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.
“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
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.
Duration of Therapy
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.