual tumor.

“The secondary tissue endpoint far exceeded our expectations on this trial,” Dr. Leidner said.

There were no reports of acute toxicity in the neoadjuvant phase, but delayed mucositis (grade 1 or 2) and immune-related grade 1 dermatologic and rhinitis events were seen. Mucositis resolved by week 4 in all patients, at least 2 weeks before surgery.

Postoperative delayed toxicities up to grade 3 were seen, with delays in mucosal healing in patients who underwent mucosal resections; there were no cases of delayed healing among patients who underwent neck dissection only.

Grade 3 oropharyngeal pain requiring opiates for more than 4 weeks after surgery was seen in both cohorts, but lasted longer among patients in the 8-Gy-times-5 cohort.

Half of all patients were found to have adrenal insufficiency, a rate higher than that previously reported with the use of anti-PD-1 immune checkpoint inhibitors in HNSCC, Dr. Leidner said.

“Clinically we’re seeing, as one might expect, substantially reduced xerostomia and ageusia, but that was not formally measured,” he said.

Based on the study findings, investigations are proceeding at the deescalated dose.

Neil Osterweil/MDedge News

Invited discussant Christine H. Chung, MD, of H. Lee Moffitt Cancer Center and Research Institute in Tampa, did not appear to share Dr. Leidner’s enthusiasm for the approach, saying that “overall, path CR in already resectable patients with an extremely high cure rate may not be clinically meaningful.”

She said that the role of adjuvant nivolumab following neoadjuvant nivolumab, radiotherapy, and surgery in HPV-positive patients is unclear, and that “the approach may be more suitable for HPV-negative patients with poor prognosis and in need of treatment intensification.”

Providence Cancer Center sponsored the study. Dr. Leidner reported having no relevant disclosures. Dr. Chung reported research funding from Lilly Oncology, and advisory board honoraria from BMS, CUE, and Ignyta.

SOURCE: Leidner RS et al. AACR 2019, Abstract CT182.

ATLANTA – For patients with locally advanced head and neck squamous cell carcinomas positive for human papillomavirus type 16, neoadjuvant therapy with the immune checkpoint inhibitor nivolumab combined with stereotactic body radiation therapy (SBRT) was associated with high response rates and a lower toxicity profile compared with the current standard of care, results of a phase 1/1b study suggest.

Neil Osterweil/MDedge News

All of five patients treated with SBRT doses of 8 Gy per day for 5 days (40 Gy total) had pathologic complete responses (pCR), as did four of five patients treated at a deescalated SBRT dose of 8 Gy on alternating days for 3 days (24 Gy total), reported Rom S. Leidner, MD, of Providence Cancer Center in Portland, Ore.

“We’ve met the primary endpoint. This approach certainly was safe as far as not preventing definitive surgery. The potency was much greater than expected, with a pCR rate of 90% and a major response in 100% of patients,” he said at the annual meeting of the American Association for Cancer Research.

Dr. Leidner and colleagues are investigating therapies for locally advanced HPV-associated head and neck squamous cell carcinoma (HNSCC) that are as effective as but less toxic than the current standard of care: definitive chemoradiotherapy or surgery followed by risk-adapted adjuvant radiotherapy with or without chemotherapy.

They enrolled 10 patients, all men, with a mean age of 64.5 years. Seven patients had HPV16-positive oropharyngeal HNSCC, and three had unknown primary HNSCC (HPV-positive lymph nodes in the neck without an identifiable mucosal primary site). All patients had clinical indications for adjuvant radiotherapy or upfront transoral robotic surgery (TORS) but were ineligible because of tumor size.

The patients were assigned to one of two dose-finding cohorts in groups of five each to receive nivolumab (Opdivo) 240 mg intravenously every other week for three cycles prior to surgery, with SBRT to gross tumor volume plus 3 mm delivered between the first and second doses of nivolumab.

One cohort of patients received SBRT 8 Gy daily for 5 consecutive days (Monday-Friday), and the other received deescalated SBRT 8 Gy delivered on alternating days (Monday, Wednesday, Friday).

Patients underwent surgery 5 weeks after SBRT, and 4 weeks after surgery were started on adjuvant nivolumab 480 mg IV every 4 weeks for three cycles.

The trial met its primary endpoint of fewer than one-third of patients having an unplanned surgical delay. None of the 10 patients required a surgical delay, in fact.

Although all patients had radiologic evidence of tumor shrinkage prior to surgery, there were no complete responses according to Response Criteria in Solid Tumors (RECIST, version 1.1). Seven patients had a partial response (PR), and three had stable disease.

Dr. Leidner noted that when a patient with stable disease according to RECIST went to surgery “we found a [pCR] in the primary site, and residual cancer in the neck nodes with less than 10% viable tumor cells and evidence of immune eradication.”

As noted, all five patients in the 40-Gy dose group had complete pathologic responses, as did four of the five patients in the deescalated dose group. The remaining patient in this group had a major pathologic response, with less than 10% residual tumor.

“The secondary tissue endpoint far exceeded our expectations on this trial,” Dr. Leidner said.

There were no reports of acute toxicity in the neoadjuvant phase, but delayed mucositis (grade 1 or 2) and immune-related grade 1 dermatologic and rhinitis events were seen. Mucositis resolved by week 4 in all patients, at least 2 weeks before surgery.

Postoperative delayed toxicities up to grade 3 were seen, with delays in mucosal healing in patients who underwent mucosal resections; there were no cases of delayed healing among patients who underwent neck dissection only.

Grade 3 oropharyngeal pain requiring opiates for more than 4 weeks after surgery was seen in both cohorts, but lasted longer among patients in the 8-Gy-times-5 cohort.

Half of all patients were found to have adrenal insufficiency, a rate higher than that previously reported with the use of anti-PD-1 immune checkpoint inhibitors in HNSCC, Dr. Leidner said.

“Clinically we’re seeing, as one might expect, substantially reduced xerostomia and ageusia, but that was not formally measured,” he said.

Based on the study findings, investigations are proceeding at the deescalated dose.

Neil Osterweil/MDedge News

Invited discussant Christine H. Chung, MD, of H. Lee Moffitt Cancer Center and Research Institute in Tampa, did not appear to share Dr. Leidner’s enthusiasm for the approach, saying that “overall, path CR in already resectable patients with an extremely high cure rate may not be clinically meaningful.”

She said that the role of adjuvant nivolumab following neoadjuvant nivolumab, radiotherapy, and surgery in HPV-positive patients is unclear, and that “the approach may be more suitable for HPV-negative patients with poor prognosis and in need of treatment intensification.”

Providence Cancer Center sponsored the study. Dr. Leidner reported having no relevant disclosures. Dr. Chung reported research funding from Lilly Oncology, and advisory board honoraria from BMS, CUE, and Ignyta.

SOURCE: Leidner RS et al. AACR 2019, Abstract CT182.

ATLANTA – Blood tumor mutational burden (bTMB) predicts survival benefit in metastatic non–small cell lung cancer (mNSCLC) patients treated with first-line durvalumab plus tremelimumab versus platinum-based chemotherapy, according to findings from the open-label, phase 3 MYSTIC trial.

Frontline Medical News

Specifically, in patients with bTMB based on circulating tumor DNA at levels of 20 mutations (mut)/megabase (Mb) or greater, overall survival (OS) was significantly improved with durvalumab alone and with durvalumab plus tremelimumab versus chemotherapy (hazard ratios, 0.74 and 0.49, respectively). Progression-free survival (PFS) was also improved (HRs, 0.76 and 0.53, respectively), Solange Peters, MD, PhD, reported at the annual meeting of the American Association for Cancer Research.

Among patients with bTMB less than 20 mut/Mb, the corresponding OS hazard ratios were 1.55 and 1.26, and the corresponding PFS hazard ratios were 1.22 and 1.16, said Dr. Peters, director of teaching and patient care in the area of medical oncology and thoracic malignancies at Centre Hospitalier Universitaire Vaudois, Lausanne (Switzerland) University, and president-elect of the European Society for Medical Oncology.

Study subjects were 1,118 patients with immunotherapy- and chemotherapy-naive EGFR and ALK wild-type mNSCLC who were randomized 1:1 to receive either the programmed death–ligand 1 (PD-L1) agent durvalumab, durvalumab plus the anti-CTLA4 agent tremelimumab, or chemotherapy. At a tissue TMB (tTMB) level of 10 mut/Mb or greater, those who received either durvalumab or durvalumab plus tremelimumab had better OS than did those who received chemotherapy (HRs, 0.70 and 0.72, respectively).

Further, bTMB levels of at least 16 mut/Mb correlated positively with tTMB (Spearman correlation coefficient, 0.6; Pearson correlation coefficient, 0.7), she said, adding that survival probability at 24 months was 41.7% with durvalumab plus tremelimumab versus 35.0% with durvalumab alone and 22.7% with chemotherapy in this patient subgroup.

“When you look at the subgroup of patients with lower number of mutations than 10, this phenomenon is not observed. If anything should be potentially stressed about these hazard ratios – all above 1 – is potentially that chemotherapy represents a better option in this patient population,” she said.

Treatment included intravenous durvalumab at a dose of 20 mg/kg every 4 weeks with or without IV tremelimumab at a dose of 1 mg/kg every 4 weeks for up to four doses (372 and 374 patients, respectively), or platinum-based chemotherapy (372 patients).

“Durvalumab ... is already approved for unresectable stage 3 NSCLC and has shown clinical activity in heavily pretreated patients with mNSCLC in the context of phase 2 and 3 previously presented trials,” Dr. Peters said, noting that the multicenter MYSTIC trial was designed to assess its potential role in the treatment of all-comers with stage IV disease.


Overall survival data from the study were presented at the 2018 ESMO Immuno-Oncology Congress, and showed that the primary endpoint of superiority of durvalumab or durvalumab plus tremelimumab versus chemotherapy for OS in patients with high PD-L1 expression (at least 25% of tumor cells expressing PD-L1) was not met. There did, however, appear to be a clinically meaningful 3-month survival benefit (HR, 0.76) with durvalumab, she said.

The idea of combining durvalumab with tremelimumab was based on the potential for “antitumor activity via nonredundant pathways,” she noted, further explaining that the interest in determining whether bTMB correlates with tTMB relates to the rapid availability and less invasive nature of the latter and the fact that bTMB measured from circulating tumor DNA, “biologically speaking, may be more representative of the heterogeneity of metastatic lesions in the context of an advanced disease.”

The current findings are from exploratory analyses looking at OS based on bTMB and tTMB at varying levels to “better understand optimal outcomes and potential contributions of tremelimumab,” she said, noting that survival benefit was observed in all subgroups defined by a high TMB (equal to or greater than vs. less than 4, 8, 12, 16, and 20 mut/Mb).

Outcomes using the bTMB cutoff of 16 or greater mut/Mb were also presented at the ESMO meeting, and showed an OS benefit with durvalumab and durvalumab plus tremelimumab versus chemotherapy in those patients; the finding was more pronounced with durvalumab plus tremelimumab (HR, 0.82 and 0.62, respectively), and the effect increased with increasing bTMB levels.

“Based on that, we decided to [use the 20 mut/Mb or greater] cutoff to conduct a subsequent analysis,” Dr. Peters said, noting again the “very significantly improved” OS and PFS for combined treatment versus chemotherapy with 20 or greater versus less than 20 mut/Mb, and the value of chemotherapy in those with lower bTMB.

Tumor response was also better with durvalumab plus tremelimumab versus chemotherapy at this cutoff; objective response rates were 29.9% and 48.4% with durvalumab and durvalumab plus tremelimumab, respectively, versus 21.4% with chemotherapy.

“Again, under this threshold [less than 20 mut/Mb], it looked like chemotherapy was offering a better response rate with 31.4% as compared to 20% and less for the immunotherapy strategy,” she said.

Also of note, the percentage of patients remaining in response at 6 and 12 months was much better in those who received immunotherapy with durvalumab plus tremelimumab versus chemotherapy; this was more pronounced in those with high TMB (85.6% vs. 14.4% at 6 months; 81.7% vs. 7.2% at 12 months).

