Meeting NewsPerspective

Entinostat plus pembrolizumab shows efficacy in anti-PD-1-resistant melanoma

Photo of Ryan Sullivan
Ryan J. Sullivan

ATLANTA — The combination of the histone deacetylase inhibitor entinostat and the anti-PD-1 inhibitor pembrolizumab induced clinical responses and appeared well-tolerated among patients with melanoma that progressed on prior anti-PD-1 treatment, according to results from the single-arm ENCORE 601 phase 1b/phase 2 clinical trial presented at American Association of Cancer Research Annual Meeting.

Histone deacetylase (HDAC) inhibitors such as entinostat (SNDX-275, Syndax) may counteract resistance to checkpoint inhibition in two ways: by suppressing regulatory cells — including myeloid-derived suppressor cells and regulatory T cells — and by increasing antigen expression on cancer cells.

“HDAC inhibition has been shown to decrease the function of T-regulatory cells (T-regs) and myeloid-derived suppressor cells, and increase antigen expression in tumors,” Ryan J. Sullivan, MD, assistant professor of hematology and oncology at Massachusetts General Hospital Cancer Center, told HemOnc Today. “A number of PD-1/PD-L1 inhibitor resistance mechanisms have been described and/or proposed and include, although are not limited to, high activity of T-regs, expression of myeloid-derived suppressor cells, and down-modulation of tumor antigen expression. Thus, it seemed logical to combine an agent like entinostat with pembrolizumab in PD-1-resistant/refractory melanoma.”

Sullivan and colleagues of ENCORE 601 aim to evaluate the efficacy of adding entinostat to pembrolizumab (Keytruda, Merck) in patients with non-small cell lung cancer, melanoma and mismatch repair-proficient colorectal cancer that had progressed on prior PD-1 therapy.

“Even in melanoma, where durable benefit to immune checkpoint inhibitor therapy ranges from 30% to 40%, the great majority of patients will need another therapy,” Sullivan said. “Further, there is no standard approach to these patients, thus developing better therapies for this indication is an urgent unmet need.”

The current analysis includes 53 patients with metastatic melanoma that progressed during or following treatment with anti-PD-1 immunotherapy (median duration of prior treatment, 4.9 months). Sixty-six percent of patients received no additional therapy between prior anti-PD-1 treatment and trial enrollment (median time from last dose to study entry, 2.7 months).

Most patients (70%) previously received ipilimumab (Yervoy, Bristol-Myers Squibb), and 23% had been treated with BRAF/MEK inhibitors.

Patients received 5 mg entinostat weekly with 200 mg pembrolizumab once every 3 weeks.

Objective response rate served as the study’s primary endpoint.

Results showed an ORR of 19% (95% CI, 9-32), which included nine partial responses and one complete response. Median duration of response was 12.5 months (range, 4-18), with five responses ongoing at the time of the data cutoff.

Seven patients have had stable disease for longer than 6 months, resulting in a clinical benefit rate of 32% (95% CI, 20-46).

Median PFS was 4.2 months.

Sullivan said these response rates are in line with other clinical trials in this setting so, although he is not surprised by the results, he is “encouraged that a clear and significant minority of patients benefitting from this regimen.”

The most common grade 3 to grade 4 adverse events included neutropenia, fatigue and hyponatremia. Five patients (9%) experienced a grade 3 to grade 4 immune-related adverse event, including two patients with rash and one patient each with colitis, pneumonitis and autoimmune hepatitis.

Biomarkers will be a key area of future research to advance this combination, Sullivan told HemOnc Today.

“It is critical that we determine whether the 15% to 30% of patients receiving benefit to various regimens are the same 15% to 30% of patients, or whether there are biomarkers that can predict benefit to specific regimens,” he said. “If so, we may already have a number of regimens that can help up to 50-60% of patients in this setting.” – by Alexandra Todak

Reference:

Sullivan RJ, et al. Abstract CT072. Presented at: AACR Annual Meeting; March 29-April 3, 2019; Atlanta.

Disclosures: Syndax sponsored this study. Sullivan reports pain consultant/advisory board roles with Amgen, Array, Bristol-Myers Squibb, Compugen, Merck, Novartis, Replimune and Syndax. Please see the abstract for all other authors’ relevant financial disclosures.

