Experts Grapple With Nuances of Navigating New Frontier in Melanoma

Keith T. Flaherty, MD

Emerging data showing improved survival with targeted and immunotherapeutic approaches are rapidly altering the standard of care for patients with melanoma. For BRAF-positive patients with metastatic or unresectable melanoma, the standard of care includes a BRAF inhibitor in combination with a MEK inhibitor. For patients with or without BRAF mutations, there are immunotherapeutic options available in frontline and in resistant disease settings.

Questions remain, however, in terms of how to optimally sequence and/or combine both targeted agents and immunotherapies. And, for BRAF-mutant disease, when is it appropriate to switch from a targeted approach to an immunotherapeutic one?

During a recent OncLive Peer Exchange, melanoma experts, led by moderator Keith T. Flaherty, MD, discussed the latest evidence in metastatic melanoma, and how they apply it to their practices in order to make these nuanced treatment decisions.

Immunotherapy in Advanced Melanoma

In December 2015, the PD-1 inhibitor pembrolizumab gained two new melanoma indications: one as a frontline treatment in patients with advanced melanoma, regardless of BRAF status; the other, as a treatment for patients refractory to the CTLA-4 inhibitor ipilimumab¹. The FDA also recently expanded its approval for the PD-1 immune checkpoint inhibitor nivolumab to include it as a frontline treatment for patients with BRAF wild-type advanced melanoma.²

Jeffrey S. Weber, MD, PhD, commented that the “tail of the curve” with ipilimumab, nivolumab, and pembrolizumab, shows there is a long-lasting treatment effect with these immunotherapies.

Sequencing

“If you get beyond 3 years in remission, partial, complete, or with stable disease, you’re probably going to stay there for a long time…I’ve been treating patients with ipilimumab for 14 years and I occasionally get an e-mail, or a letter, or a postcard from a patient I treated 13, 14 years ago when I was in Los Angeles, and they’re alive and doing well.” Weber said.In clinical practice, optimal sequencing with the anti-PD-1 and anti-CTLA-4 antibodies remains unclear. Despite initial approvals with both pembrolizumab and nivolumab as second- line therapies following ipilimumab treatment, there is evidence that PD-1 inhibition upfront may be a better approach. Jason J. Luke, MD, referred to CheckMate-064 data, presented at the 2015 European Cancer Congress meeting, showing a confirmed objective response rate (ORR) by modified RECIST criteria at week 25 of 41.2% in patients who received nivolumab followed by ipilimumab compared with 20.0% in patients receiving the 2 therapies in the opposite sequence.³

“I think there are pretty good data now that suggest that anti-PD-1 antibody, absent other particular caveats, really ought to be the frontline therapy,” Luke stated. “I have to say that my personal opinion right now is I prefer to use a single-agent anti-PD-1 antibody upfront because it’s robust, you get response rates, you get disease control, and you don’t have this massive increase in toxicity profile.”

Rene Gonzalez, MD, expressed a divergent viewpoint.

“I would quibble a little bit with that for two reasons,” he said. “One, is we have the really long tail with ipilimumab that nothing comes even close to, IL-2 maybe. But, the other thing is we don’t know how long to treat people with PD-1 [inhibitors]. One of the beauties of ipilimumab is you get your 4 doses, and you’re done.”

There appear to be higher response rates and more immediate disease control with the PD-1 inhibitors than with ipilimumab, said Flaherty.

Weber, who was a lead investigator on the CheckMate-064 trial, also supported using a PD-1 inhibitor prior to the CTLA-4 inhibitor. “They all got the same therapy. Very few patients dropped out,” added Weber. “The only difference was the sequence.”

Jeffery S. Weber, MD, PhD

Duration of Therapy

It is also important to consider who is most likely to benefit from its use. In a patient with bulky disease who has a high lactate dehydrogenase (LDH) level and is rapidly progressing, “I think we’d all agree, those patients are less likely to respond to anything, particularly ipilimumab,” said Weber.Another area of debate pertains to the duration of therapy with the PD-1 inhibitors. The FDA approvals did not specify a duration, leaving it open to interpretation. Flaherty asked the panelists whether they stop giving therapy in patients who are still responding.