No differences were seen in toxicity patterns in the subgroup of patients with bTMB greater than 20 mut/Mb when compared with the overall safety population from MYSTIC, she added.

“Based on this exploratory analysis, further investigation and prospective validation of bTMB as a predictive biomarker for immunotherapy is warranted and should potentially be evaluated in as many as possible future clinical trials looking at immunotherapy across various solid tumors,” Dr. Peters said.

MYSTIC is sponsored by AstraZeneca. Dr. Peters reported relationships – including receipt of honoraria or consulting fees, receipt of grant/research support, and/or speaking engagements – with numerous pharmaceutical companies.

[email protected]

ATLANTA – Blood tumor mutational burden (bTMB) predicts survival benefit in metastatic non–small cell lung cancer (mNSCLC) patients treated with first-line durvalumab plus tremelimumab versus platinum-based chemotherapy, according to findings from the open-label, phase 3 MYSTIC trial.

Frontline Medical News

Specifically, in patients with bTMB based on circulating tumor DNA at levels of 20 mutations (mut)/megabase (Mb) or greater, overall survival (OS) was significantly improved with durvalumab alone and with durvalumab plus tremelimumab versus chemotherapy (hazard ratios, 0.74 and 0.49, respectively). Progression-free survival (PFS) was also improved (HRs, 0.76 and 0.53, respectively), Solange Peters, MD, PhD, reported at the annual meeting of the American Association for Cancer Research.

Among patients with bTMB less than 20 mut/Mb, the corresponding OS hazard ratios were 1.55 and 1.26, and the corresponding PFS hazard ratios were 1.22 and 1.16, said Dr. Peters, director of teaching and patient care in the area of medical oncology and thoracic malignancies at Centre Hospitalier Universitaire Vaudois, Lausanne (Switzerland) University, and president-elect of the European Society for Medical Oncology.

Study subjects were 1,118 patients with immunotherapy- and chemotherapy-naive EGFR and ALK wild-type mNSCLC who were randomized 1:1 to receive either the programmed death–ligand 1 (PD-L1) agent durvalumab, durvalumab plus the anti-CTLA4 agent tremelimumab, or chemotherapy. At a tissue TMB (tTMB) level of 10 mut/Mb or greater, those who received either durvalumab or durvalumab plus tremelimumab had better OS than did those who received chemotherapy (HRs, 0.70 and 0.72, respectively).

Further, bTMB levels of at least 16 mut/Mb correlated positively with tTMB (Spearman correlation coefficient, 0.6; Pearson correlation coefficient, 0.7), she said, adding that survival probability at 24 months was 41.7% with durvalumab plus tremelimumab versus 35.0% with durvalumab alone and 22.7% with chemotherapy in this patient subgroup.

“When you look at the subgroup of patients with lower number of mutations than 10, this phenomenon is not observed. If anything should be potentially stressed about these hazard ratios – all above 1 – is potentially that chemotherapy represents a better option in this patient population,” she said.

Treatment included intravenous durvalumab at a dose of 20 mg/kg every 4 weeks with or without IV tremelimumab at a dose of 1 mg/kg every 4 weeks for up to four doses (372 and 374 patients, respectively), or platinum-based chemotherapy (372 patients).

“Durvalumab ... is already approved for unresectable stage 3 NSCLC and has shown clinical activity in heavily pretreated patients with mNSCLC in the context of phase 2 and 3 previously presented trials,” Dr. Peters said, noting that the multicenter MYSTIC trial was designed to assess its potential role in the treatment of all-comers with stage IV disease.


Overall survival data from the study were presented at the 2018 ESMO Immuno-Oncology Congress, and showed that the primary endpoint of superiority of durvalumab or durvalumab plus tremelimumab versus chemotherapy for OS in patients with high PD-L1 expression (at least 25% of tumor cells expressing PD-L1) was not met. There did, however, appear to be a clinically meaningful 3-month survival benefit (HR, 0.76) with durvalumab, she said.

The idea of combining durvalumab with tremelimumab was based on the potential for “antitumor activity via nonredundant pathways,” she noted, further explaining that the interest in determining whether bTMB correlates with tTMB relates to the rapid availability and less invasive nature of the latter and the fact that bTMB measured from circulating tumor DNA, “biologically speaking, may be more representative of the heterogeneity of metastatic lesions in the context of an advanced disease.”

The current findings are from exploratory analyses looking at OS based on bTMB and tTMB at varying levels to “better understand optimal outcomes and potential contributions of tremelimumab,” she said, noting that survival benefit was observed in all subgroups defined by a high TMB (equal to or greater than vs. less than 4, 8, 12, 16, and 20 mut/Mb).

Outcomes using the bTMB cutoff of 16 or greater mut/Mb were also presented at the ESMO meeting, and showed an OS benefit with durvalumab and durvalumab plus tremelimumab versus chemotherapy in those patients; the finding was more pronounced with durvalumab plus tremelimumab (HR, 0.82 and 0.62, respectively), and the effect increased with increasing bTMB levels.

“Based on that, we decided to [use the 20 mut/Mb or greater] cutoff to conduct a subsequent analysis,” Dr. Peters said, noting again the “very significantly improved” OS and PFS for combined treatment versus chemotherapy with 20 or greater versus less than 20 mut/Mb, and the value of chemotherapy in those with lower bTMB.

Tumor response was also better with durvalumab plus tremelimumab versus chemotherapy at this cutoff; objective response rates were 29.9% and 48.4% with durvalumab and durvalumab plus tremelimumab, respectively, versus 21.4% with chemotherapy.

“Again, under this threshold [less than 20 mut/Mb], it looked like chemotherapy was offering a better response rate with 31.4% as compared to 20% and less for the immunotherapy strategy,” she said.

Also of note, the percentage of patients remaining in response at 6 and 12 months was much better in those who received immunotherapy with durvalumab plus tremelimumab versus chemotherapy; this was more pronounced in those with high TMB (85.6% vs. 14.4% at 6 months; 81.7% vs. 7.2% at 12 months).

No differences were seen in toxicity patterns in the subgroup of patients with bTMB greater than 20 mut/Mb when compared with the overall safety population from MYSTIC, she added.

“Based on this exploratory analysis, further investigation and prospective validation of bTMB as a predictive biomarker for immunotherapy is warranted and should potentially be evaluated in as many as possible future clinical trials looking at immunotherapy across various solid tumors,” Dr. Peters said.

MYSTIC is sponsored by AstraZeneca. Dr. Peters reported relationships – including receipt of honoraria or consulting fees, receipt of grant/research support, and/or speaking engagements – with numerous pharmaceutical companies.

[email protected]

ATLANTA – Blood tumor mutational burden (bTMB) predicts survival benefit in metastatic non–small cell lung cancer (mNSCLC) patients treated with first-line durvalumab plus tremelimumab versus platinum-based chemotherapy, according to findings from the open-label, phase 3 MYSTIC trial.

Frontline Medical News

Specifically, in patients with bTMB based on circulating tumor DNA at levels of 20 mutations (mut)/megabase (Mb) or greater, overall survival (OS) was significantly improved with durvalumab alone and with durvalumab plus tremelimumab versus chemotherapy (hazard ratios, 0.74 and 0.49, respectively). Progression-free survival (PFS) was also improved (HRs, 0.76 and 0.53, respectively), Solange Peters, MD, PhD, reported at the annual meeting of the American Association for Cancer Research.

Among patients with bTMB less than 20 mut/Mb, the corresponding OS hazard ratios were 1.55 and 1.26, and the corresponding PFS hazard ratios were 1.22 and 1.16, said Dr. Peters, director of teaching and patient care in the area of medical oncology and thoracic malignancies at Centre Hospitalier Universitaire Vaudois, Lausanne (Switzerland) University, and president-elect of the European Society for Medical Oncology.

Study subjects were 1,118 patients with immunotherapy- and chemotherapy-naive EGFR and ALK wild-type mNSCLC who were randomized 1:1 to receive either the programmed death–ligand 1 (PD-L1) agent durvalumab, durvalumab plus the anti-CTLA4 agent tremelimumab, or chemotherapy. At a tissue TMB (tTMB) level of 10 mut/Mb or greater, those who received either durvalumab or durvalumab plus tremelimumab had better OS than did those who received chemotherapy (HRs, 0.70 and 0.72, respectively).

Further, bTMB levels of at least 16 mut/Mb correlated positively with tTMB (Spearman correlation coefficient, 0.6; Pearson correlation coefficient, 0.7), she said, adding that survival probability at 24 months was 41.7% with durvalumab plus tremelimumab versus 35.0% with durvalumab alone and 22.7% with chemotherapy in this patient subgroup.

“When you look at the subgroup of patients with lower number of mutations than 10, this phenomenon is not observed. If anything should be potentially stressed about these hazard ratios – all above 1 – is potentially that chemotherapy represents a better option in this patient population,” she said.

Treatment included intravenous durvalumab at a dose of 20 mg/kg every 4 weeks with or without IV tremelimumab at a dose of 1 mg/kg every 4 weeks for up to four doses (372 and 374 patients, respectively), or platinum-based chemotherapy (372 patients).

“Durvalumab ... is already approved for unresectable stage 3 NSCLC and has shown clinical activity in heavily pretreated patients with mNSCLC in the context of phase 2 and 3 previously presented trials,” Dr. Peters said, noting that the multicenter MYSTIC trial was designed to assess its potential role in the treatment of all-comers with stage IV disease.


Overall survival data from the study were presented at the 2018 ESMO Immuno-Oncology Congress, and showed that the primary endpoint of superiority of durvalumab or durvalumab plus tremelimumab versus chemotherapy for OS in patients with high PD-L1 expression (at least 25% of tumor cells expressing PD-L1) was not met. There did, however, appear to be a clinically meaningful 3-month survival benefit (HR, 0.76) with durvalumab, she said.

The idea of combining durvalumab with tremelimumab was based on the potential for “antitumor activity via nonredundant pathways,” she noted, further explaining that the interest in determining whether bTMB correlates with tTMB relates to the rapid availability and less invasive nature of the latter and the fact that bTMB measured from circulating tumor DNA, “biologically speaking, may be more representative of the heterogeneity of metastatic lesions in the context of an advanced disease.”

The current findings are from exploratory analyses looking at OS based on bTMB and tTMB at varying levels to “better understand optimal outcomes and potential contributions of tremelimumab,” she said, noting that survival benefit was observed in all subgroups defined by a high TMB (equal to or greater than vs. less than 4, 8, 12, 16, and 20 mut/Mb).

Outcomes using the bTMB cutoff of 16 or greater mut/Mb were also presented at the ESMO meeting, and showed an OS benefit with durvalumab and durvalumab plus tremelimumab versus chemotherapy in those patients; the finding was more pronounced with durvalumab plus tremelimumab (HR, 0.82 and 0.62, respectively), and the effect increased with increasing bTMB levels.

“Based on that, we decided to [use the 20 mut/Mb or greater] cutoff to conduct a subsequent analysis,” Dr. Peters said, noting again the “very significantly improved” OS and PFS for combined treatment versus chemotherapy with 20 or greater versus less than 20 mut/Mb, and the value of chemotherapy in those with lower bTMB.

Tumor response was also better with durvalumab plus tremelimumab versus chemotherapy at this cutoff; objective response rates were 29.9% and 48.4% with durvalumab and durvalumab plus tremelimumab, respectively, versus 21.4% with chemotherapy.

“Again, under this threshold [less than 20 mut/Mb], it looked like chemotherapy was offering a better response rate with 31.4% as compared to 20% and less for the immunotherapy strategy,” she said.

Also of note, the percentage of patients remaining in response at 6 and 12 months was much better in those who received immunotherapy with durvalumab plus tremelimumab versus chemotherapy; this was more pronounced in those with high TMB (85.6% vs. 14.4% at 6 months; 81.7% vs. 7.2% at 12 months).

No differences were seen in toxicity patterns in the subgroup of patients with bTMB greater than 20 mut/Mb when compared with the overall safety population from MYSTIC, she added.

