Expert Details "Intriguing" Findings With Entinostat/Pembrolizumab Combo in Advanced Melanoma

Sanjiv S. Agarwala, MD

Sanjiv S. Agarwala, MD

The combination of pembrolizumab (Keytruda) and entinostat showed promising activity in patients with advanced melanoma, according to initial results from the ongoing ENCORE 601 trial presented during the 2018 ASCO Annual Meeting.

The multicohort study is evaluating the addition of the class I selective histone deacetylase (HDAC) inhibitor to pembrolizumab in patients with non—small cell lung cancer, colorectal cancer, and melanoma. Cohort 3 is comprised of patients with unresectable or metastatic melanoma who experienced progression on or after treatment with a PD-1 or PD-L1-inhibitor. The phase II expansion phase of the study utilized a Simon 2-stage design to assess activity. Among 13 melanoma patients in the stage 1 portion, 4 patients had responses, which met the criteria to expand to stage 2. Planned enrollment for stage 2 was originally set at 34 patients, but was increased to 52 patients to increase statistical power and decrease type I error. Initial findings from the first 34 patients in the melanoma cohort were presented during ASCO.

Patients were treated with entinostat at a dose of 5 mg weekly and intravenous pembrolizumab at 200 mg every 3 weeks in 21-day cycles. The primary endpoint of the trial was overall response rate (ORR).

Of the first 34 patients, 16 had refractory disease to prior PD-1 or PD-L1 therapy. Two patients had documented prior response. The median duration of prior PD-1 or PD-L1 therapy was < 6 months and the median time from last dose was 64 days. Twenty-two patients had received prior ipilimumab (Yervoy) and 7 had prior exposure to a BRAF inhibitor. The majority of the patients (65%) were male, with a median age of 64 (range, 20-86). Nineteen patients (56%) had an ECOG performance score of 0 and 15 patients (44%) had an ECOG performance score of 1. The majority of the patients (n=17) were PD-L1-positive and 50% had no visceral metastases.

Among the 34 patients, there were 6 confirmed partial responses, with an ORR of 18% (95% CI, 6.8-34.5). At the data cutoff on April 24, 2018, 4 patients remained on treatment, and the longest response was over 80 weeks. Fifteen patients (44%) achieved stable disease. The median duration of response was 9.0 months (range, 2.1-14.4). The median progression-free survival was 90 days.

Treatment-related adverse events (AEs) grade 3 or higher were observed in 14 patients. Two patients experienced grade 3/4 AEs, with anemia, rash, neutropenia, and hyponatremia occurring in 2 or more patients. Four patients discontinued treatment due a treatment-related AE, which included liver enzyme increase, mucosal inflammation, colitis, and autoimmune hepatitis.

In an interview withTargeted Oncology, lead author Sanjiv S. Agarwala, MD, chairman of medical oncology for St. Luke&rsquo;s University Health Network, discussed the findings for this cohort of patients with melanoma, as well as how this treatment regimen may fit into the treatment paradigm.

TARGETED ONCOLOGY:Can you provide some background on this study?

Agarwala:Pembrolizumab is an anti-PD-1 monoclonal antibody that has efficacy in melanoma, and we know that it has a significant response rate and benefit in survival and duration. Unfortunately, there are many patients that either don't respond or become refractory to treatment over time. One of the major works in progress is to find ways to make patients who are refractory become responsive to immunotherapy.

There are many combinations that have been designed to do just that. One approach is to use HDAC inhibitors, which have biology that might affect the tumor microenvironment to make immunotherapy more successful. Entinostat is an HDAC inhibitor, and the idea behind this clinical trial was to take patients who had become refractory to immunotherapy with anti-PD-1 antibodies or anti-PD-L1 antibodies, mostly anti-PD-1, and see if we could turn that immune switch back on to make the tumor sensitive to immunotherapy again. [This was done] by keeping the same immunotherapy on board [and] adding entinostat to see if we could make the patient respond or become stable. That was the design of this trial.

TARGETED ONCOLOGY:What were the findings thus far and why were they significant?

Agarwala:The real significance of the findings was [that] there were a significant number of patients who were proven to be refractory to anti-PD-1 or anti-PD-L1 therapy within 12 weeks of going on the trial, and then we kept them on the same drug, in this case pembrolizumab, and then added entinostat at a weekly dose of 5 mg. We saw that there was a response rate. In fact, the response rate was 18% in terms of the confirmed responses. It was higher for the unconfirmed, because the study is ongoing, but if you look at the clinical benefit rates, if patients were progressing and then became stable and you put that number together, it goes up to 29%. That is a significant number of patients who were proven to be non-responsive or progressing on the same treatment, not changing that treatment, adding something, and then turning that switch. That was very intriguing to us.

TARGETED ONCOLOGY:Can you discuss the safety profile?

Agarwala:The safety was very good. In fact, if you look at [the number of] grade 3/4 toxicities, it was all single digits. It was mostly those related to the immunotherapy, but nothing major in terms of safety that was dose-limiting or affected patients that much. Some patients had fatigue, but it's hard to tease out if that was from the disease, the pembrolizumab, or the entinostat.

TARGETED ONCOLOGY:What are some of the unanswered questions we still have about this combination?

Agarwala:The first unanswered question is how we make this even better. Having about 30% of people getting clinical benefit is great, but we want to be at 100%. In terms of what can be done, I think that's one thing that we have to figure out. We need a large sample size. In fact, it is being done. The study has accrued 55 patients now. We're presenting on 34 today, but there will be more data coming out to see if this clinical benefit we're seeing is robust. There are ongoing biomarker studies and we have some we are presenting here. Some of the biomarker studies showed that gene signatures of inflammation and immune response went up after treatment with entinostat compared to pre-treatment and tumor biopsies and seem to correlate with the benefit. The patients who had a clinical benefit had a higher upregulation of that immune signature, which is very interesting, so I think we need to do more work there and find the exact biomarker. We need to figure out who might be more responsive to this combination and those that might not respond.

TARGETED ONCOLOGY:How would this regimen fit in the treatment landscape?

Agarwala:To get this regimen approved, we would probably need a larger study and potentially a phase III trial. If it does get approved —and it's certainly a promising combination regimen&ndash; this would be a perfect second-line therapy for people that are receiving monotherapy with a PD-1 antibody. If they respond for a while and then become refractory and start to progress, we are looking for options in that setting, and this could be a great option for them. I see that becoming something very easy to think about as an approach if this got approved. If [this combination becomes a] successful approach, then I think the next intriguing question is how we take it into the frontline. [We might want to] add entinostat to frontline therapy with pembrolizumab right at the get-go to make that response rate with pembrolizumab even higher than it is and the durability even more. I think that is where this is going to play out over time.

TARGETED ONCOLOGY:Could this combination work with another immunotherapy agent?

Agarwala:This combination is a proof of concept —immunotherapy plus an HDAC inhibitor. Whichever one you pick, in this case, entinostat with pembrolizumab. I would say that if this is a successful combination. You could add entinostat to nivolumab and any other PD-1 or PD-L1 antibody, and not just in melanoma, in any disease. This trial is ongoing in other diseases because it's a proof of principle [of] if you can make that immune system effective again. We have this terminology, we say the tumor is cold and you want to make it hot to be recognized by the immune system. This would apply to any cancer, so I think this could really be something quite expansive down the road.

Reference:

Agarwala SS, Moschos SJ, Johnson ML, et al. Efficacy and safety of entinostat (ENT) and pembrolizumab (PEMBRO) in patients with melanoma progressing on or after a PD-1/L1 blocking antibody.J Clin Oncol. 2018;36(supp; abstr 9530).