Luke remarked that it is reasonable to consider stopping therapy if a patient is stable for more than 3 to 6 months, a follow-up PET scan shows no hypermetabolic activity, and a biopsy shows no residual tumor.

Combination Strategies

Weber said that he typically would not stop treatment with nivolumab or pembrolizumab until at least 12 months on therapy, but would not go beyond 2 years. For a patient, it can be viewed as a lifeline. “It’s a tough one, because put yourself in the patient’s shoes,” Weber remarked. “You’ve been getting this drug either every 2 weeks, or every 3 weeks in the case of pembrolizumab, for 2 years, and then somebody comes in the room and says, well, listen, I think you look great, it’s OK, you can stop.”Data from CheckMate-069, which showed a 60% reduction in the risk of progression or death with the combination of nivolumab and ipilimumab versus ipilimumab alone, led to the approval of the combination in patients with BRAF V600 wild-type unresectable or metastatic melanoma. With the combination, the ORR was 61% compared with 11% with ipilimumab alone. The ORR was independent of PD-L1 status.⁴

The combination was also associated with significantly higher rates of grade 3/4 adverse events, 54% with the doublet versus 24% with the monotherapy. An FDA decision is pending on a full approval for the combination in patients who are previously untreated, the application for which is based on the phase III CheckMate-067 trial.⁵

The PD-1/CTLA4 combination approach may be the right one in patients who need a rapid response, noted Luke, such as a younger patient who has brain metastases. However, in most patients, he is more comfortable using anti-PD-1 frontline monotherapy. Different patients have differing tolerances for the toxicities. Some prefer “the kitchen sink” approach, he said. “The question becomes, can we find patients where we don’t have to expose them to the toxicity? We don’t know how to answer it yet,” said Luke.

The toxicities with the combination are more frequent and more severe, added Gonzales. Weber pointed out that the very steep and immediate response makes the combination “a perfect therapy for a BRAF wild-type patient who has aggressive, high LDH bulk, rapidly growing disease, or even a BRAF-mutated patient.”

Are All Doses Needed?

Although the toxicities can be more intense, much of the reaction is biochemical, such as grade 3 hyperamylasemia with no symptoms, noted Weber. Grade 3/4 colitis or diarrhea can be very problematic, however.Given the known intensity of the toxicities with the combination, Flaherty asked the panel to share their thoughts regarding whether 4 induction doses of ipilimumab/nivolumab are necessary.

Jason J. Luke, MD

Luke commented that anyone who has toxicity that requires steroids should probably not receive more ipilimumab, but restarting anti-PD-1 therapy depends on the situation. The evidence suggests the responses last well past treatment. “Most of the side effects happen very quickly…a lot of [patients] came off very early from treatment, and yet they’re ongoing in response far later,” Luke said. “So, I don’t think that we need to push all these doses.”

Biomarkers

BRAF-Positive Melanoma

Weber pointed out that patients in the Check- Mate-064 trial who had toxicities with ipilimumab were able to continue with nivolumab. “I think you could have combination toxicity, much of which may well be the ipilimumab, stop, recover, and then go to the nivolumab maintenance,” Weber said.Weber explained that testing for PD-L1 expression is more helpful in some cancers than in others. For example, in nonsquamous non-small cell lung cancer, PD-L1 status is predictive, while in squamous disease it is not. In melanoma, PDL1 status can give an indication of who is more likely to respond. However, “as a marker to decide whom you shouldn’t treat, PD-L1 staining falls short, certainly in melanoma,” said Weber.In November, the FDA approved the BRAF/ MEK combination of vemurafenib/cobimetinib for patients with BRAF-positive metastatic or unresectable melanoma, based on the phase III coBRIM study. The study showed a median progression- free survival of 12.3 months with the combination versus 7.2 months for vemurafenib alone.⁶ Also in November, the FDA granted a full approval to the combination of dabrafenib and trametinib in patients with unresectable or metastatic BRAF-mutated melanoma after the combination demonstrated a nearly 8-month extension in overall survival when compared with vemurafenib in the COMBI-v trial and a more than 6-month overall survival compared with dabrafenib alone in the COMBI-d trial.^7,8 “All three of those studies were positive in the sense that it without a doubt showed that combination therapy is better than single-agent BRAF inhibitor,” said Gonzales. “They are the new standard of care in terms of targeted agents for melanoma.”