“Based on this exploratory analysis, further investigation and prospective validation of bTMB as a predictive biomarker for immunotherapy is warranted and should potentially be evaluated in as many as possible future clinical trials looking at immunotherapy across various solid tumors,” Dr. Peters said.

MYSTIC is sponsored by AstraZeneca. Dr. Peters reported relationships – including receipt of honoraria or consulting fees, receipt of grant/research support, and/or speaking engagements – with numerous pharmaceutical companies.

[email protected]

The National Institutes of Health has released an amended guideline on research involving gene therapy.

As part of the streamlining process, the Recombinant DNA Advisory Committee has been renamed as the Novel and Exceptional Technology and Research Advisory Committee to better align with the committee’s original intention – following and providing advice on safety and ethical issues associated with emerging biotechnologies, according to a statement from Francis S. Collins, MD, PhD, director of the NIH.

We previously covered this story; find our coverage at the link below.

[email protected]

The National Institutes of Health has released an amended guideline on research involving gene therapy.

As part of the streamlining process, the Recombinant DNA Advisory Committee has been renamed as the Novel and Exceptional Technology and Research Advisory Committee to better align with the committee’s original intention – following and providing advice on safety and ethical issues associated with emerging biotechnologies, according to a statement from Francis S. Collins, MD, PhD, director of the NIH.

We previously covered this story; find our coverage at the link below.

[email protected]

The National Institutes of Health has released an amended guideline on research involving gene therapy.

As part of the streamlining process, the Recombinant DNA Advisory Committee has been renamed as the Novel and Exceptional Technology and Research Advisory Committee to better align with the committee’s original intention – following and providing advice on safety and ethical issues associated with emerging biotechnologies, according to a statement from Francis S. Collins, MD, PhD, director of the NIH.

We previously covered this story; find our coverage at the link below.

[email protected]

In this edition of “How I will treat my next patient,” I take a look at two recent trials – one offers potential in previously-treated cervical cancer patients with poor prognosis and the other confirms the role of R-CHOP as the standard of care in diffuse large B-cell lymphoma.

Pembrolizumab in KEYNOTE-158

In an international phase 2 “basket trial,” Hyun Cheol Chung, MD, PhD, and colleagues used pembrolizumab 200 mg every 3 weeks in 98 previously treated patients with advanced cervical cancer. Almost 84% of o the patients had PD-L1 positive tumors (greater than 1%). The authors said that viral induction of malignancy leads to antigen production and upregulation of PD-1. Therefore, advanced cervical cancer patients would likely express PD-L1 on tumor cells and respond to immune checkpoint inhibitor therapy.

In this interim report, there were 12 responses (all in PD-L1 positive patients), with three complete responses. Median response duration had not been reached at median follow-up of 10.2 months. Seven of 12 responses were ongoing at 12 months. There were grade 3-4 adverse events in 12.2% of patients and no treatment-related deaths.

The study – “Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study” – was published in the Journal of Clinical Oncology (2019 April 3. doi: 10.1200/JCO.18.01265).


The encouraging results of pembrolizumab in this generally chemotherapy-refractory patient population were consistent with other small, early-phase studies investigating immune checkpoint inhibitors that led to the accelerated approval of pembrolizumab in previously treated PD-L1 advanced cervical cancer patients with progressive disease after chemotherapy.
 

What this means in practice

Although excitement should be tempered about an interim report of an organ-specific subset of a phase 2 international basket trial that was heavily populated by young PS 0-1 patients and generated an overall response rate of less than 15%, no conventional chemotherapy or biologic agent offers the potential of complete or prolonged response, and disease control rates of 30%.

Clinical trials should always be the first choice, but immune checkpoint inhibitors offer an attractive off-study option.

Among many single agents in National Comprehensive Cancer Network guidelines for recurrent advanced cervical cancer after first-line cisplatin-based chemotherapy, there is a reason why pembrolizumab is listed first. For patients with PD-L1 expressing tumors or MSI-H/dMMR tumors, I would use it.
 

Frontline therapy in DLBCL

In a large, randomized phase 3 trial, close to 500 stage III-IV patients with diffuse large B-cell lymphoma (DLBCL), including primary mediastinal B-cell lymphoma and intravascular large B-cell lymphoma, were assigned to receive either conventional R-CHOP chemotherapy or the more complex, more toxic DA-EPOCH-R regimen that appeared superior in single-institution studies and was feasible in multi-institutional phase 2 trials.

The study – “Dose-Adjusted EPOCH-R Compared With R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303” – was published in the Journal of Clinical Oncology (2019 Apr 2. doi: 10.1200/JCO.18.01994).

In the study, progression-free survival and overall survival were no different for R-CHOP and DA-EPOCH-R, but – predictably – DA-EPOCH-R was more toxic and had more treatment discontinuations.

R-CHOP had better outcomes than expected. This suggests that patient-selection bias (more favorable histology, fewer high-risk subsets who required urgent therapy) may have been at work.

Further study of DA-EPOCH-R in higher IPI patients or in patients selected because of more adverse molecular features (DE phenotype, MYC+, double hit) is warranted given the poor outcomes with R-CHOP in high-risk patients, intriguing results in single institution trials of DA-EPOCH-R, and the underrepresentation of high-risk patients in the current study.
 

What this means in practice

Whether by virtue of the types of patients enrolled or because it is the best regimen in all DLBCL patients, R-CHOP remains the standard of care outside of a clinical trial.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers, and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I will treat my next patient,” I take a look at two recent trials – one offers potential in previously-treated cervical cancer patients with poor prognosis and the other confirms the role of R-CHOP as the standard of care in diffuse large B-cell lymphoma.

Pembrolizumab in KEYNOTE-158

In an international phase 2 “basket trial,” Hyun Cheol Chung, MD, PhD, and colleagues used pembrolizumab 200 mg every 3 weeks in 98 previously treated patients with advanced cervical cancer. Almost 84% of o the patients had PD-L1 positive tumors (greater than 1%). The authors said that viral induction of malignancy leads to antigen production and upregulation of PD-1. Therefore, advanced cervical cancer patients would likely express PD-L1 on tumor cells and respond to immune checkpoint inhibitor therapy.

In this interim report, there were 12 responses (all in PD-L1 positive patients), with three complete responses. Median response duration had not been reached at median follow-up of 10.2 months. Seven of 12 responses were ongoing at 12 months. There were grade 3-4 adverse events in 12.2% of patients and no treatment-related deaths.

The study – “Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study” – was published in the Journal of Clinical Oncology (2019 April 3. doi: 10.1200/JCO.18.01265).


The encouraging results of pembrolizumab in this generally chemotherapy-refractory patient population were consistent with other small, early-phase studies investigating immune checkpoint inhibitors that led to the accelerated approval of pembrolizumab in previously treated PD-L1 advanced cervical cancer patients with progressive disease after chemotherapy.
 

What this means in practice

Although excitement should be tempered about an interim report of an organ-specific subset of a phase 2 international basket trial that was heavily populated by young PS 0-1 patients and generated an overall response rate of less than 15%, no conventional chemotherapy or biologic agent offers the potential of complete or prolonged response, and disease control rates of 30%.

Clinical trials should always be the first choice, but immune checkpoint inhibitors offer an attractive off-study option.

Among many single agents in National Comprehensive Cancer Network guidelines for recurrent advanced cervical cancer after first-line cisplatin-based chemotherapy, there is a reason why pembrolizumab is listed first. For patients with PD-L1 expressing tumors or MSI-H/dMMR tumors, I would use it.
 

Frontline therapy in DLBCL

In a large, randomized phase 3 trial, close to 500 stage III-IV patients with diffuse large B-cell lymphoma (DLBCL), including primary mediastinal B-cell lymphoma and intravascular large B-cell lymphoma, were assigned to receive either conventional R-CHOP chemotherapy or the more complex, more toxic DA-EPOCH-R regimen that appeared superior in single-institution studies and was feasible in multi-institutional phase 2 trials.

The study – “Dose-Adjusted EPOCH-R Compared With R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303” – was published in the Journal of Clinical Oncology (2019 Apr 2. doi: 10.1200/JCO.18.01994).

In the study, progression-free survival and overall survival were no different for R-CHOP and DA-EPOCH-R, but – predictably – DA-EPOCH-R was more toxic and had more treatment discontinuations.

R-CHOP had better outcomes than expected. This suggests that patient-selection bias (more favorable histology, fewer high-risk subsets who required urgent therapy) may have been at work.

Further study of DA-EPOCH-R in higher IPI patients or in patients selected because of more adverse molecular features (DE phenotype, MYC+, double hit) is warranted given the poor outcomes with R-CHOP in high-risk patients, intriguing results in single institution trials of DA-EPOCH-R, and the underrepresentation of high-risk patients in the current study.
 

What this means in practice

Whether by virtue of the types of patients enrolled or because it is the best regimen in all DLBCL patients, R-CHOP remains the standard of care outside of a clinical trial.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers, and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I will treat my next patient,” I take a look at two recent trials – one offers potential in previously-treated cervical cancer patients with poor prognosis and the other confirms the role of R-CHOP as the standard of care in diffuse large B-cell lymphoma.

Pembrolizumab in KEYNOTE-158

In an international phase 2 “basket trial,” Hyun Cheol Chung, MD, PhD, and colleagues used pembrolizumab 200 mg every 3 weeks in 98 previously treated patients with advanced cervical cancer. Almost 84% of o the patients had PD-L1 positive tumors (greater than 1%). The authors said that viral induction of malignancy leads to antigen production and upregulation of PD-1. Therefore, advanced cervical cancer patients would likely express PD-L1 on tumor cells and respond to immune checkpoint inhibitor therapy.

In this interim report, there were 12 responses (all in PD-L1 positive patients), with three complete responses. Median response duration had not been reached at median follow-up of 10.2 months. Seven of 12 responses were ongoing at 12 months. There were grade 3-4 adverse events in 12.2% of patients and no treatment-related deaths.

The study – “Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study” – was published in the Journal of Clinical Oncology (2019 April 3. doi: 10.1200/JCO.18.01265).


The encouraging results of pembrolizumab in this generally chemotherapy-refractory patient population were consistent with other small, early-phase studies investigating immune checkpoint inhibitors that led to the accelerated approval of pembrolizumab in previously treated PD-L1 advanced cervical cancer patients with progressive disease after chemotherapy.
 

What this means in practice

Although excitement should be tempered about an interim report of an organ-specific subset of a phase 2 international basket trial that was heavily populated by young PS 0-1 patients and generated an overall response rate of less than 15%, no conventional chemotherapy or biologic agent offers the potential of complete or prolonged response, and disease control rates of 30%.

Clinical trials should always be the first choice, but immune checkpoint inhibitors offer an attractive off-study option.

Among many single agents in National Comprehensive Cancer Network guidelines for recurrent advanced cervical cancer after first-line cisplatin-based chemotherapy, there is a reason why pembrolizumab is listed first. For patients with PD-L1 expressing tumors or MSI-H/dMMR tumors, I would use it.
 

Frontline therapy in DLBCL

In a large, randomized phase 3 trial, close to 500 stage III-IV patients with diffuse large B-cell lymphoma (DLBCL), including primary mediastinal B-cell lymphoma and intravascular large B-cell lymphoma, were assigned to receive either conventional R-CHOP chemotherapy or the more complex, more toxic DA-EPOCH-R regimen that appeared superior in single-institution studies and was feasible in multi-institutional phase 2 trials.

The study – “Dose-Adjusted EPOCH-R Compared With R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303” – was published in the Journal of Clinical Oncology (2019 Apr 2. doi: 10.1200/JCO.18.01994).

In the study, progression-free survival and overall survival were no different for R-CHOP and DA-EPOCH-R, but – predictably – DA-EPOCH-R was more toxic and had more treatment discontinuations.

R-CHOP had better outcomes than expected. This suggests that patient-selection bias (more favorable histology, fewer high-risk subsets who required urgent therapy) may have been at work.

Further study of DA-EPOCH-R in higher IPI patients or in patients selected because of more adverse molecular features (DE phenotype, MYC+, double hit) is warranted given the poor outcomes with R-CHOP in high-risk patients, intriguing results in single institution trials of DA-EPOCH-R, and the underrepresentation of high-risk patients in the current study.
 

