Molecular Targeted Therapy or Immunotherapy Recommended as Initial Therapy in BRAF Mutation–Positive Melanoma

July 2016, Vol 7, No 6

Holding what was essentially a one-person debate, Michael B. Atkins, MD, Deputy Director of the Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC, described strong cases for immunotherapy or molecularly targeted therapy as initial treatment for patients with advanced BRAF mutation–positive melanoma.

The survival probability curves cross over at a little past 2 years; BRAF inhibition was superior initially, but ipilimumab maintained a higher survival plateau from there onward past 5 years, said Dr Atkins at the 2016 HemOnc Today Melanoma and Cutaneous Malignancies meeting.

Offering the case for frontline immunotherapy, Dr Atkins noted, “Immunotherapy produces treatment-free tumor responses, while BRAF inhibitors do not.” In addition, the 3-year overall survival (OS) rate with ipilimumab of 21% in a 2015 pooled analysis compares well with his own research finding of a high-dose interleukin-2 rate of 11% at >5 years, and a median OS with BRAF inhibition of approximately 26 months (median progression-free survival [PFS], approximately 10-13 months).

Although combined BRAF/MEK inhibition has produced the best outcomes in patients with normal lactate dehydrogenase (LDH), the benefit is strongest in patients with elevated LDH, a more advanced disease stage (M1c vs IIIc/M1a/M1b), and greater tumor burden (≥3 disease sites). Immunotherapy, however, works as well against BRAF V600 mutation–positive melanoma as it does against wild-type tumors.

In a previous poster, Mangana and colleagues reported a similar 1-year survival rate in patients receiving ipilimumab who were BRAF V600 mutation–positive or –negative; NRAS mutation status, as well, did not have a significant effect on survival. In the CheckMate 069 trial comparing nivolumab with or without ipilimumab, complete responses were reported in 22% of patients with the combination for BRAF wild type and BRAF mutation–positive patients (Postow MA, et al. N Engl J Med. 2015;372:2006-2017).

Dr Atkins also pointed out that although BRAF inhibitors work as well in patients who previously received immunotherapy, the converse is not supported by the evidence. In the 2011 BRIM2 trial, an objective response rate of approximately 53% with vemurafenib was observed regardless of previous interleukin-2 treatment. However, there were no tumor responses among 34 patients when single-agent immunotherapy with ipilimumab was given after MAPK inhibition, and the median OS was 5 months (all surviving patients at a year were again receiving MAPK inhibitors). “Patients progressing on BRAF inhibitors appear unlikely to respond to ipilimumab,” Dr Atkins said.

In a trial comparing ipilimumab and BRAF inhibitor sequencing, when ipi­limumab was given first, the median OS was 14.5 months compared with 9.9 months for BRAF inhibition followed by ipilimumab. The implication is that for many patients with BRAF V600E mutation–positive melanoma, starting with immunotherapy “offers a chance for long-term benefit without compromising benefit from subsequent BRAF inhibition,” Dr Atkins noted.

The immunotherapy-first strategy is further supported by data from the 2015 Keynote-006 trial, which showed superior 1-year OS with the PD-1 inhibitor pembrolizumab, with longer PFS and a nearly tripled overall response rate.

Combining ipilimumab with the PD-1 inhibitor nivolumab produced a median PFS of 11.5 months compared with 6.9 months for ipilimumab alone (Larkin J, et al. N Engl J Med. 2015;373:23-34). The grade 3/4 serious adverse event rate for the combination was 16% versus 55% with ipilimumab alone.

Although the overall antitumor activity appears similar between BRAF inhibitors and the newer immunotherapies, durability (3-year OS of 68% with nivolumab plus ipilimumab in the CheckMate 004 trial) is greater with the immunotherapies.

Even with all of this said for the immunotherapies, there is still a case for the use of molecularly targeted therapies, according to Dr Atkins. The BRAF/MEK inhibitor combination produces responses in a majority of patients, and, in the subgroup of patients with M1a/b disease, high response rates, median OS rates, and complete response rates are being observed. In patients with the BRAF V600 mutation and metastatic melanoma who were receiving dabrafenib combined with trametinib, the 3-year OS rates were 68% in patients with stage IIIc, M1a, or M1b disease and 62% in patients with normal LDH (Long GV, et al. J Clin Oncol. 2016;34:871-878) and fewer disease sites.

When resistance to BRAF/MEK inhibitor therapy does arise, responses are being observed with PD-1 pathway blockers. Because toxicity with a BRAF/MEK inhibitor may be worse after immunotherapy, initial therapy with this treatment is preferred.

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