NEW YORK — The optimal sequence of immunotherapy and BRAF/MEK inhibition for the first-line treatment of melanoma has only been evaluated retrospectively and remains to be defined, according to a presenter at HemOnc Today Melanoma and Cutaneous Malignancies.
“This is a difficult topic. We started with immunotherapy and chemotherapy, and we now have multiple drugs developed in the last 10 years,” Igor Puzanov, MD, MSCI, FACP, director of the early-phase clinical trials program and chief of the melanoma section at Roswell Park Cancer Institute, said during his presentation.
When determining frontline treatment, decision-making factors include mutational status, performance status, high vs. low tumor load, progression pattern, the presence of brain metastases, and the available of approved agents or clinical trials, Puzanov said.
BRAF is present in 8% of all cancers, but 50% of melanomas. Dual BRAF/MEK inhibition is associated with high response rates and a median PFS of 9 to 12 months.
“However, there is a problem of heterogeneity,” Puzanov said. “Heterogeneity is going to hinder us, and we have to change how we think about cancer. It’s not just between patients, but it’s also between sites of disease within one patient, and also within one tumor after repeated biopsies.”
Resistance occurs to BRAF/MEK inhibition due to reactivation of MEK kinase pathways 60% of the time or other pathways 40% of the time.
Further, fifty percent of patients who progress per RESIST criteria on a BRAF/MEK combination will have “empty” tumors, meaning that if you “use targeted therapy until the bitter end, you are probably not going to be able to salvage those patients,” Puzanov said. “The problem is, when are you going to switch them?”
Currently, researchers believe that using a BRAF inhibitor alone or with a MEK inhibitor first will lead to rapid and clinically significant responses, whereas using immunotherapy first yields less frequent objective responses that are more durable, and the combination of the two may lead to durable response and prolonged survival.
Only retrospective data are available to look at the sequence of BRAF inhibitors and immunotherapy.
A study by Ackerman and colleagues showed that BRAF–targeted therapy was useful after ipilimumab (Yervoy, Bristol-Myers Squibb), but ipilimumab is not useful after BRAF–targeted therapy.
“We don’t know if that was because of selection, or if there is a mechanistic reason for that,” Puzanov said.
Another study by Ascierto and colleagues showed longer OS in patients treated with ipilimumab first than in patients treated with BRAF inhibitors first.
Puzanov and colleagues retrospectively collected data from four cancer centers of 114 patients who were treated with BRAF or BRAF/MEK inhibition first and immunotherapy after progression, or the opposite sequence. Immunotherapy treatment usually consisted of a single-agent PD-1 inhibitor.
The groups were not completely balanced, because usually patients are selected for immunotherapy or targeted therapy first based on a variety of clinical factors that may predict which therapy they’re more likely to benefit from, Puzanov said.
OS with either strategy appeared similar. But, when looking at individual groups, patients who received BRAF inhibition after PD-1/PD-L1 therapy, especially those who progressed quickly, did poorly.
“Something happens in those patients who do not respond to the immunotherapy, so that you cannot salvage them with BRAF or BRAF/MET targeting,” Puzanov said. “On the other hand, patients who got the anti–PD-1 therapy and did well seemingly continue to do well. Patients who start with BRAF therapy and then switch to a PD-1 were in-between.”
Overall, the data suggest that BRAF inhibition as a salvage strategy may not be active in patients who fail on anti–PD-1 therapy.
“Frontline BRAF/MEK–inhibitor therapy should be considered for these patients,” Puzanov said. “The problem is you don’t know who they are until you see them at the end.”
Patients who benefited from BRAF–directed therapy for more than 6 months had an overall response rate of 34% to subsequent anti–PD-1 therapy.
“There could be a shared phenotype between those patients,” Puzanov said. “Perhaps BRAF/MEK inhibitors actually activate the immune system with the interferon gamma signature and PD-L1 expression that influences CD8 killer cells in the tumors.”
Conversely, patients who benefited for fewer than 6 months had a subsequent ORR of 15% (P = .04).
“This could also suggest a shared-response phenotype for BRAF inhibitors and PD-1,” Puzanov said. “We would like to know who those patients are, and more importantly, who the patients are who do dismally.”
Until better markers for selection are identified, it may be best to avoid large phase 3 trials and individualize approaches, Puzanov added. – by Alexandra Todak
Puzanov I. Targeted therapy and immunotherapy: What’s the correct sequence? Presented at: HemOnc Today Melanoma and Cutaneous Malignancies; March 24-25, 2017; New York.
Disclosure: Puzanov reports consultant roles with Amgen, Bristol-Myers Squibb and Hoffmann-La Roche, and clinical trial support from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Hoffmann-La Roche, Merck and Plexxikon.