Targeted induction before immunotherapy shows limited benefit in advanced melanoma
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Key takeaways:
- Encorafenib plus binimetinib induction did not confer a PFS benefit in advanced melanoma.
- Patients with high lactate dehydrogenase or liver metastases may benefit from induction therapy with targeted agents.
CHICAGO — Sequencing encorafenib plus binimetinib with nivolumab and ipilimumab did not delay disease progression in adults with advanced BRAF-mutated melanoma, results from a randomized phase 2 trial showed.
However, findings presented at ASCO Annual Meeting suggest that individuals with elevated lactate dehydrogenase or liver metastases may benefit from the treatment regimen.
“These are, most of the time, the patients for whom we are giving a targeted therapy first line,” Caroline Robert, MD, PhD, head of dermatology at Gustave Roussy Cancer Campus and co-director of the melanoma research unit at INSERM 981 Paris-Sud University, said during a presentation.
Background and methodology
Multiple treatments exist for patients with advanced BRAF V600E or V600K melanoma, including various immunotherapies or targeted therapy with BRAF plus MEK in inhibitors, according to background information Robert presented.
“The optimal sequence of treatments is immunotherapy first (ipilimumab plus nivolumab) followed by targeted therapy when treatments are given until progression,” Robert said. “The benefit of induction treatment with targeted therapy followed by immunotherapy without waiting for progression is still unclear.”
EBIN, an international trial, compared treatment results of nivolumab (Opdivo, Bristol Myers Squibb) and ipilimumab (Yervoy, Bristol Myers Squibb) against encorafenib (Braftovi, Pfizer) plus binimetinib (Mektovi, Pfizer) then the nivolumab and ipilimumab regimen.
Eligible patients had to have unresected or metastatic BRAF V600E- or BRAF V600K-positive stage III/stage IV melanoma. Researchers included individuals who had adjuvant treatment at least 6 months prior to randomization, but no previous therapies for advanced melanoma.
Robert and colleagues also excluded patients with uveal melanoma, or untreated or symptomatic brain or leptomeningeal involvement.
Researchers randomly assigned 271 patients in a 1:1 ratio to the nivolumab plus ipilimumab control arm or the investigative arm regimen of encorafenib plus binimetinib followed by nivolumab and ipilimumab.
Of the participants assigned to treatment arms, most had stage M1c melanoma (59% in investigative arm; 60% in control) and lactate dehydrogenase below the upper limit normal (52% in investigative arm; 53% in control).
In the encorafenib plus binimetinib arm, 30% of individuals had liver metastases compared with 24% in the control group.
Results and next steps
At a median follow-up of 21 months, researchers did not observe a PFS difference between the two treatment arms (HR = 0.87; 90% CI, 0.67-1.12).
Patients with the highest lactate dehydrogenase levels did benefit from the encorafenib plus binimetinib treatment (HR = 0.46; 95% CI, 0.21-1.03), however, as did those with liver metastases (HR = 0.49; 95% CI, 0.29-0.84).
Participants with at least three metastatic disease sites did not derive a PFS benefit from the investigative regimen.
The induction group had fewer patients progress without new metastases than the control group (18 vs. 33), but had more develop new CNS metastases (34 vs. 11).
In the encorafenib plus binimetinib cohort, 53% of participants had an objective response to therapy vs. 45% in the control arm. Researchers also reported similar complete response rates of 12% in the investigative arm vs. 10% in the control group.
More patients in the encorafenib plus binimetinib group had grade 3 or worse adverse events (43% vs. 32%). However, the researchers anticipated these toxicities.
“We were expecting to see two waves of adverse events, one related to the targeted agents, and one related to the immunotherapy,” Robert said. “What is reassuring [is] that the waves are not higher,” she added “We don’t seem to have much more amplitude of toxicity with this combination, with this sequence.”
Researchers could not derive any significance from OS data, but they are continuing analysis.
Sunandana Chandra, MD, MS, associate professor in the division of hematology and oncology at Robert H. Lurie Comprehensive Cancer Center at Northwestern University, said the EBIN trial had efficacy similarities to two other sequencing trials, SECOMBIT and DREAMseq, although she cautioned the cross-trial comparison during her discussion.
“I think these studies show quite clearly although our patients do seem to benefit significantly when we start them on combination immunotherapy, but there is a subset of patients for whom immunotherapy may not be possible or reasonable at the outset,” Chandra said. “They may not tolerate it, and for them, this induction-targeted therapy approach may be quite reasonable to consider.”
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Robert C, et al. Abstract LBA9503. Presented at: ASCO Annual Meeting 2024; May 31-June 4, 2024: Chicago.
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