Sequencing trial shows ‘interesting trend’ with ‘sandwich’ approach to melanoma treatment
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A “sandwich” approach to melanoma treatment consisting of immunotherapy between two targeted therapy courses showed a trend toward improved total PFS, according to study results presented at ESMO Virtual Congress 2020.
However, overall, this first report of safety and efficacy from the phase 2 SECOMBIT trial showed no significant PFS differences based on various sequences of targeted therapy and immune checkpoint blockade among a population of patients with untreated, BRAF V600-mutated metastatic melanoma.
“Targeted therapy and immunotherapy have revolutionized the treatment of metastatic melanoma,” Paolo Antonio Ascierto, MD, director of the unit of melanoma, cancer immunotherapy and innovative therapy at National Tumor Institute Fondazione G. Pascale in Naples, Italy, said during his presentation. “Today, thanks to these treatments, more than half of patients with metastatic melanoma can reach long-term benefits. However, there is no consensus about the right sequence of targeted therapy and immunotherapy; we only have retrospective data. At the moment, the treatment choice is driven more by patients’ characteristics than evidence from studies about the sequences.”
For this reason, Ascierto and colleagues analyzed data from 209 treatment-naive patients with BRAF V600-mutated metastatic melanoma randomly assigned to one of three treatment arms evaluating different sequences of treatment:
- Arm A: 450 mg encorafenib (Braftovi, Array Biopharma/Pfizer Oncology) plus 45 mg binimetinib (Mektovi, Array Biopharma/Pfizer Oncology) until disease progression, followed by 3 mg/kg ipilimumab (Yervoy, Bristol Myers Squibb) plus 1 mg/kg nivolumab (Opdivo, Bristol Myers Squibb) until disease progression (n = 69);
- Arm B: ipilimumab plus nivolumab until disease progression, followed by encorafenib plus binimetinib until disease progression (n = 71); or
- Arm C: encorafenib plus binimetinib for 8 weeks, followed by ipilimumab plus nivolumab until disease progression, followed by encorafenib plus binimetinib until disease progression (n = 69).
“Arm C is the so-called ‘sandwich’ arm, meaning that immunotherapy is given between two courses of targeted therapy,” Ascierto said. “The concept of this arm is to start the action with targeted therapy with encorafenib plus binimetinib for 8 weeks to reach a response and then switch to ipilimumab plus nivolumab prior to progression, followed by treatment again with encorafenib plus binimetinib.”
In terms of baseline characteristics, Ascierto noted that arm B enrolled fewer men (47.9%) than arms A and C (60.9% for both). Also, arm B had a greater proportion of patients with lactate dehydrogenase (LDH) one or more times the upper limit of normal than arms A and C (47.9% vs. 40.6% vs. 36.2%), as well as more patients with three or more lesion sites (40.9% vs. 36.2% vs. 36.2%).
OS served as the study’s primary endpoint. Secondary endpoints included PFS; total PFS, defined as time from randomization until the date of second progression; time to second progression; percentage of patients alive at 2 and 3 years; best overall response rate and duration of response.
Median follow-up was 17.5 months (interquartile range, 10.2-23.4).
Median PFS was 15.8 months (95% CI, 9.5-22.2) in arm A, which is consistent with data from the COLUMBUS trial, Ascierto said, and 11.4 months (95% CI, 7.2-15.5) in arm C. In arm B, median PFS was 7.2 months (95% CI, 3.2-11.3), which is lower than that of CheckMate 067, likely due to the number of patients with elevated LDH in that arm, he added.
At 2 years, 35% (95% CI, 21-49) of patients achieved PFS in arm A, compared with 38% (95% CI, 26-50) in arm B and 39% (95% CI, 27-51) in arm C.
Best overall response rates were 82.6% (95% CI, 73.7-91.6) in arm A, 45.1% (95% CI, 33.5-53.6) in arm B and 78.3% (95% CI, 68.5-88) in arm C. Median duration of response was not reached in arm B, showing more durable response in that group, and 17.8 months in arm A and 9.8 months in arm C.
Safety data appeared comparable with previous trials of these combinations.
A preliminary report of total PFS — which can serve as a surrogate for survival — showed an “interesting trend” for arm C, with a 2-year rate of 62% (95% CI, 50-74), compared with 48% (95% CI, 33-63) in arm A and 58% (95% CI, 45-71) in arm B, Ascierto said.
“However, the number of patients was low,” he said. “This is just a preliminary report; over the next year, we will see more mature data. In the second half of 2021 we will report additional data about total PFS and the first report of OS. It’s also important to keep in mind that there are ongoing biomarker studies which will give us additional information about responders and mechanisms of resistance.”
Perspective
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Bartosz Chmielowski, MD, PhD
The results of this trial are quite preliminary based on very short follow-up for this patient population. But, the responses were consistent with previously published data. As expected, PFS at 12 months was better for patients who started on targeted therapy, but this difference disappeared at 24 months.
Very interesting initial results are those for PFS after both therapies. It appears that patients who were treated with the sandwich approach had the best PFS, but the follow-up is very short and the number of patients is low.
We cannot interpret the results of this clinical trial without looking at its statistical design. The primary endpoint was OS. At the time the trial was designed, there were no long-term follow-up results of treatment with immunotherapy or targeted therapy. The null hypothesis was median OS of 15 months and the alternative hypothesis was 23 months. Now we know median OS after nivolumab-ipilimumab is more than 60 months, and after encorafenib-binimetinib it is more than 33 months. This tells us that any results of this trial will have to be interpreted with caution, and unless the differences are very large between the arms of the trial, they may not be statistically significant.
This is not the only trial addressing this question. DREAMseq, a trial by ECOG and SWOG Cancer Research Network, has a clinical trial of patients who are first randomly assigned to immunotherapy followed by targeted therapy, or targeted therapy followed by immunotherapy. Results of this trial will provide us with additional information to understand how we should sequence treatments in BRAF-mutated melanoma.
Jonsson Comprehensive Cancer Center
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Ascierto PA, et al. Abstract LBA45. Presented at: European Society for Medical Oncology Virtual Congress 2020; Sept. 19-21, 2020.
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