What this means in practice

Whether by virtue of the types of patients enrolled or because it is the best regimen in all DLBCL patients, R-CHOP remains the standard of care outside of a clinical trial.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers, and in expanding access to clinical trials to medically underserved populations.

GLASGOW – Constant patient monitoring and early intervention with tocilizumab and steroids are essential to the safe delivery of chimeric antigen receptor (CAR) T-cell therapy in patients with non-Hodgkin lymphoma (NHL), according to a leading expert.

As a clinical researcher at MD Anderson Cancer Center in Houston, Loretta Nastoupil, MD has played an active role in the evolution of CAR T-cell therapy, from early trials to ongoing development of treatment protocols. During a presentation at the annual meeting of the British Society for Haematology, Dr. Nastoupil discussed leading topics in CAR T-cell therapy, with an emphasis on safe delivery.

“[Toxicity] is something we don’t talk about as much as we should, partly because this therapy works and it’s really exciting,” Dr. Nastoupil said. “But the toxicity is not something that I minimize, and it’s very challenging. It’s led us to restructure our inpatient services. It’s led to a lot of sleepless nights. These patients can do very, very well, or they can do very, very poorly in terms of toxicity and I think the most important strategy is recognition and early intervention.”

Monitoring

Early recognition depends on close monitoring, Dr. Nastoupil said, which is carried out by highly trained nursing staff who follow therapy-specific decision algorithms.

“We have nurses that are on the front line,” Dr. Nastoupil said. “They’re the most important group. We have staff that round on [patients] daily, but the nurses are there 24 hours a day. We have a flow sheet where they grade cytokine release syndrome and neurotoxicity every 8 hours, or if there is an acute change in symptoms or toxicity, they’ll do it in real time.”

Dr. Nastoupil said that if these toxicities are detected, intervention is occurring sooner than it did with some of the first patients to receive CAR-T cell therapy.

“Initially there was a lot of fear surrounding anything that would abort the CAR-T cell therapy,” Dr. Nastoupil said. “There was concern that if you were trying to mitigate some of the toxicity you might have a negative impact on efficacy ... [W]ith the first iteration of studies, generally we were waiting until grade 3 or higher cytokine release syndrome before initiating either tocilizumab and/or steroids. As the studies evolved, it started to move into grade 2 toxicity that we started using therapy, mostly because we started to see that those patients were still responding.”

At MD Anderson, these earlier interventions have decreased severity of adverse events.

“It’s rare nowadays to have grade 3 or 4 cytokine release syndrome because we are generally introducing abortive therapy at grade 2,” Dr. Nastoupil said, citing increased use of steroids and tocilizumab.

Currently, no consensus exists for managing these events, partly because clinicians are still learning about best management practices.

“There will be a consensus on management,” Dr. Nastoupil said. “I think that’s needed. The problem is, it will probably evolve as we get more experience with managing these patients. I think there’s been a little hesitation to put something out on paper knowing that a year from now that might change.”

Grading toxicity

In contrast, Dr. Nastoupil said that a consensus has been reached for grading acute toxicity. Of note, fever is now considered an essential element of cytokine release syndrome.

“The first thing we see [with cytokine release syndrome] is fever, generally speaking,” Dr. Nastoupil said. “That will prompt a workup for infection because these patients are going to be neutropenic. And we initiate broad spectrum antimicrobials.”

She said that some patients treated with CAR T-cell therapy have had disseminated fungal infections, so clinicians need to be on the lookout for septic shock.

To assess neurotoxicity, the team at MD Anderson uses an objective scoring system, called “CARTOX.” This helps maintain consistency when facing broadly different neurological presentations.

“There’s such a wide ranging spectrum of patients that are undergoing neurotoxicity you can’t expect someone, even myself, to be consistent when you are trying to tease out how serious it is,” Dr. Nastoupil said.

With CARTOX, nurses can easily score patients and call clinicians with results. Still, this doesn’t eliminate difficulties inherent to managing neurotoxicity, particularly when it is severe.

“I’d say one of the areas that is still very challenging is when [patients with neurotoxicity] are no longer responding,” Dr. Nastoupil said. “You have to be very mindful of seizure activity. We’ve had a couple of patients with status [epilepticus]. You don’t see seizure activity physically, but when you do an EEG, you pick it up.”

Dr. Nastoupil added that most centers are now giving patients prophylactic levetiracetam (Keppra) to lower seizure risk.

Choosing therapy

When selecting between the two therapies currently approved by the Food and Drug Administration – tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) – based on safety, Dr. Nastoupil said that rates of cytokine release syndrome appear similar, but neurotoxicity rates may differ.

“Cytokine release syndrome in my opinion is probably more similar than different in terms of grade 3 or higher because tocilizumab and steroids work quite well in aborting those toxicities,” Dr. Nastoupil said. “But neurotoxicity still sticks out in my mind as the most striking difference, where with axicabtagene you see more grade 3 or higher neurotoxicity, though very, very few deaths as a result of this. But it’s very challenging in terms of management.”

According to Dr. Nastoupil, comparisons between CAR T-cell therapies have been complicated by differences in clinical trial methodologies. However, she offered a general conclusion regarding efficacy.

“[W]hat I’ll tell you, at the end of the day, is [that existing CAR T-cell therapies] all seem to sort of settle out around 30%-40% in terms of durable responses,” Dr. Nastoupil said.

Dr. Nastoupil concluded her presentation with an overview and look to the future.

“I do think [CAR T-cell therapy] is transformative, particularly for our chemo refractory patients,” she said. “There is nothing else like it. The problem right now is that it is only durable in 40% of patients. So can we be better at selecting out patients that are more likely to respond? Does introducing this in earlier lines of therapy increase that fraction of patients that are potentially cured?”

Considering these questions, she said: “We need more patients. We need more data. We need longer follow-up to understand the nuances of this therapy.”

Dr. Nastoupil previously reported financial relationships with Celgene, Genentech, Gilead, Merck, Novartis, Spectrum, and TG Therapeutics.

GLASGOW – Constant patient monitoring and early intervention with tocilizumab and steroids are essential to the safe delivery of chimeric antigen receptor (CAR) T-cell therapy in patients with non-Hodgkin lymphoma (NHL), according to a leading expert.

As a clinical researcher at MD Anderson Cancer Center in Houston, Loretta Nastoupil, MD has played an active role in the evolution of CAR T-cell therapy, from early trials to ongoing development of treatment protocols. During a presentation at the annual meeting of the British Society for Haematology, Dr. Nastoupil discussed leading topics in CAR T-cell therapy, with an emphasis on safe delivery.

“[Toxicity] is something we don’t talk about as much as we should, partly because this therapy works and it’s really exciting,” Dr. Nastoupil said. “But the toxicity is not something that I minimize, and it’s very challenging. It’s led us to restructure our inpatient services. It’s led to a lot of sleepless nights. These patients can do very, very well, or they can do very, very poorly in terms of toxicity and I think the most important strategy is recognition and early intervention.”

Monitoring

Early recognition depends on close monitoring, Dr. Nastoupil said, which is carried out by highly trained nursing staff who follow therapy-specific decision algorithms.

“We have nurses that are on the front line,” Dr. Nastoupil said. “They’re the most important group. We have staff that round on [patients] daily, but the nurses are there 24 hours a day. We have a flow sheet where they grade cytokine release syndrome and neurotoxicity every 8 hours, or if there is an acute change in symptoms or toxicity, they’ll do it in real time.”

Dr. Nastoupil said that if these toxicities are detected, intervention is occurring sooner than it did with some of the first patients to receive CAR-T cell therapy.

“Initially there was a lot of fear surrounding anything that would abort the CAR-T cell therapy,” Dr. Nastoupil said. “There was concern that if you were trying to mitigate some of the toxicity you might have a negative impact on efficacy ... [W]ith the first iteration of studies, generally we were waiting until grade 3 or higher cytokine release syndrome before initiating either tocilizumab and/or steroids. As the studies evolved, it started to move into grade 2 toxicity that we started using therapy, mostly because we started to see that those patients were still responding.”

At MD Anderson, these earlier interventions have decreased severity of adverse events.

“It’s rare nowadays to have grade 3 or 4 cytokine release syndrome because we are generally introducing abortive therapy at grade 2,” Dr. Nastoupil said, citing increased use of steroids and tocilizumab.

Currently, no consensus exists for managing these events, partly because clinicians are still learning about best management practices.

“There will be a consensus on management,” Dr. Nastoupil said. “I think that’s needed. The problem is, it will probably evolve as we get more experience with managing these patients. I think there’s been a little hesitation to put something out on paper knowing that a year from now that might change.”

Grading toxicity

In contrast, Dr. Nastoupil said that a consensus has been reached for grading acute toxicity. Of note, fever is now considered an essential element of cytokine release syndrome.

“The first thing we see [with cytokine release syndrome] is fever, generally speaking,” Dr. Nastoupil said. “That will prompt a workup for infection because these patients are going to be neutropenic. And we initiate broad spectrum antimicrobials.”

She said that some patients treated with CAR T-cell therapy have had disseminated fungal infections, so clinicians need to be on the lookout for septic shock.

To assess neurotoxicity, the team at MD Anderson uses an objective scoring system, called “CARTOX.” This helps maintain consistency when facing broadly different neurological presentations.

“There’s such a wide ranging spectrum of patients that are undergoing neurotoxicity you can’t expect someone, even myself, to be consistent when you are trying to tease out how serious it is,” Dr. Nastoupil said.

With CARTOX, nurses can easily score patients and call clinicians with results. Still, this doesn’t eliminate difficulties inherent to managing neurotoxicity, particularly when it is severe.

“I’d say one of the areas that is still very challenging is when [patients with neurotoxicity] are no longer responding,” Dr. Nastoupil said. “You have to be very mindful of seizure activity. We’ve had a couple of patients with status [epilepticus]. You don’t see seizure activity physically, but when you do an EEG, you pick it up.”

Dr. Nastoupil added that most centers are now giving patients prophylactic levetiracetam (Keppra) to lower seizure risk.

Choosing therapy

When selecting between the two therapies currently approved by the Food and Drug Administration – tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) – based on safety, Dr. Nastoupil said that rates of cytokine release syndrome appear similar, but neurotoxicity rates may differ.

“Cytokine release syndrome in my opinion is probably more similar than different in terms of grade 3 or higher because tocilizumab and steroids work quite well in aborting those toxicities,” Dr. Nastoupil said. “But neurotoxicity still sticks out in my mind as the most striking difference, where with axicabtagene you see more grade 3 or higher neurotoxicity, though very, very few deaths as a result of this. But it’s very challenging in terms of management.”

According to Dr. Nastoupil, comparisons between CAR T-cell therapies have been complicated by differences in clinical trial methodologies. However, she offered a general conclusion regarding efficacy.

“[W]hat I’ll tell you, at the end of the day, is [that existing CAR T-cell therapies] all seem to sort of settle out around 30%-40% in terms of durable responses,” Dr. Nastoupil said.

Dr. Nastoupil concluded her presentation with an overview and look to the future.

“I do think [CAR T-cell therapy] is transformative, particularly for our chemo refractory patients,” she said. “There is nothing else like it. The problem right now is that it is only durable in 40% of patients. So can we be better at selecting out patients that are more likely to respond? Does introducing this in earlier lines of therapy increase that fraction of patients that are potentially cured?”

Considering these questions, she said: “We need more patients. We need more data. We need longer follow-up to understand the nuances of this therapy.”

Dr. Nastoupil previously reported financial relationships with Celgene, Genentech, Gilead, Merck, Novartis, Spectrum, and TG Therapeutics.

GLASGOW – Constant patient monitoring and early intervention with tocilizumab and steroids are essential to the safe delivery of chimeric antigen receptor (CAR) T-cell therapy in patients with non-Hodgkin lymphoma (NHL), according to a leading expert.

As a clinical researcher at MD Anderson Cancer Center in Houston, Loretta Nastoupil, MD has played an active role in the evolution of CAR T-cell therapy, from early trials to ongoing development of treatment protocols. During a presentation at the annual meeting of the British Society for Haematology, Dr. Nastoupil discussed leading topics in CAR T-cell therapy, with an emphasis on safe delivery.