Photo of Ryan Sullivan
Ryan J. Sullivan

ATLANTA — The combination of the histone deacetylase inhibitor entinostat and the anti-PD-1 inhibitor pembrolizumab induced clinical responses and appeared well-tolerated among patients with melanoma that progressed on prior anti-PD-1 treatment, according to results from the single-arm ENCORE 601 phase 1b/phase 2 clinical trial presented at American Association of Cancer Research Annual Meeting.

Histone deacetylase (HDAC) inhibitors such as entinostat (SNDX-275, Syndax) may counteract resistance to checkpoint inhibition in two ways: by suppressing regulatory cells — including myeloid-derived suppressor cells and regulatory T cells — and by increasing antigen expression on cancer cells.

“HDAC inhibition has been shown to decrease the function of T-regulatory cells (T-regs) and myeloid-derived suppressor cells, and increase antigen expression in tumors,” Ryan J. Sullivan, MD, assistant professor of hematology and oncology at Massachusetts General Hospital Cancer Center, told HemOnc Today. “A number of PD-1/PD-L1 inhibitor resistance mechanisms have been described and/or proposed and include, although are not limited to, high activity of T-regs, expression of myeloid-derived suppressor cells, and down-modulation of tumor antigen expression. Thus, it seemed logical to combine an agent like entinostat with pembrolizumab in PD-1-resistant/refractory melanoma.”

Sullivan and colleagues of ENCORE 601 aim to evaluate the efficacy of adding entinostat to pembrolizumab (Keytruda, Merck) in patients with non-small cell lung cancer, melanoma and mismatch repair-proficient colorectal cancer that had progressed on prior PD-1 therapy.

“Even in melanoma, where durable benefit to immune checkpoint inhibitor therapy ranges from 30% to 40%, the great majority of patients will need another therapy,” Sullivan said. “Further, there is no standard approach to these patients, thus developing better therapies for this indication is an urgent unmet need.”

The current analysis includes 53 patients with metastatic melanoma that progressed during or following treatment with anti-PD-1 immunotherapy (median duration of prior treatment, 4.9 months). Sixty-six percent of patients received no additional therapy between prior anti-PD-1 treatment and trial enrollment (median time from last dose to study entry, 2.7 months).

Most patients (70%) previously received ipilimumab (Yervoy, Bristol-Myers Squibb), and 23% had been treated with BRAF/MEK inhibitors.

Patients received 5 mg entinostat weekly with 200 mg pembrolizumab once every 3 weeks.

Objective response rate served as the study’s primary endpoint.

Results showed an ORR of 19% (95% CI, 9-32), which included nine partial responses and one complete response. Median duration of response was 12.5 months (range, 4-18), with five responses ongoing at the time of the data cutoff.

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Seven patients have had stable disease for longer than 6 months, resulting in a clinical benefit rate of 32% (95% CI, 20-46).

Median PFS was 4.2 months.

Sullivan said these response rates are in line with other clinical trials in this setting so, although he is not surprised by the results, he is “encouraged that a clear and significant minority of patients benefitting from this regimen.”

The most common grade 3 to grade 4 adverse events included neutropenia, fatigue and hyponatremia. Five patients (9%) experienced a grade 3 to grade 4 immune-related adverse event, including two patients with rash and one patient each with colitis, pneumonitis and autoimmune hepatitis.

Biomarkers will be a key area of future research to advance this combination, Sullivan told HemOnc Today.

“It is critical that we determine whether the 15% to 30% of patients receiving benefit to various regimens are the same 15% to 30% of patients, or whether there are biomarkers that can predict benefit to specific regimens,” he said. “If so, we may already have a number of regimens that can help up to 50-60% of patients in this setting.” – by Alexandra Todak

Reference:

Sullivan RJ, et al. Abstract CT072. Presented at: AACR Annual Meeting; March 29-April 3, 2019; Atlanta.

Disclosures: Syndax sponsored this study. Sullivan reports pain consultant/advisory board roles with Amgen, Array, Bristol-Myers Squibb, Compugen, Merck, Novartis, Replimune and Syndax. Please see the abstract for all other authors’ relevant financial disclosures.