Switching Therapies

As a biomarker for melanoma, BRAF status is very predictive, noted Weber.Pembrolizumab and ipilimumab have indications that are independent of BRAF status. The approval of the nivolumab/ipilimumab combination is limited to BRAF wild-type disease. Weber pointed out that the evidence suggests “there is no difference in BRAF-mutated, BRAF wild-type patients in how well they respond to the combination.” A recent retrospective analysis by Larkin et al showed that nivolumab had similar efficacy and safety in both BRAF-mutant and BRAF wild-type disease. In addition, the efficacy and safety outcomes were similar regardless of prior BRAF inhibitor or ipilimumab treatment.⁹

Gonzales commented on the difficulty of knowing when to switch a patient from BRAF/MEK therapy to immunotherapy. “When I’ve started a BRAF/MEK combination on a patient and he’s had a great response, when do I switch him? Do I switch him to ipilimumab/PD-1 [inhibitor] combination…in the hopes of getting that durable remission?” Gonzales said.

Luke commented that he uses the BRAF/MEK inhibitor combination therapy as the backbone. “I know I can always go to it,” said Luke. “If patients come off of other things, we’re going to go back to it, get this back under control for a few months, and then we can think of what else can we try to do.”

Gonzales noted that the data with the combination of ipilimumab/nivolumab have prompted him to more often consider switching some patients to immunotherapy from the BRAF/MEK combination. “And I think my bar is falling as to when I do that because with BRAF/MEK combination, half the patients will die in about 2 years,” Gonzales said. “And so I’m not worried about the half that go beyond that, but it’s the front end of that curve that we might be able to impact better now rather than later.”

Rene Gonzalez, MD

“I think in the context of some of this data that we’re getting now that a sizable fraction of patients do very, very well for a long time on targeted therapy,” Luke stated. “I think we need to push back on that message that everyone needs to get on [an anti PD-1 therapy]. There are other drugs that are very effective.”

References

1. Broderick J. FDA approves two new indications for pembrolizumab in advanced melanoma. OncLive.com. http://goo.gl/7yv1wV. Published December 18, 2015. Accessed January 2, 2016.
2. Inman S. FDA approves frontline nivolumab for advanced melanoma. OncLive.com. http://goo.gl/0XltAI. Published November 24, 2015. Accessed January 2, 2016.
3. Hodi FS, Gibney G, Sullivan R, et al. An open-label, randomized, phase 2 study of nivolumab (NIVO) given sequentially with ipilimumab (IPI) in patients with advanced melanoma (CheckMate 064). Presented at: 2015 European Cancer Congress; September 25-29, 2015; Vienna, Austria. Abstract 23LBA.
4. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Eng J Med. 2015;372(21):2006-2017.
5. Bristol-Myers Squibb announces regulatory update for Opdivo (nivolumab) in advanced melanoma [press release]. Princeton, NJ: Bristol-Myers Squibb Company; November 27, 2015; http://goo.gl/z1LBnj. Accessed January 2, 2016.
6. Larkin JMG, Yan Y, McArthur GA, et al. Update of progression-free survival (PFS) and correlative biomarker analysis from coBRIM: phase III study of cobimetinib (cobi) plus vemurafenib (vem) in advanced BRAF-mutated melanoma. J Clin Oncol. 2015;33 (suppl; abstr 9006).
7. Robert C, Karaszewska B, Schachter J, et al. Two year estimate of overall survival in COMBI-v, a randomized, open-label, phase III study comparing the combination of dabrafenib (D) and trametinib (T) with vemurafenib (Vem) as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 3301.
8. Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386(9992):444-451.
9. Larkin J, Lao CD, Urba WJ, et al. Efficacy and safety of nivolumab in patients with BRAF V600 mutant and BRAF wild-type advanced melanoma: a pooled analysis of 4 clinical trials. JAMA Oncol. 2015;1(4):433-440.