Michael Atkins, MD
In the fast-moving world of melanoma treatment, new therapeutic options for patients with metastatic disease are emerging faster than oncology researchers can establish guidelines for their optimal clinical use. In less than 2 months last year, the FDA approved five new or expanded indications for drugs. As it stands now, the National Comprehensive Cancer Network (NCCN) has identified seven single or combination therapies for first-line treatment of metastatic or unresectable disease including three checkpoint immunotherapy agents and four targeted therapies (Table)
Notably, single-agent ipilimumab (Yervoy), the CTLA-4–targeting antibody that launched the checkpoint therapy era, is now considered a second- line choice for metastatic or unresectable disease in the NCCN recommendations.1
(High-dose, single-agent ipilimumab is recommended in the adjuvant setting. Another novel therapy, talimogene laherparepvec [TVEC; Imlygic] is recommended as primary treatment for stage 3 in-transit disease and in certain unresectable disease settings).
Until recently, the choice of first-line therapy in the metastatic setting would have turned on whether the patient had a BRAF
mutation, a population that includes 37% to 50% of malignant melanomas, according to My Cancer Genome.2
Patients whose tumors harbor a BRAF
V600 or V600K mutation would most likely be recommended for therapy with a regimen including a BRAF inhibitor.
Now, however, nivolumab (Opdivo) and pembrolizumab (Keytruda), both PD-1–targeting immunotherapies, are approved for first-line treatment for patients with metastatic disease even for those with BRAF
mutations. Although this bounty of choices is good news for patients with melanoma, several key questions have emerged: Should immunotherapy or targeted agents be the first-line choice for metastatic melanoma? And, does it make a difference how these agents are sequenced?
Those questions were discussed in detail recently at the 12th Annual International Symposium on Melanoma and Other Cutaneous Malignancies ® that Physicians’ Education Resource (PER®) hosted in Miami Beach, Florida, on February 20, 2016.
Indeed, the issue was the focus of a special Medical Crossfire® session in which two of the world’s leading experts on melanoma therapy, Michael B. Atkins, MD, deputy director of the Georgetown-Lombardi Comprehensive Cancer Center, and Jeffrey S. Weber, MD, PhD, deputy director of NYU Langone’s Laura and Isaac Perlmutter Cancer Center, tackled the question in a debate-style format.
Despite making strong arguments for each viewpoint, both presenters and other leading researchers at the conference noted that questions about first-line systemic therapy for metastatic melanoma have not yet been fully resolved in clinical studies or by oncology experts. The NCCN is in the process of updating its guidelines—even though they were last revised in November 2015—and the Society for Immunotherapy of Cancer, which published the first consensus statement on the use of the emerging therapies in 2013, also is working on a new version.
The Case for Immunotherapy
Atkins, who helped pioneer the development of interleukin and interferon in melanoma treatment starting more than 20 years ago, argued that immunotherapy is the better choice for first-line treatment because of several factors.
He said immunotherapy produces durable, treatment-free responses while patients must continue to take BRAF inhibitors, and that clinical trials have demonstrated the checkpoint-targeting agents work as well against BRAF
-mutant tumors as they do against wild-type disease.
“I think immunotherapy accomplishes what the patients want, which is that it produces complete responses where you can stop the treatment and the response is maintained—so treatment-free survival,” Atkins said in an interview. “You don’t see that with the targeted therapies except in a rare patient population.”
As far as sequencing is concerned, Atkins said the use of immunotherapy followed by targeted therapy if needed offers the potential for “two shots on goal.” He cited a retrospective study that found prior treatment with ipilimumab did not negatively influence response to BRAF inhibition (which included single-agent and combination BRAF/MEK regimens) but that outcomes with ipilimumab therapy following targeted therapy were poor.3