BRAF/MEK inhibitor therapy a preferred option for metastatic melanoma
NEW YORK — Combination therapy with BRAF and MEK inhibitors can confer long-term survival for patients with low-burden metastatic melanoma and should be a preferred treatment option, according to a presenter at HemOnc Today New York.
Patients with BRAF V600 mutant metastatic melanoma can be treated with targeted therapy or immune checkpoint therapy.
However, clinicians do not have clear direction regarding the superior treatment option, Keith T. Flaherty, MD, director of clinical research at Massachusetts General Hospital Cancer Center and professor of medicine at Harvard Medical School, said during his presentation.
“This is the only population that we have an anguishing, hand-wringing opportunity in the metastatic setting,” Flaherty said. “In this setting, we’re stuck looking at this clinical trial data and drawing comparisons.”
In a meta-analysis — which could not account for all confounding factors and different inclusion criteria — BRAF/MEK inhibitor combination therapy appeared superior during the first year; however, PD-1 inhibitor therapy appeared superior in the longer term, compared with chemotherapy, BRAF inhibitor monotherapy, CTLA-4 inhibitors and PD-1 inhibitors.
Another study showed patients with melanoma treated with frontline BRAF/MEK inhibitors dabrafenib (Tafinlar, Novartis) and trametinib (Mekinist, Novartis) achieved median PFS of 11.1 months (95% CI, 9.5-12.9) and median OS of 26.2 months (95% CI, 9-32).
“If you have a patient who walks in the door with high disease burden and symptomatic disease, where you’re worried that [they] are one step away from hospice or even fatality, the idea that you can most confidently pull them away from that state comes from BRAF/MEK therapy,” Flaherty said.
Some clinical factors may help predict treatment response, Flaherty said.
Normal lactate dehydrogenase (LDH) has been observed as a strong predictor of PFS. Disease burden — as measured by organ sites or size of target lesions — also appeared associated with PFS.
“If you pull out this subpopulation of [patients with] normal LDH and just two organs or one organ involved with disease, that is a large majority of those patients who do well at 3 years and beyond,” Flaherty said. “And if you start off with adverse features, like two times normal LDH, you are basically precluded from having lasting benefit. [Although this is] not a surprise, it is important because the goals of therapy discussion with patients have to take this into account.”
Discrimination between hot and cold tumors may be another factor that can predict treatment response; however, this delineation is not easily determined in the clinic with the existing tests.
“The notion of hot vs. cold may not be satisfactorily addressed with just PD-L1 as a biomarker. I think we can all acknowledge that,” Flaherty said. “But I also think we’re not very far from adding a couple more analytes to come up with a pretty good discrimination between definitions of hot vs. cold, prior to the start of therapy, where you’re using that information to help inform therapy selection for patients with this BRAF mutation.”
Additionally, on-therapy experience has become “critically important” to determine which patients will have deep and durable responses to therapy, Flaherty said.
Data show patients who do well at 3 years and beyond are those who had a complete response.
Patients who achieved a near complete response had similar PFS and OS outcomes as those who achieved complete remission. One study of vemurafenib (Zelboraf, Genentech) in combination with cobimetinib (Cotellic, Genentech) showed comparable results between patients who achieved compete response and those in the first quartile of tumor reduction (91.7% to 100%).
“Deep responses, whether they’re complete or near complete, seem to identify nearly all of the patients who derive long-term benefit,” Flaherty said.
These data are not beneficial for clinicians to break the tie for which treatment to use in this population, Flaherty said. However, it may provide clinicians with data about which patients to be most concerned about after the first few months of therapy.
“If you’re monitoring patients and you’re wondering who should I worry about in the years to come versus who are the ones [of whom] I should be more reassured? It’s the complete-remission patients who are, by far, in a better state of affairs, although they’re not perfect.”
Molecular features and tumor mutational burden may soon be able to inform therapy selection, but the tests and data are not at a class 1 level of evidence yet, according to Flaherty.
Immunotherapy and combination therapy
Among patients who receive immune checkpoint inhibitors, elevated serum LDH and greater disease burden appear associated with worse outcomes than more favorable disease profiles, regardless of which immunotherapy strategy is used.
Combination targeted therapy and immunotherapy have appeared associated with more toxicities than either therapy alone, Flaherty said.
“My great concern as we look at early outcome data for BRAF/MEK/PD-1 is that these types of regimens are not going to address those patients who are predicted to be refractory to either therapy,” he said. “What we can hope for is that the combination of these therapies for those who are predicted to benefit from either one are the ones who could get deeper and more durable responses.”
Treatment gaps still exist for patients with metastatic melanoma, despite the availability of novel targeted and immunotherapy agents.
“We really need an entirely new classification of therapies, or maybe multiple new classes of therapies, that might address the immunotherapy side,” Flaherty said. “But we need to poison this subpopulation of cells that appears to be emerging as a dual-resistant population that are nonsensitive to any of the therapies that we have currently available.” – by Cassie Homer
Flaherty KT. How I treat metastatic melanoma in my clinic: Immunotherapy, targeted therapy or both? Presented at: HemOnc Today New York; March 8-10, 2018; New York.
Disclosures: Flaherty reports consultant or advisory roles with Adaptimmune, Aeglea, Amgen, Array BioPharma, Asana, Bristol-Myers Squibb, Genentech, Incyte, Merck, Novartis, Takeda and Viralytics.