    Perspective
    Morganna Freeman

    Morganna Freeman

    Many patients with advanced melanoma respond to anti-PD-1 therapy; however, not all patients benefit. If you look across trials, about 40% of patients respond, but not all of them maintain a prolonged response. Cancer specialists recognize a concept of ‘tumor escape’ from the immune system, where eventually melanoma (and other cancers) can regrow and those patients will relapse. We can run into difficulties determining the next line of therapy for these patients, especially if their melanoma does not harbor a BRAF mutation.

    What’s interesting about HDAC inhibitors is they can increase PD-L1 expression and make that melanoma more vulnerable to immunotherapy, so it’s very smart to look at them as an option for relapsed patients. We may even end up thinking about them as an option for patients as a first line of therapy, so that when combining them with anti-PD-1 therapy, we can take that 40% response rate and maybe bring it closer to 50% or 60%, as we’ve seen with combination CTLA-4 checkpoint inhibitors.

    To select patients for dual upfront therapy, one suggested mechanism is to test PD-L1 expression because the HDAC inhibitors increase PD-L1. A patient who is a low expressor or has a “cold” tumor might be selected for HDAC plus PD-1, whereas a patient who is a high PD-L1 expressor and thus more likely to respond to treatment may not need dual therapy. We don’t typically test for PD-L1 in melanoma, but this may end up changing our perspective if that’s the biomarker we should be using based on clinical trials.

    This trial enrolled a small number of patients, and it would be important to look at this combination in a larger group to see if the study results remain consistent. We learned that lesson from indoleamine 2,3 dioxygenase, or IDO, plus PD-1 inhibitors in melanoma, which looked very promising in phase II trials but showed no difference in terms of PFS or OS when tested in in a larger phase III trial. This combination of HDAC and PD-1 inhibitors appears very promising and is a combination therapy that has a favorable toxicity profile compared with other combinations tested in melanoma, but we need to see how it shakes out in a larger number of patients to know if it’s going to clinically benefit the majority. There is always a lot of excitement and enthusiasm when new data come out of these meetings, but from a practical standpoint and patient counseling standpoint, I always try to take these early data with a grain of salt. As with any clinical trial of cancer therapy, we need to look at long-term outcomes as they pertain to safety, tolerability and efficacy in a large cohort of patients in order to extrapolate that data for the greater good.

    As with any new melanoma therapy, although we might see some responses early on, do we know that is going to translate into durable responses later? Are we recapturing that immune response in a way that the tumor will stay in remission for a long time?

    Another important question is whether HDAC inhibitors could have any long-term toxicities for patients. Traditionally, HDAC inhibitor drugs have a risk for myelosuppression, so we would want to know whether these patients develop hematologic toxicities later, after many months of drug exposure.

    Lastly, I would like to know whether Dr. Sullivan and colleagues are thinking about using this in noncutaneous melanomas, such as mucosal melanoma or ocular melanoma, where we don’t see as robust of an immune response. Although this is a smaller number of patients, both are also orphan disease states, so it would be interesting to see if we can apply the same concept.

    • Morganna Freeman, DO
    • City of Hope

    Disclosures: Freeman reports consultant roles with Bristol-Myers Squibb, Merck, Novartis and Sanofi-Regeneron.

    Perspective
    Anthony Olszanski

    Anthony Olszanski

    Checkpoint inhibitors have revolutionized the treatment of many cancers, including melanoma; but, not all patients respond. For such patients, there remains a high unmet medical need to find therapies that can help such patients.

    Dr. Sullivan and his colleagues report on the potential benefit of adding HDAC inhibitors to checkpoint inhibitors in an effort to enhance the response to checkpoint inhibition, coaxing the patient's immune system to attack the cancer. These preliminary results are encouraging, with nearly 20% of patients responding to the combination despite the failure of prior single-agent checkpoint inhibition.

    Importantly, responses also appear to be durable, lasting about 1 year on average. New combinations which may enhance the effects of PD-1 inhibitors or reverse resistance to these agents is of paramount importance and offer hope to those patients who have not responded. This study offers promise and will spur further study in this situation.

    • Anthony Olszanski, MD, RPh
    • Fox Chase Cancer Center

    Disclosures: Olszanski reports no relevant financial disclosures.

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