Considerations for Single-Agent Versus Combo Melanoma Immunotherapy

Patrick Ott, MD, PhD

The combination of ipilimumab (Yervoy) and nivolumab (Opdivo) continues to show promise, with recent data demonstrating a 26% improvement in overall survival (OS) with the 2 drugs compared with ipilimumab alone for patients with advanced melanoma.

In a 2-year assessment of the phase II CheckMate-069 trial,¹which was recently presented at the 2016 AACR Annual Meeting, 142 treatment-naïve patients with unresectable stage III or metastatic stage IV melanoma were randomized to receive either the combination (n = 95) or ipilimumab plus placebo (n = 47) every 3 weeks for 4 doses followed by nivolumab or placebo every 2 weeks until disease progression or unacceptable toxicity.

In the overall treatment population, the 2-year OS rate was 64% with the combination compared with 54% for ipilimumab alone (HR, 0.74; 95% CI, 0.43-1.26). The median OS at 2 years in patients randomized to either the combination or monotherapy has not been reached.

The 2-year OS rate with nivolumab/ipilimumab was 69% compared with 53% for ipilimumab alone in patients withBRAFwild-type melanoma. The median OS among patients was not reached with the combination regimen and was 24.8 months with ipilimumab monotherapy (HR, 0.58; 95% CI, 0.31-1.08).

Previous findings from the CheckMate-067 study demonstrated a superior progression-free survival and overall response rate with the combination over the monotherapy.

The data make it clear that, for many patients, nivolumab/ipilimumab is the best option, says Patrick Ott, MD, PhD, clinical director, Melanoma Center, Center for Immuno-Oncology, physician, assistant professor of Medicine, Harvard Medical School, Dana-Farber Cancer Institute.

“I feel very strongly that the combination is the way to go,” Ott says. “The data says it all. Due to the potential durability with the combination, I think it is hard to argue that we could just start out with PD-1 monotherapy.”

Despite its benefits, there are still many questions that remain regarding the use of nivolumab/ipilimumab in advanced melanoma. In an interview withTargeted Oncology, Ott discusses toxicity management and patient selection considerations required with the combination, and its role inBRAF-mutant melanoma.

TARGETED ONCOLOGY:How do you decide which patients should receive the combination therapy versus monotherapy? 

Ott:We really consider everybody for the combination. Patients who have high comorbidities may not be candidates for the combination, but we have had 80-year-old patients who have received it; they have had great outcomes.

Therefore, I wouldn’t say, “Don’t try it with older people.” We do have some patients who don’t want it, but that is relatively rare. We also enroll patients in clinical trials where other combinations are explored, and it is certainly very reasonable to try that approach.

TARGETED ONCOLOGY:How much of a factor are toxicities in determining whether patients should receive the combination?

Ott:The toxicities with nivolumab/ipilimumab are a big problem; however, it’s often worth it for patients. Patients have a 20% higher chance of having a durable response for metastatic melanoma. That may mean that they have to spend a few weeks in the hospital or go on steroids for a few months and be OK. For most patients, the 20% improvement in chance is worth that. If you talk to patients who went through it and had good outcomes, they certainly think it’s worth it.

TARGETED ONCOLOGY:What questions remain to be answered regarding the use of nivolumab/ipilimumab in melanoma?

There is primary resistance and some patients also develop resistance to immunotherapies. Increasing the response from 40% to 60% is really remarkable, but there are still 40% of patients who don’t respond in the first place.

Ott:There are also patients who progress on the nivolumab/ipilimumab combination, but those numbers are very low so far. There is a lot of work to do to assess why that is—in terms of studying the immune infiltrates and biopsies and doing a comprehensive immune analysis.

TARGETED ONCOLOGY:What other immunotherapy combinations have potential in melanoma?

Ott:There is the PD-1 and IDO inhibitor combination that has been fairly successful. Ipilimumab plus T-VEC is also being investigated. Data were presented 2 years ago on 16 or 17 patients that showed fairly provocative response rates with that combination. There is now a larger study with 200 patients.

There are other combinations of checkpoint inhibitors plus vaccines that are interesting.

TARGETED ONCOLOGY:What is the optimal approach for patients withBRAF-mutant melanoma?

Ott:We have a clinical trial where we first use a targeted agent for 1 month, and then we start with nivolumab/ipilimumab. They will get the targeted therapy again if they progress after nivolumab/ipilimumab. That is 1 sequential approach under consideration.

TARGETED ONCOLOGY:There is potential synergy between BRAF inhibition and immunotherapy. Hopefully, there will be higher durability of responses with this approach.

Ott:The question of what agent should be the frontline inBRAFmelanoma is being investigated in a large study; however, that study is currently on hold. It is a phase III study starting with immunotherapy or a BRAF-targeted agent. Then, it switches when the patient progresses.

Looking at the survival of those patients will hopefully answer this question. In the meantime, I think it is conceivable that, depending on how aggressive one is to start with immunotherapies, the majority of melanoma doctors start with immunotherapies now, unless there needs to be an immediate response.

Depending on what treatment you use—because the responses are very durable—some patients may never need it.

TARGETED ONCOLOGY:What can researchers in other cancer types learn from the use of immunotherapy in melanoma?

Ott:Melanoma is a trailblazer for other diseases in immunotherapy. It is leading the way in terms of where things are going. With the approval of nivolumab/ipilimumab in melanoma, similar combinations are being investigated in all types of cancers.

The toxicities are different in other tumors, and that has led to different dosing and scheduling of the combination in other cancers. I have a feeling that may even come back to melanoma where some other schedules prove to be much less toxic. If we can cut the toxicities with melanoma from 50% to 25%, it may actually be very worthwhile.

Postow MA, Chesney J, Pavlick AC, et al. Initial report of overall survival rates from a randomized phase II trial evaluating the combination of nivolumab (NIVO) and ipilimumab (IPI) in patients with advanced melanoma (MEL). Presented at: 2016 AACR Annual Meeting; April 16-20, 2016; New Orleans, LA. Abstract CT002.