“[Toxicity] is something we don’t talk about as much as we should, partly because this therapy works and it’s really exciting,” Dr. Nastoupil said. “But the toxicity is not something that I minimize, and it’s very challenging. It’s led us to restructure our inpatient services. It’s led to a lot of sleepless nights. These patients can do very, very well, or they can do very, very poorly in terms of toxicity and I think the most important strategy is recognition and early intervention.”

Monitoring

Early recognition depends on close monitoring, Dr. Nastoupil said, which is carried out by highly trained nursing staff who follow therapy-specific decision algorithms.

“We have nurses that are on the front line,” Dr. Nastoupil said. “They’re the most important group. We have staff that round on [patients] daily, but the nurses are there 24 hours a day. We have a flow sheet where they grade cytokine release syndrome and neurotoxicity every 8 hours, or if there is an acute change in symptoms or toxicity, they’ll do it in real time.”

Dr. Nastoupil said that if these toxicities are detected, intervention is occurring sooner than it did with some of the first patients to receive CAR-T cell therapy.

“Initially there was a lot of fear surrounding anything that would abort the CAR-T cell therapy,” Dr. Nastoupil said. “There was concern that if you were trying to mitigate some of the toxicity you might have a negative impact on efficacy ... [W]ith the first iteration of studies, generally we were waiting until grade 3 or higher cytokine release syndrome before initiating either tocilizumab and/or steroids. As the studies evolved, it started to move into grade 2 toxicity that we started using therapy, mostly because we started to see that those patients were still responding.”

At MD Anderson, these earlier interventions have decreased severity of adverse events.

“It’s rare nowadays to have grade 3 or 4 cytokine release syndrome because we are generally introducing abortive therapy at grade 2,” Dr. Nastoupil said, citing increased use of steroids and tocilizumab.

Currently, no consensus exists for managing these events, partly because clinicians are still learning about best management practices.

“There will be a consensus on management,” Dr. Nastoupil said. “I think that’s needed. The problem is, it will probably evolve as we get more experience with managing these patients. I think there’s been a little hesitation to put something out on paper knowing that a year from now that might change.”

Grading toxicity

In contrast, Dr. Nastoupil said that a consensus has been reached for grading acute toxicity. Of note, fever is now considered an essential element of cytokine release syndrome.

“The first thing we see [with cytokine release syndrome] is fever, generally speaking,” Dr. Nastoupil said. “That will prompt a workup for infection because these patients are going to be neutropenic. And we initiate broad spectrum antimicrobials.”

She said that some patients treated with CAR T-cell therapy have had disseminated fungal infections, so clinicians need to be on the lookout for septic shock.

To assess neurotoxicity, the team at MD Anderson uses an objective scoring system, called “CARTOX.” This helps maintain consistency when facing broadly different neurological presentations.

“There’s such a wide ranging spectrum of patients that are undergoing neurotoxicity you can’t expect someone, even myself, to be consistent when you are trying to tease out how serious it is,” Dr. Nastoupil said.

With CARTOX, nurses can easily score patients and call clinicians with results. Still, this doesn’t eliminate difficulties inherent to managing neurotoxicity, particularly when it is severe.

“I’d say one of the areas that is still very challenging is when [patients with neurotoxicity] are no longer responding,” Dr. Nastoupil said. “You have to be very mindful of seizure activity. We’ve had a couple of patients with status [epilepticus]. You don’t see seizure activity physically, but when you do an EEG, you pick it up.”

Dr. Nastoupil added that most centers are now giving patients prophylactic levetiracetam (Keppra) to lower seizure risk.

Choosing therapy

When selecting between the two therapies currently approved by the Food and Drug Administration – tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) – based on safety, Dr. Nastoupil said that rates of cytokine release syndrome appear similar, but neurotoxicity rates may differ.

“Cytokine release syndrome in my opinion is probably more similar than different in terms of grade 3 or higher because tocilizumab and steroids work quite well in aborting those toxicities,” Dr. Nastoupil said. “But neurotoxicity still sticks out in my mind as the most striking difference, where with axicabtagene you see more grade 3 or higher neurotoxicity, though very, very few deaths as a result of this. But it’s very challenging in terms of management.”

According to Dr. Nastoupil, comparisons between CAR T-cell therapies have been complicated by differences in clinical trial methodologies. However, she offered a general conclusion regarding efficacy.

“[W]hat I’ll tell you, at the end of the day, is [that existing CAR T-cell therapies] all seem to sort of settle out around 30%-40% in terms of durable responses,” Dr. Nastoupil said.

Dr. Nastoupil concluded her presentation with an overview and look to the future.

“I do think [CAR T-cell therapy] is transformative, particularly for our chemo refractory patients,” she said. “There is nothing else like it. The problem right now is that it is only durable in 40% of patients. So can we be better at selecting out patients that are more likely to respond? Does introducing this in earlier lines of therapy increase that fraction of patients that are potentially cured?”

Considering these questions, she said: “We need more patients. We need more data. We need longer follow-up to understand the nuances of this therapy.”

Dr. Nastoupil previously reported financial relationships with Celgene, Genentech, Gilead, Merck, Novartis, Spectrum, and TG Therapeutics.

GENEVA – Level of programmed death-ligand 1 (PD-L1) expression does not impact patient-reported outcomes (PROs) among those receiving durvalumab for stage III non–small cell lung cancer (NSCLC), according to a retrospective analysis of the phase III PACIFIC trial.

Will Pass/MDedge News

The findings support durvalumab for all comers regardless of PD-L1 expression, reported lead author Marina Garassino, MD, of Fondazione IRCCS – Instituto Nazionale dei Tumori in Milan, who presented findings at the European Lung Cancer Congress.

The PACIFIC trial involved 713 patients with stage III NSCLC who did not progress after platinum-based concurrent chemoradiotherapy, demonstrating both improved progression-free and overall survival. Patients were randomized 2:1 to receive either durvalumab (10 mg/kg) or placebo IV every 2 weeks for up to 1 year. Out of 713 patients involved in the trial, 63% had PD-L1 tumor expression level data available for the present analysis, allowing for subgrouping into five categories: expression level of at least 25%, less than 25%, at least 1%, less than 1%, or unknown. The investigators compared PROs from these cohorts using the European Organisation for Research and Treatment of Cancer core quality of life questionnaire and lung cancer module (EORTC QLQ-C30 and -LC13). With scores ranging from 1 to 100 points, clinically meaningful differences were defined by score changes exceeding 10 points. Changes during treatment, from baseline to week 48, were analyzed by a mixed model for repeated measures, overall responses for improvement rates by logistic regression, and hazard ratios for time to deterioration (TTD) by a stratified Cox proportional-hazards model.

The investigators found that most PROs remained consistent over time, without clinically meaningful variations between PD-L1 expression levels. However, as with the entire PACIFIC treatment population, patients in the present analysis showed changes in some PROs. At the meeting presented by the European Society for Medical Oncology, Dr. Garassino noted that it would be unrealistic to describe all PRO comparisons; instead, she presented several examples. For one, in patients receiving durvalumab, dysphagia and alopecia improved in four out of five PD-L1 subgroups and all subgroups, respectively, while patients in the placebo arm reported improvements in both measures regardless of PD-L1 expression. Other improvements tended to favor the durvalumab group; for instance, compared with other subgroups, patients with PD-L1 expression of at least 25% were more likely to report improved chest pain, physical functioning, pain, emotional functioning, and hemoptysis. In contrast, patients receiving placebo with PD-L1 expression less than 25% were more likely to report improved cough. Still, the investigators concluded that the overall picture did not suggest major differences in PROs by PD-L1 expression level, noting that global quality of life did not differ, and symptom improvement rates and time-to-deterioration measures generally aligned with the intent-to-treat population, judging by overlapping 95% confidence intervals and hazard ratios.

“These data support the PACIFIC regimen for the standard of care for stage III unresectable non–small cell lung cancer patients,” Dr. Garassino concluded.

Will Pass/MDedge News

Invited discussant Fabrice Barlesi, MD, PhD, of Aix-Marseille University, said that studies such as this one are important to ensure that investigator-implemented measures of response are calibrated to patient experiences. As an example, Dr. Barlesi noted that many clinicians would say that grade 2 diarrhea is a completely manageable adverse event, but not all patients would agree.

In this light, Dr. Barlesi said that the present findings are valuable, but they are not without flaws. He noted that 11 out of 13 symptoms from the quality of life lung cancer module were not reported, and that one-third of patients in the PACIFIC trial lacked PD-L1 expression level data.

Considering these shortcomings, and more broadly, difficulties comparing patient-reported outcome studies because of various measurement techniques, Dr. Barlesi called for standardization.

“We need to standardize the analysis of quality of life data,” Dr. Barlesi said. “We should correct for the multiplicity of tests. … we should identify some specific quality of life outcomes that we want to look at in the protocol.” He continued to suggest a variety of ideal characteristics for studies evaluating patient-reported outcomes, including defined statistical measures and protocols for missing data.

Without a standardized approach, “cross trial comparison will be a nightmare for all of us,” Dr. Barlesi said.

The study was funded by AstraZeneca. The investigators reported financial relationships with Roche, BMS, Lilly, and others.

SOURCE: Garassino et al. ELCC 2019. Abstract LBA2.

GENEVA – Level of programmed death-ligand 1 (PD-L1) expression does not impact patient-reported outcomes (PROs) among those receiving durvalumab for stage III non–small cell lung cancer (NSCLC), according to a retrospective analysis of the phase III PACIFIC trial.

Will Pass/MDedge News

The findings support durvalumab for all comers regardless of PD-L1 expression, reported lead author Marina Garassino, MD, of Fondazione IRCCS – Instituto Nazionale dei Tumori in Milan, who presented findings at the European Lung Cancer Congress.

The PACIFIC trial involved 713 patients with stage III NSCLC who did not progress after platinum-based concurrent chemoradiotherapy, demonstrating both improved progression-free and overall survival. Patients were randomized 2:1 to receive either durvalumab (10 mg/kg) or placebo IV every 2 weeks for up to 1 year. Out of 713 patients involved in the trial, 63% had PD-L1 tumor expression level data available for the present analysis, allowing for subgrouping into five categories: expression level of at least 25%, less than 25%, at least 1%, less than 1%, or unknown. The investigators compared PROs from these cohorts using the European Organisation for Research and Treatment of Cancer core quality of life questionnaire and lung cancer module (EORTC QLQ-C30 and -LC13). With scores ranging from 1 to 100 points, clinically meaningful differences were defined by score changes exceeding 10 points. Changes during treatment, from baseline to week 48, were analyzed by a mixed model for repeated measures, overall responses for improvement rates by logistic regression, and hazard ratios for time to deterioration (TTD) by a stratified Cox proportional-hazards model.

The investigators found that most PROs remained consistent over time, without clinically meaningful variations between PD-L1 expression levels. However, as with the entire PACIFIC treatment population, patients in the present analysis showed changes in some PROs. At the meeting presented by the European Society for Medical Oncology, Dr. Garassino noted that it would be unrealistic to describe all PRO comparisons; instead, she presented several examples. For one, in patients receiving durvalumab, dysphagia and alopecia improved in four out of five PD-L1 subgroups and all subgroups, respectively, while patients in the placebo arm reported improvements in both measures regardless of PD-L1 expression. Other improvements tended to favor the durvalumab group; for instance, compared with other subgroups, patients with PD-L1 expression of at least 25% were more likely to report improved chest pain, physical functioning, pain, emotional functioning, and hemoptysis. In contrast, patients receiving placebo with PD-L1 expression less than 25% were more likely to report improved cough. Still, the investigators concluded that the overall picture did not suggest major differences in PROs by PD-L1 expression level, noting that global quality of life did not differ, and symptom improvement rates and time-to-deterioration measures generally aligned with the intent-to-treat population, judging by overlapping 95% confidence intervals and hazard ratios.

“These data support the PACIFIC regimen for the standard of care for stage III unresectable non–small cell lung cancer patients,” Dr. Garassino concluded.

