Combination Therapies Continue to Advance in Melanoma

Anna C. Pavlick, DO

Both targeted therapy and immunotherapy regimens, as combinations, have shown significant benefit in the treatment of melanoma.

Combination treatment with the BRAF inhibitor vemurafenib (Zelboraf) and the MEK inhibitor cobimetinib showed promise in patients with BRAF^V600-positive advanced melanoma in both the BRIM7 and coBRIM studies.

Follow-up data for BRIM7 presented at the 2015 ASCO Annual Meeting continued to show a response rate of 87% in patients who had not previously received a BRAF inhibitor; however, investigators reported 4 additional complete responses (CRs), raising the CR rate from 10% (n = 6) to 16% (n = 10). Median progression-free survival (PFS) was unchanged at 13.8 months. With extended follow-up, median overall survival (OS) was reached at 28.5 months and 2-year OS was 61%. Despite these additional benefits after extended follow-up, the adverse event frequency and severity remained stable.

Updated results were also presented at ASCO for the phase III coBRIM study, showing a median PFS with the vemurafenib/cobimetinib combination of 12.25 months versus 7.20 months with vemurafenib plus placebo (HR = 0.58; 95% CI, 0.46-0.72). The overall response rate (ORR) was 69.6% versus 50%, respectively. Based on the coBRIM results, the FDA is currently reviewing an application for cobimetinib/vemurafenib for patients with BRAF^V600-positive advanced melanoma, with a decision deadline of November 11, 2015.

The frontline checkpoint combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) has also shown promise for patients with advanced melanoma. In data from the phase II CheckMate-069 trial presented at ASCO 2015, ORR was 60% with the combination compared with 11% with ipilimumab alone in patients with BRAF—wild-type disease (P <.0001). There were 12 CRs with nivolumab/ipilimumab versus none with single-agent ipilimumab. Median PFS was 8.9 versus 4.7 months, respectively (P = .0012). Similar ORR and PFS results were reported in the BRAF-positive subgroup.

Toxicities were increased with the checkpoint combination, with grade 3/4 adverse events of 51% versus 20% in the control arm.

What were the goals of the extended follow-up study of BRIM7?

inhibitor cobimetinib. We knew the correct dose of vemurafenib, but we dose escalated the cobimetinib.

We also investigated scheduling. The outcome was that it was safe to administer vemurafenib at a full dose of 960 mg twice daily in combination with 60 mg daily, 21 days on with a 7-day drug-free break during every 28-cycle.

What do you think the impact of these findings will be for patients?

What questions still remain after this analysis?

Were there any concerning or new toxicities determined in this follow-up?

The CheckMate-069 study also examined a significant combination regimen for patients with previously untreated advanced melanoma. What are your thoughts on the impact of these findings?

The longer we followed these patients, the more complete responses we were able to see. The time to progression was also extended and the patients were alive for much longer than we had predicted. The toxicities were also very tolerable. The combination studies have clearly shown that the excitement we had about single-agent BRAF inhibitors was very much quelled when saw all these patients starting to progress after 9 months. However, we are more confident now that we are starting to understand that you can treat patients with combination therapy if they have very aggressive disease; immunotherapy might not be the right choice for them. There is a clear subset of patients who are going to go on and have durable responses from inhibitor therapy, without ever having to receive immunotherapy. The phase III study of vemurafenib and cobimetinib [coBRIM] has already been published. Our follow-up analysis confirms the data from almost 7 years ago. However, a few questions remain to be answered. How do we identify the patients that will be the complete responders? How do we better integrate immunotherapy into the inhibitor platform, so that we can give the patients who progress the ability to have longer responses? Toxicities were what we expected for the most part. We actually had fewer toxicities than we predicted. We were very nervous about giving two different targeted therapies at that point, because we did not know what the overlapping toxicity might cause. Our biggest concern was rash, as there were a significant amount of rashes with vemurafenib as well as with cobimetinib. However, the level of rash was actually very tolerable. Interestingly, the combination did not diminish the photosensitivity side effect we had with vemurafenib. However, it did decrease the rate of invasive squamous cell skin cancers that patients might develop. Clearly, we have taken a huge stride in combining two immunotherapies. Ipilimumab has a more dynamic toxicity profile than nivolumab, and so we had to tread lightly when we combined the two to make sure we could administer them safely. We found out we can give them safely if we adjust the dose of nivolumab when we combine it with ipilimumab.

Even with this adjustment, we still ran into challenges with managing toxicities. Giving the two drugs together gave at least 50%-60% toxicities that we needed to manage. Most of those toxicities did not preclude us from continuing therapy; however, there were a good number of patients who did need to come off the study right in the beginning of the trial because of toxicity.

What were the most common toxicities found in this trial?

What role do you believe this combination will have in the future?

The interesting thing about that is, even when patients were never able to get any more combination therapy due to toxicities, many still went on to have strong, durable responses. Because of this, many of us feel very comfortable stating that, if a patient has a toxicity that causes them to discontinue treatment, they may still go on to have a durable response if they received at least 50% of the combination regimen before discontinuing. Toxicities include rash, itching, and diarrhea. What we were not expecting to see that we did was an early unset of endocrinopathies, which normally occur with ipilimumab 16 to 20 weeks after starting therapy. In the combination, the endocrinopathies occurred much earlier, at about 6 to 8 weeks after starting therapy. When using these treatments together, we now know to be prepared for that. Although the response rate was clearly outstanding, this should not become the standard of care for everyone due to the toxicities. The toxicities can be serious, and they need to be managed promptly and effectively so that patients do not end up in the hospital. Deciding who gets this treatment is really where the art of medicine is going to come into play. Doctors need to look at the patients’ comorbidities, their overall performance status, and the bulk of their disease, and decide if they will be able to withstand the toxicities. The benefit is there, but doctors really need to select the right patients and have the right staff in place to handle this combination.

OncLive sat down with Anna Pavlick, DO, associate professor, Department of Medicine, Ronald O. Perelman Department of Dermatology, assistant director for Clinical Research Education, and co-director of the Melanoma Program at NYU Langone Medical Center, to discuss the future outlook of combination therapies in advanced melanoma and the challenges oncologists should consider regarding them moving forward.Dr Pavlick: We looked at the 2-year OS of patients who participated in the BRIM7 study. The BRIM7 study examined vemurafenib, which is a BRAF inhibitor, in combination with the MEK