Will Pass/MDedge News

Invited discussant Fabrice Barlesi, MD, PhD, of Aix-Marseille University, said that studies such as this one are important to ensure that investigator-implemented measures of response are calibrated to patient experiences. As an example, Dr. Barlesi noted that many clinicians would say that grade 2 diarrhea is a completely manageable adverse event, but not all patients would agree.

In this light, Dr. Barlesi said that the present findings are valuable, but they are not without flaws. He noted that 11 out of 13 symptoms from the quality of life lung cancer module were not reported, and that one-third of patients in the PACIFIC trial lacked PD-L1 expression level data.

Considering these shortcomings, and more broadly, difficulties comparing patient-reported outcome studies because of various measurement techniques, Dr. Barlesi called for standardization.

“We need to standardize the analysis of quality of life data,” Dr. Barlesi said. “We should correct for the multiplicity of tests. … we should identify some specific quality of life outcomes that we want to look at in the protocol.” He continued to suggest a variety of ideal characteristics for studies evaluating patient-reported outcomes, including defined statistical measures and protocols for missing data.

Without a standardized approach, “cross trial comparison will be a nightmare for all of us,” Dr. Barlesi said.

The study was funded by AstraZeneca. The investigators reported financial relationships with Roche, BMS, Lilly, and others.

SOURCE: Garassino et al. ELCC 2019. Abstract LBA2.

GENEVA – Level of programmed death-ligand 1 (PD-L1) expression does not impact patient-reported outcomes (PROs) among those receiving durvalumab for stage III non–small cell lung cancer (NSCLC), according to a retrospective analysis of the phase III PACIFIC trial.

Will Pass/MDedge News

The findings support durvalumab for all comers regardless of PD-L1 expression, reported lead author Marina Garassino, MD, of Fondazione IRCCS – Instituto Nazionale dei Tumori in Milan, who presented findings at the European Lung Cancer Congress.

The PACIFIC trial involved 713 patients with stage III NSCLC who did not progress after platinum-based concurrent chemoradiotherapy, demonstrating both improved progression-free and overall survival. Patients were randomized 2:1 to receive either durvalumab (10 mg/kg) or placebo IV every 2 weeks for up to 1 year. Out of 713 patients involved in the trial, 63% had PD-L1 tumor expression level data available for the present analysis, allowing for subgrouping into five categories: expression level of at least 25%, less than 25%, at least 1%, less than 1%, or unknown. The investigators compared PROs from these cohorts using the European Organisation for Research and Treatment of Cancer core quality of life questionnaire and lung cancer module (EORTC QLQ-C30 and -LC13). With scores ranging from 1 to 100 points, clinically meaningful differences were defined by score changes exceeding 10 points. Changes during treatment, from baseline to week 48, were analyzed by a mixed model for repeated measures, overall responses for improvement rates by logistic regression, and hazard ratios for time to deterioration (TTD) by a stratified Cox proportional-hazards model.

The investigators found that most PROs remained consistent over time, without clinically meaningful variations between PD-L1 expression levels. However, as with the entire PACIFIC treatment population, patients in the present analysis showed changes in some PROs. At the meeting presented by the European Society for Medical Oncology, Dr. Garassino noted that it would be unrealistic to describe all PRO comparisons; instead, she presented several examples. For one, in patients receiving durvalumab, dysphagia and alopecia improved in four out of five PD-L1 subgroups and all subgroups, respectively, while patients in the placebo arm reported improvements in both measures regardless of PD-L1 expression. Other improvements tended to favor the durvalumab group; for instance, compared with other subgroups, patients with PD-L1 expression of at least 25% were more likely to report improved chest pain, physical functioning, pain, emotional functioning, and hemoptysis. In contrast, patients receiving placebo with PD-L1 expression less than 25% were more likely to report improved cough. Still, the investigators concluded that the overall picture did not suggest major differences in PROs by PD-L1 expression level, noting that global quality of life did not differ, and symptom improvement rates and time-to-deterioration measures generally aligned with the intent-to-treat population, judging by overlapping 95% confidence intervals and hazard ratios.

“These data support the PACIFIC regimen for the standard of care for stage III unresectable non–small cell lung cancer patients,” Dr. Garassino concluded.

Will Pass/MDedge News

Invited discussant Fabrice Barlesi, MD, PhD, of Aix-Marseille University, said that studies such as this one are important to ensure that investigator-implemented measures of response are calibrated to patient experiences. As an example, Dr. Barlesi noted that many clinicians would say that grade 2 diarrhea is a completely manageable adverse event, but not all patients would agree.

In this light, Dr. Barlesi said that the present findings are valuable, but they are not without flaws. He noted that 11 out of 13 symptoms from the quality of life lung cancer module were not reported, and that one-third of patients in the PACIFIC trial lacked PD-L1 expression level data.

Considering these shortcomings, and more broadly, difficulties comparing patient-reported outcome studies because of various measurement techniques, Dr. Barlesi called for standardization.

“We need to standardize the analysis of quality of life data,” Dr. Barlesi said. “We should correct for the multiplicity of tests. … we should identify some specific quality of life outcomes that we want to look at in the protocol.” He continued to suggest a variety of ideal characteristics for studies evaluating patient-reported outcomes, including defined statistical measures and protocols for missing data.

Without a standardized approach, “cross trial comparison will be a nightmare for all of us,” Dr. Barlesi said.

The study was funded by AstraZeneca. The investigators reported financial relationships with Roche, BMS, Lilly, and others.

SOURCE: Garassino et al. ELCC 2019. Abstract LBA2.

HOUSTON – Cytokine release syndrome and neurotoxicity frequently occur with CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapies, but targetable factors for mitigating the risk and effects of these complications are emerging, according to Cameron Turtle, MBBS, PhD.

Novartis

These factors include infused CAR T-cell dose, bone marrow disease burden, immune response, and the lymphodepletion regimen used, Dr. Turtle, of Fred Hutchinson Cancer Research Center, Seattle, said at the Transplantation & Cellular Therapies Meetings. This list is based on an analysis of several studies that included a total of 195 patients with B-cell malignancies who were treated with defined-composition CD19 CAR T cells.

In a 2016 study included in the analysis, for instance, Dr. Turtle and his colleagues found that CD19 CAR T cells administered to adults with B-cell acute lymphoblastic leukemia (B-ALL) after lymphodepletion chemotherapy were “remarkably potent.” Remission was achieved in 27 of 29 patients (J Clin Invest. 2016 Jun 1;126[6]:2123-38).

However, the study also established that high CAR T-cell doses and tumor burden increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, Dr. Turtle said at the meeting, held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

“Importantly, we identified serum biomarkers that allow testing of early intervention strategies in the patients who have the highest risk of toxicity,” he said.

Dr. Turtle explained that significantly higher peak interleuken-6 (IL-6) and interferon (IFN)-gamma levels were seen after CAR T-cell infusion in patients with high bone marrow tumor burden and in patients requiring treatment in an intensive care unit (ICU).


ICU care correlated with a higher percentage of bone marrow blasts before lymphodepletion chemotherapy, he added.

Elevations of serum C-reactive protein (CRP) and ferritin also correlated with bone marrow disease burden and with the occurrence of severe CRS requiring ICU care, he said, noting that ferritin and CRP levels declined after tocilizumab or corticosteroid therapy.

In addition, all patients in the study who developed neurotoxicity had evidence of CRS. Peak levels of IL-6, IFN-gamma, ferritin, and CRP were significantly higher in those who developed grade 3 or higher neurotoxicity. Further, serum IL-6 and IFN-gamma concentrations on day 1 after infusion were significantly higher in those who required ICU care and in those who subsequently developed grade 4 neurotoxicity than in patients who developed grade 3 neurotoxicity.

Multivariate analysis indicated that serum IL-6 concentration of more than 30 pg/mL on day 1 and the total number of CD19+ cells in bone marrow before therapy were independent predictors of subsequent development of grade 3 or higher neurotoxicity.

Notably, serum IL-6 of more than 30 pg/mL on day 1 identified all patients in the study who subsequently developed grade 4 or higher neurotoxicity, Dr. Turtle and his colleagues noted.

“The findings suggested that evaluation of serum IL-6 concentration early after CAR T-cell infusion might be useful for identifying patients at high risk of severe neurotoxicity and to evaluate early intervention approaches,” he said.

Neurotoxicity

In a 2017 study from Juliane Gust, MD, PhD, and her colleagues, bone marrow disease burden, lymphodepletion regimen, and CAR T-cell dose were found to be significantly associated with neurotoxicity during multivariate analysis (Cancer Discov. 2017 Dec;7[12]:1404-19).

Patients with severe neurotoxicity in that study demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier permeability – with the latter leading to a failure to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFN-gamma. These high levels of cytokines may cause vascular pericyte activation and stress, Dr. Turtle explained.

Patients who subsequently developed grade 4 or higher neurotoxicity had higher pretreatment levels of endothelial activation biomarkers.

CRS

In another 2017 study, from Kevin A. Hay, MD, and his colleagues, similar factors were found to be associated with CRS (Blood. 2017 Nov 23;130[21]:2295-306).

Multivariable analysis identified high marrow tumor burden, lymphodepletion using cyclophosphamide and fludarabine, higher CAR T-cell dose, thrombocytopenia before lymphodepletion, and manufacturing of CAR T cells without selection of CD8+ central memory T cells as independent predictors of CRS.

Severe CRS was characterized by hemodynamic instability, capillary leak, and consumptive coagulopathy. As in the study by Dr. Gust and her colleagues, biomarkers of endothelial activation, including angiopoietin-2 and von Willebrand factor, were increased during severe CRS and before lymphodepletion in patients who subsequently developed CRS.
 

Potential modifications

The findings to date suggest that risk stratification, prophylaxis, early intervention and therapeutic intervention are among potential strategies for mitigating the risk of CD19-directed CAR T toxicity, Dr. Turtle said. Steroids, tocilizumab, siltuximab, anakinra, anti-GM-CSF, small molecules, plasma exchange, angiopoietin-1, and hypertransfusion are among candidates under consideration for such interventions, he noted.

Other approaches that have been tested in small studies, and which may reduce toxicity and improve the therapeutic index of CD19 CAR T-cell therapy for B-ALL, include split dosing and risk-adapted dosing.

“These approaches do appear to mitigate toxicity, but larger studies are needed to confirm that treatment efficacy is maintained,” Dr. Turtle said.

Toxicity prediction and early intervention to maintain the CAR T-cell dose while avoiding grade 4 or greater toxicities would be helpful and is within reach, he said, noting that the findings by Dr. Hay and his colleagues led to the development of “day-1 cytokine combination algorithms that predict grade 4-5 CRS and could direct preemptive intervention.”

One algorithm based on three cytokines had high sensitivity and specificity, but would require screening of all patients.

Early intervention in patients in whom toxicity is predicted has not been extensively evaluated in clinical studies, he said.

Dr. Hay and his colleagues did, however, develop a “classification tree model of early intervention strategies” using their findings.

A complicating factor in predicting risk and intervening is that each CAR T-cell product is associated with differing levels of toxicity risk. The varying rates of toxicity suggest that promising approaches for addressing CAR T toxicity require validation for each product with respect to cutpoints, efficacy, and maintenance of response, Dr. Turtle said.

“The findings to date are encouraging and show that potentially targetable factors for mitigating the toxicity of CAR T-cell therapy can be identified,” he said. “But clinical studies have yet to convincingly establish the best approach.”

Dr. Turtle has served on advisory boards for Juno/Celgene, Kite/Gilead, Novartis, Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, Nektar Therapeutics, Humanigen, and Aptevo; has intellectual property rights licensed to Juno; has stock options with Precision Biosciences, Eureka Therapeutics, and Caribou Biosciences; and has received research funding from Juno and Nektar Therapeutics.

[email protected]

HOUSTON – Cytokine release syndrome and neurotoxicity frequently occur with CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapies, but targetable factors for mitigating the risk and effects of these complications are emerging, according to Cameron Turtle, MBBS, PhD.

Novartis

These factors include infused CAR T-cell dose, bone marrow disease burden, immune response, and the lymphodepletion regimen used, Dr. Turtle, of Fred Hutchinson Cancer Research Center, Seattle, said at the Transplantation & Cellular Therapies Meetings. This list is based on an analysis of several studies that included a total of 195 patients with B-cell malignancies who were treated with defined-composition CD19 CAR T cells.

In a 2016 study included in the analysis, for instance, Dr. Turtle and his colleagues found that CD19 CAR T cells administered to adults with B-cell acute lymphoblastic leukemia (B-ALL) after lymphodepletion chemotherapy were “remarkably potent.” Remission was achieved in 27 of 29 patients (J Clin Invest. 2016 Jun 1;126[6]:2123-38).

However, the study also established that high CAR T-cell doses and tumor burden increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, Dr. Turtle said at the meeting, held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

“Importantly, we identified serum biomarkers that allow testing of early intervention strategies in the patients who have the highest risk of toxicity,” he said.

Dr. Turtle explained that significantly higher peak interleuken-6 (IL-6) and interferon (IFN)-gamma levels were seen after CAR T-cell infusion in patients with high bone marrow tumor burden and in patients requiring treatment in an intensive care unit (ICU).


ICU care correlated with a higher percentage of bone marrow blasts before lymphodepletion chemotherapy, he added.

Elevations of serum C-reactive protein (CRP) and ferritin also correlated with bone marrow disease burden and with the occurrence of severe CRS requiring ICU care, he said, noting that ferritin and CRP levels declined after tocilizumab or corticosteroid therapy.

In addition, all patients in the study who developed neurotoxicity had evidence of CRS. Peak levels of IL-6, IFN-gamma, ferritin, and CRP were significantly higher in those who developed grade 3 or higher neurotoxicity. Further, serum IL-6 and IFN-gamma concentrations on day 1 after infusion were significantly higher in those who required ICU care and in those who subsequently developed grade 4 neurotoxicity than in patients who developed grade 3 neurotoxicity.

Multivariate analysis indicated that serum IL-6 concentration of more than 30 pg/mL on day 1 and the total number of CD19+ cells in bone marrow before therapy were independent predictors of subsequent development of grade 3 or higher neurotoxicity.

Notably, serum IL-6 of more than 30 pg/mL on day 1 identified all patients in the study who subsequently developed grade 4 or higher neurotoxicity, Dr. Turtle and his colleagues noted.

“The findings suggested that evaluation of serum IL-6 concentration early after CAR T-cell infusion might be useful for identifying patients at high risk of severe neurotoxicity and to evaluate early intervention approaches,” he said.

Neurotoxicity

In a 2017 study from Juliane Gust, MD, PhD, and her colleagues, bone marrow disease burden, lymphodepletion regimen, and CAR T-cell dose were found to be significantly associated with neurotoxicity during multivariate analysis (Cancer Discov. 2017 Dec;7[12]:1404-19).

Patients with severe neurotoxicity in that study demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier permeability – with the latter leading to a failure to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFN-gamma. These high levels of cytokines may cause vascular pericyte activation and stress, Dr. Turtle explained.

Patients who subsequently developed grade 4 or higher neurotoxicity had higher pretreatment levels of endothelial activation biomarkers.

CRS

In another 2017 study, from Kevin A. Hay, MD, and his colleagues, similar factors were found to be associated with CRS (Blood. 2017 Nov 23;130[21]:2295-306).

Multivariable analysis identified high marrow tumor burden, lymphodepletion using cyclophosphamide and fludarabine, higher CAR T-cell dose, thrombocytopenia before lymphodepletion, and manufacturing of CAR T cells without selection of CD8+ central memory T cells as independent predictors of CRS.

Severe CRS was characterized by hemodynamic instability, capillary leak, and consumptive coagulopathy. As in the study by Dr. Gust and her colleagues, biomarkers of endothelial activation, including angiopoietin-2 and von Willebrand factor, were increased during severe CRS and before lymphodepletion in patients who subsequently developed CRS.
 

Potential modifications

The findings to date suggest that risk stratification, prophylaxis, early intervention and therapeutic intervention are among potential strategies for mitigating the risk of CD19-directed CAR T toxicity, Dr. Turtle said. Steroids, tocilizumab, siltuximab, anakinra, anti-GM-CSF, small molecules, plasma exchange, angiopoietin-1, and hypertransfusion are among candidates under consideration for such interventions, he noted.

Other approaches that have been tested in small studies, and which may reduce toxicity and improve the therapeutic index of CD19 CAR T-cell therapy for B-ALL, include split dosing and risk-adapted dosing.

“These approaches do appear to mitigate toxicity, but larger studies are needed to confirm that treatment efficacy is maintained,” Dr. Turtle said.

Toxicity prediction and early intervention to maintain the CAR T-cell dose while avoiding grade 4 or greater toxicities would be helpful and is within reach, he said, noting that the findings by Dr. Hay and his colleagues led to the development of “day-1 cytokine combination algorithms that predict grade 4-5 CRS and could direct preemptive intervention.”

One algorithm based on three cytokines had high sensitivity and specificity, but would require screening of all patients.

Early intervention in patients in whom toxicity is predicted has not been extensively evaluated in clinical studies, he said.

Dr. Hay and his colleagues did, however, develop a “classification tree model of early intervention strategies” using their findings.

A complicating factor in predicting risk and intervening is that each CAR T-cell product is associated with differing levels of toxicity risk. The varying rates of toxicity suggest that promising approaches for addressing CAR T toxicity require validation for each product with respect to cutpoints, efficacy, and maintenance of response, Dr. Turtle said.

“The findings to date are encouraging and show that potentially targetable factors for mitigating the toxicity of CAR T-cell therapy can be identified,” he said. “But clinical studies have yet to convincingly establish the best approach.”

Dr. Turtle has served on advisory boards for Juno/Celgene, Kite/Gilead, Novartis, Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, Nektar Therapeutics, Humanigen, and Aptevo; has intellectual property rights licensed to Juno; has stock options with Precision Biosciences, Eureka Therapeutics, and Caribou Biosciences; and has received research funding from Juno and Nektar Therapeutics.

[email protected]

HOUSTON – Cytokine release syndrome and neurotoxicity frequently occur with CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapies, but targetable factors for mitigating the risk and effects of these complications are emerging, according to Cameron Turtle, MBBS, PhD.

Novartis

These factors include infused CAR T-cell dose, bone marrow disease burden, immune response, and the lymphodepletion regimen used, Dr. Turtle, of Fred Hutchinson Cancer Research Center, Seattle, said at the Transplantation & Cellular Therapies Meetings. This list is based on an analysis of several studies that included a total of 195 patients with B-cell malignancies who were treated with defined-composition CD19 CAR T cells.

In a 2016 study included in the analysis, for instance, Dr. Turtle and his colleagues found that CD19 CAR T cells administered to adults with B-cell acute lymphoblastic leukemia (B-ALL) after lymphodepletion chemotherapy were “remarkably potent.” Remission was achieved in 27 of 29 patients (J Clin Invest. 2016 Jun 1;126[6]:2123-38).

However, the study also established that high CAR T-cell doses and tumor burden increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, Dr. Turtle said at the meeting, held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

“Importantly, we identified serum biomarkers that allow testing of early intervention strategies in the patients who have the highest risk of toxicity,” he said.

Dr. Turtle explained that significantly higher peak interleuken-6 (IL-6) and interferon (IFN)-gamma levels were seen after CAR T-cell infusion in patients with high bone marrow tumor burden and in patients requiring treatment in an intensive care unit (ICU).


ICU care correlated with a higher percentage of bone marrow blasts before lymphodepletion chemotherapy, he added.

Elevations of serum C-reactive protein (CRP) and ferritin also correlated with bone marrow disease burden and with the occurrence of severe CRS requiring ICU care, he said, noting that ferritin and CRP levels declined after tocilizumab or corticosteroid therapy.

In addition, all patients in the study who developed neurotoxicity had evidence of CRS. Peak levels of IL-6, IFN-gamma, ferritin, and CRP were significantly higher in those who developed grade 3 or higher neurotoxicity. Further, serum IL-6 and IFN-gamma concentrations on day 1 after infusion were significantly higher in those who required ICU care and in those who subsequently developed grade 4 neurotoxicity than in patients who developed grade 3 neurotoxicity.

Multivariate analysis indicated that serum IL-6 concentration of more than 30 pg/mL on day 1 and the total number of CD19+ cells in bone marrow before therapy were independent predictors of subsequent development of grade 3 or higher neurotoxicity.

Notably, serum IL-6 of more than 30 pg/mL on day 1 identified all patients in the study who subsequently developed grade 4 or higher neurotoxicity, Dr. Turtle and his colleagues noted.

“The findings suggested that evaluation of serum IL-6 concentration early after CAR T-cell infusion might be useful for identifying patients at high risk of severe neurotoxicity and to evaluate early intervention approaches,” he said.

Neurotoxicity

In a 2017 study from Juliane Gust, MD, PhD, and her colleagues, bone marrow disease burden, lymphodepletion regimen, and CAR T-cell dose were found to be significantly associated with neurotoxicity during multivariate analysis (Cancer Discov. 2017 Dec;7[12]:1404-19).

Patients with severe neurotoxicity in that study demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier permeability – with the latter leading to a failure to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFN-gamma. These high levels of cytokines may cause vascular pericyte activation and stress, Dr. Turtle explained.

Patients who subsequently developed grade 4 or higher neurotoxicity had higher pretreatment levels of endothelial activation biomarkers.

CRS

In another 2017 study, from Kevin A. Hay, MD, and his colleagues, similar factors were found to be associated with CRS (Blood. 2017 Nov 23;130[21]:2295-306).

Multivariable analysis identified high marrow tumor burden, lymphodepletion using cyclophosphamide and fludarabine, higher CAR T-cell dose, thrombocytopenia before lymphodepletion, and manufacturing of CAR T cells without selection of CD8+ central memory T cells as independent predictors of CRS.

Severe CRS was characterized by hemodynamic instability, capillary leak, and consumptive coagulopathy. As in the study by Dr. Gust and her colleagues, biomarkers of endothelial activation, including angiopoietin-2 and von Willebrand factor, were increased during severe CRS and before lymphodepletion in patients who subsequently developed CRS.
 

Potential modifications

The findings to date suggest that risk stratification, prophylaxis, early intervention and therapeutic intervention are among potential strategies for mitigating the risk of CD19-directed CAR T toxicity, Dr. Turtle said. Steroids, tocilizumab, siltuximab, anakinra, anti-GM-CSF, small molecules, plasma exchange, angiopoietin-1, and hypertransfusion are among candidates under consideration for such interventions, he noted.

Other approaches that have been tested in small studies, and which may reduce toxicity and improve the therapeutic index of CD19 CAR T-cell therapy for B-ALL, include split dosing and risk-adapted dosing.

“These approaches do appear to mitigate toxicity, but larger studies are needed to confirm that treatment efficacy is maintained,” Dr. Turtle said.

Toxicity prediction and early intervention to maintain the CAR T-cell dose while avoiding grade 4 or greater toxicities would be helpful and is within reach, he said, noting that the findings by Dr. Hay and his colleagues led to the development of “day-1 cytokine combination algorithms that predict grade 4-5 CRS and could direct preemptive intervention.”

One algorithm based on three cytokines had high sensitivity and specificity, but would require screening of all patients.

Early intervention in patients in whom toxicity is predicted has not been extensively evaluated in clinical studies, he said.

Dr. Hay and his colleagues did, however, develop a “classification tree model of early intervention strategies” using their findings.

A complicating factor in predicting risk and intervening is that each CAR T-cell product is associated with differing levels of toxicity risk. The varying rates of toxicity suggest that promising approaches for addressing CAR T toxicity require validation for each product with respect to cutpoints, efficacy, and maintenance of response, Dr. Turtle said.

“The findings to date are encouraging and show that potentially targetable factors for mitigating the toxicity of CAR T-cell therapy can be identified,” he said. “But clinical studies have yet to convincingly establish the best approach.”

Dr. Turtle has served on advisory boards for Juno/Celgene, Kite/Gilead, Novartis, Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, Nektar Therapeutics, Humanigen, and Aptevo; has intellectual property rights licensed to Juno; has stock options with Precision Biosciences, Eureka Therapeutics, and Caribou Biosciences; and has received research funding from Juno and Nektar Therapeutics.

[email protected]

ATLANTA – Combined therapy with the class I selective histone deacetylase (HDAC) inhibitor entinostat and the programmed cell death 1 (PD-1) inhibitor pembrolizumab has significant clinical activity and acceptable safety in melanoma patients who progressed on prior PD-1 blockade, according to findings from the open-label ENCORE-601 trial.

Of 53 patients with recurrent or metastatic melanoma who were treated with 5 mg of oral entinostat weekly plus 200 mg of intravenous pembrolizumab every 3 weeks, 1 had a complete response, and 9 had a partial response, for an objective response rate of 19%, Ryan J. Sullivan, MD, reported at the annual meeting of the American Association for Cancer Research.

The median duration of response at the January 2018 data cut-off was 13 months, and four responders had ongoing responses. An additional nine patients had stable disease for at least 6 months at that time, for a clinical benefit rate of 36%, said Dr. Sullivan of Massachusetts General Hospital, Boston.

“At 1 year, 10 patients remained on therapy or in response,” he said, noting that, although one patient had received only a very short course of therapy before developing “significant hepatitis” and coming off therapy, but this patient still had a response at 1 year. Five others also went off therapy and continue to have a response, and four patients remain on active therapy and are being followed, he said.

Study participants are adults with Eastern Cooperative Oncology Group Performance Status of less than 2 who were previously treated with a PD-1–blocking antibody and experienced progression on or after therapy. The 23% of patients with a BRAF V600 mutation were required to have received BRAF/MEK therapy, and 70% of patients had received both a prior PD-1 inhibitor and ipilimumab, either in combination or in sequence.

The response rate to prior anti–PD-1 therapy was 13%, which was “much lower than you would imagine in all-comers,” Dr Sullivan said.

Inhibitors of PD-1 and its ligand (PD-L1) have improved outcomes in patients with advanced melanoma, but despite the progress, most patients develop resistance and most will still die from metastatic melanoma, he said.

“I think its always important to define what the unmet need is, and here it’s quite clear: Most patients are not receiving ultimate benefit, and as a result we need a better therapeutic approach,” he said, adding that “the front-line treatment setting is a critical place to be in terms of clinical trials ... but the most relevant and most unmet need now is what do we do in patients who have received anti–PD-1 therapy and need something else.”


Addressing the unmet need requires an improved understanding of the mechanisms of resistance and the development of more effective therapies, he said.

Dr. Sullivan and his colleagues previously reported preliminary data from the current cohort showing promising activity with entinostat in combination with pembrolizumab, which was found to alter the immunosuppressive tumor microenvironment. The rationale for using entinostat in this setting relates to its down-regulation of immunosuppressive cell types in the tumor microenvironment and its “quite robust” synergy with PD-1 inhibition as demonstrated in preclinical models, he explained.

Following those initial dose and safety findings, four phase 2 expansion cohorts were opened, including two non–small cell lung cancer cohorts, one mismatched-repair proficient colorectal cancer cohort, and the melanoma cohort. The current report, which focused on the latter, showed that the treatment-related adverse events (AEs) occurring in at least 15% of patients included nausea, fatigue, diarrhea, and myelosuppression.

“Six patients discontinued due to related AEs, and importantly, there were only five grade 3 or 4 immune-related AEs,” Dr. Sullivan said, adding that these included one case each of immune-related hepatitis, pneumonitis, and colitis and two cases of significant dermatitis.

The findings show that in this group of patients with limited treatment options, entinostat with pembrolizumab is “clearly safe and tolerable,” he said.

Additionally, “very preliminary biomarker analyses” in a small number of patients demonstrated findings consistent with the mechanism of action of entinostat, including a reduction in circulating myeloid-derived suppressor cells, he said.

Dr. Sullivan reported consulting or serving on an advisory board for Novartis, Amgen, Merck, Array, Syndax, Replimmune, and Bristol-Myers Squibb and receiving research sponsorship from Amgen and Merck & Co.

[email protected]

SOURCE: Sullivan R et al. AACR 2019, Abstract CT-072.

ATLANTA – Combined therapy with the class I selective histone deacetylase (HDAC) inhibitor entinostat and the programmed cell death 1 (PD-1) inhibitor pembrolizumab has significant clinical activity and acceptable safety in melanoma patients who progressed on prior PD-1 blockade, according to findings from the open-label ENCORE-601 trial.

Of 53 patients with recurrent or metastatic melanoma who were treated with 5 mg of oral entinostat weekly plus 200 mg of intravenous pembrolizumab every 3 weeks, 1 had a complete response, and 9 had a partial response, for an objective response rate of 19%, Ryan J. Sullivan, MD, reported at the annual meeting of the American Association for Cancer Research.

The median duration of response at the January 2018 data cut-off was 13 months, and four responders had ongoing responses. An additional nine patients had stable disease for at least 6 months at that time, for a clinical benefit rate of 36%, said Dr. Sullivan of Massachusetts General Hospital, Boston.

“At 1 year, 10 patients remained on therapy or in response,” he said, noting that, although one patient had received only a very short course of therapy before developing “significant hepatitis” and coming off therapy, but this patient still had a response at 1 year. Five others also went off therapy and continue to have a response, and four patients remain on active therapy and are being followed, he said.

Study participants are adults with Eastern Cooperative Oncology Group Performance Status of less than 2 who were previously treated with a PD-1–blocking antibody and experienced progression on or after therapy. The 23% of patients with a BRAF V600 mutation were required to have received BRAF/MEK therapy, and 70% of patients had received both a prior PD-1 inhibitor and ipilimumab, either in combination or in sequence.

The response rate to prior anti–PD-1 therapy was 13%, which was “much lower than you would imagine in all-comers,” Dr Sullivan said.

Inhibitors of PD-1 and its ligand (PD-L1) have improved outcomes in patients with advanced melanoma, but despite the progress, most patients develop resistance and most will still die from metastatic melanoma, he said.

“I think its always important to define what the unmet need is, and here it’s quite clear: Most patients are not receiving ultimate benefit, and as a result we need a better therapeutic approach,” he said, adding that “the front-line treatment setting is a critical place to be in terms of clinical trials ... but the most relevant and most unmet need now is what do we do in patients who have received anti–PD-1 therapy and need something else.”


Addressing the unmet need requires an improved understanding of the mechanisms of resistance and the development of more effective therapies, he said.

Dr. Sullivan and his colleagues previously reported preliminary data from the current cohort showing promising activity with entinostat in combination with pembrolizumab, which was found to alter the immunosuppressive tumor microenvironment. The rationale for using entinostat in this setting relates to its down-regulation of immunosuppressive cell types in the tumor microenvironment and its “quite robust” synergy with PD-1 inhibition as demonstrated in preclinical models, he explained.

Following those initial dose and safety findings, four phase 2 expansion cohorts were opened, including two non–small cell lung cancer cohorts, one mismatched-repair proficient colorectal cancer cohort, and the melanoma cohort. The current report, which focused on the latter, showed that the treatment-related adverse events (AEs) occurring in at least 15% of patients included nausea, fatigue, diarrhea, and myelosuppression.

“Six patients discontinued due to related AEs, and importantly, there were only five grade 3 or 4 immune-related AEs,” Dr. Sullivan said, adding that these included one case each of immune-related hepatitis, pneumonitis, and colitis and two cases of significant dermatitis.

The findings show that in this group of patients with limited treatment options, entinostat with pembrolizumab is “clearly safe and tolerable,” he said.

Additionally, “very preliminary biomarker analyses” in a small number of patients demonstrated findings consistent with the mechanism of action of entinostat, including a reduction in circulating myeloid-derived suppressor cells, he said.

Dr. Sullivan reported consulting or serving on an advisory board for Novartis, Amgen, Merck, Array, Syndax, Replimmune, and Bristol-Myers Squibb and receiving research sponsorship from Amgen and Merck & Co.

[email protected]

SOURCE: Sullivan R et al. AACR 2019, Abstract CT-072.

ATLANTA – Combined therapy with the class I selective histone deacetylase (HDAC) inhibitor entinostat and the programmed cell death 1 (PD-1) inhibitor pembrolizumab has significant clinical activity and acceptable safety in melanoma patients who progressed on prior PD-1 blockade, according to findings from the open-label ENCORE-601 trial.

Of 53 patients with recurrent or metastatic melanoma who were treated with 5 mg of oral entinostat weekly plus 200 mg of intravenous pembrolizumab every 3 weeks, 1 had a complete response, and 9 had a partial response, for an objective response rate of 19%, Ryan J. Sullivan, MD, reported at the annual meeting of the American Association for Cancer Research.

The median duration of response at the January 2018 data cut-off was 13 months, and four responders had ongoing responses. An additional nine patients had stable disease for at least 6 months at that time, for a clinical benefit rate of 36%, said Dr. Sullivan of Massachusetts General Hospital, Boston.

“At 1 year, 10 patients remained on therapy or in response,” he said, noting that, although one patient had received only a very short course of therapy before developing “significant hepatitis” and coming off therapy, but this patient still had a response at 1 year. Five others also went off therapy and continue to have a response, and four patients remain on active therapy and are being followed, he said.

Study participants are adults with Eastern Cooperative Oncology Group Performance Status of less than 2 who were previously treated with a PD-1–blocking antibody and experienced progression on or after therapy. The 23% of patients with a BRAF V600 mutation were required to have received BRAF/MEK therapy, and 70% of patients had received both a prior PD-1 inhibitor and ipilimumab, either in combination or in sequence.

The response rate to prior anti–PD-1 therapy was 13%, which was “much lower than you would imagine in all-comers,” Dr Sullivan said.

Inhibitors of PD-1 and its ligand (PD-L1) have improved outcomes in patients with advanced melanoma, but despite the progress, most patients develop resistance and most will still die from metastatic melanoma, he said.

“I think its always important to define what the unmet need is, and here it’s quite clear: Most patients are not receiving ultimate benefit, and as a result we need a better therapeutic approach,” he said, adding that “the front-line treatment setting is a critical place to be in terms of clinical trials ... but the most relevant and most unmet need now is what do we do in patients who have received anti–PD-1 therapy and need something else.”


Addressing the unmet need requires an improved understanding of the mechanisms of resistance and the development of more effective therapies, he said.

Dr. Sullivan and his colleagues previously reported preliminary data from the current cohort showing promising activity with entinostat in combination with pembrolizumab, which was found to alter the immunosuppressive tumor microenvironment. The rationale for using entinostat in this setting relates to its down-regulation of immunosuppressive cell types in the tumor microenvironment and its “quite robust” synergy with PD-1 inhibition as demonstrated in preclinical models, he explained.

Following those initial dose and safety findings, four phase 2 expansion cohorts were opened, including two non–small cell lung cancer cohorts, one mismatched-repair proficient colorectal cancer cohort, and the melanoma cohort. The current report, which focused on the latter, showed that the treatment-related adverse events (AEs) occurring in at least 15% of patients included nausea, fatigue, diarrhea, and myelosuppression.

“Six patients discontinued due to related AEs, and importantly, there were only five grade 3 or 4 immune-related AEs,” Dr. Sullivan said, adding that these included one case each of immune-related hepatitis, pneumonitis, and colitis and two cases of significant dermatitis.

The findings show that in this group of patients with limited treatment options, entinostat with pembrolizumab is “clearly safe and tolerable,” he said.

Additionally, “very preliminary biomarker analyses” in a small number of patients demonstrated findings consistent with the mechanism of action of entinostat, including a reduction in circulating myeloid-derived suppressor cells, he said.

Dr. Sullivan reported consulting or serving on an advisory board for Novartis, Amgen, Merck, Array, Syndax, Replimmune, and Bristol-Myers Squibb and receiving research sponsorship from Amgen and Merck & Co.

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SOURCE: Sullivan R et al. AACR 2019, Abstract CT-072.