Novel Triplet Emerges as a Promising Option in BRAF-Mutant Melanoma

Georgina V. Long, BSc, PhD, MBBS, FRACP

Combinations of PD-1 and BRAF and MEK inhibitors have become an area of significant research in BRAF V600­–mutant metastatic melanoma, said Georgina V. Long, BSc, PhD, MBBS, FRACP, who added that one such novel triplet is emerging as a promising option.

“As we know, BRAF and MEK inhibitors alone induce response or tumor shrinkage in more than 90% of patients,” said Long. “However, we are looking for longevity of that response. We thought that if we combine BRAF and MEK inhibitors with an immune therapy, we may be able to have a more durable response.”

During the 2020 ASCO Virtual Scientific Program, findings from parts 1 and 2 of the phase 3 COMBI-i trial showed marked clinical activity and potentially durable responses with the combination of the anti–PD-1 antibody spartalizumab, the BRAF inhibitor dabrafenib (Tafinlar), and the MEK inhibitor trametinib (Mekinist) in patients with unresectable or metastatic BRAF V600­–mutant melanoma.¹

The triplet elicited an overall response rate (ORR) of 78% with a complete response (CR) rate of 44% among 36 evaluable patients. At 24 months, the median progression-free survival (PFS) and overall survival (OS) rates were 41% and 74%, respectively.

Additionally, a biomarker analysis presented at the meeting revealed that immunosuppressive features such as high lactate dehydrogenase (LDH), neutrophil-lymphocyte ratio (NLR), and interleukin-8 (IL-8) may predict for poor prognosis in this patient population.²

In an interview with OncLive, Long, co-medical director of Melanoma Institute Australia (MIA), chair of Melanoma Medical Oncology and Translational Research at MIA and Royal North Shore Hospital, University of Sydney, discussed the safety profile of the triplet regimen, the clinical implications of the biomarker data observed from this trial, and other emerging combinations on the horizon.

OncLive: What was the rationale for combining these agents in a triplet regimen?

Long: The COMBI-i trial [evaluated] the combination of spartalizumab, dabrafenib, and trametinib. This was a phase 1/2 trial that went onto a phase 3 trial. The results we have so far are from the first part of the trial looking at the tolerability and activity of the triplet therapy.

When we use a BRAF and MEK inhibitor together, [patient biopsies] show this influx of T cells into the tumor within the first week of treatment. That got us thinking that we could perhaps leverage that and add in immunotherapy to induce prolonged, durable responses.

What did the results of the COMBI-i trial show?

The data that were presented during the 2020 ASCO Virtual Scientific Program—which had been previously presented—was an update in the first 36 patients. Nine of these patients were part of the run-in phase. These patients were included to see how tolerable the triplet regimen was. Then, 27 patients [were included] in the biomarker part of the study.

What we saw was an ORR of 78% and a CR rate of 44%. That was quite impressive. These [responses] seem to be durable if you look at the PFS. Again, it is only 36 patients, but the 1-year PFS rate in this group of patients was 67%, and 2-year PFS was 41%. This compares favorably with any set of drugs out there, but we do need to [confirm] this in a bigger patient population.

We have completed enrollment for the phase 3 trial of the triplet therapy versus the doublet of dabrafenib and trametinib.

The interesting thing is that when we looked at [the data from] COMBI-i, we found that the patients who had a normal LDH did particularly well. We see this across the board for all melanoma treatments. If you have normal baseline LDH, the 1-year PFS rate was 95% and the 2-year PFS rate was 46%; it’s very high.

This triplet has good activity in those patients with an elevated LDH. They are the most difficult patients to treat and they do poorly with most treatments. Therefore, for that group that had an elevated LDH, the 1-year PFS rate was 33%. We did lose a lot of patients to progression in that first year, but at 2 years, the PFS rate was 27%. Therefore, we saw durable response without progression in that group of patients as well.

Biomarker [data] were also presented at the 2020 ASCO Virtual Scientific Program in this group of patients. The biomarker cohort [enrolled] 27 patients and showed that those who had an elevated NLR had a [shorter] PFS. However, those who had a low baseline IL-8—a cytokine that tells you about the inflammatory state of the patient—had prolonged PFS and a higher likelihood of CR.

What does the safety profile of this regimen look like?

The toxicities were manageable. We did not see any new toxicities over and above what we see with dabrafenib/trametinib alone or with what we see with anti–PD-1 alone, but we saw a high frequency of toxicities. Therefore, 72% of patients did have a grade 3 or higher toxicity, and 94% of patients had to interrupt their treatment because of toxicities.

However, these were all manageable. The most frequent toxicity was pyrexia, which we see with dabrafenib and trametinib alone. In this study, we saw it more frequently in 86% of patients. That was over and above the [second] most common toxicity, but it was managed by decreasing dabrafenib/trametinib temporarily. There was a higher level of toxicities [with the triplet], but they were all toxicities that we are familiar with and that we were able to manage.

What is your take-home message for your colleagues regarding this trial?

These are early days as [the data set only included] 36 patients. [It’ll be important to] watch this space. We do know that other triplet combinations of anti–PD-L1 inhibitors plus BRAF and MEK inhibitors [are being evaluated]. We have seen that with the KEYNOTE-022 trial of pembrolizumab (Keytruda) combined with dabrafenib and trametinib and the IMspire150 trial of vemurafenib (Zelboraf), cobimetinib (Cotellic), and atezolizumab (Tecentriq).

[The latter] showed, in a phase 3 trial, that PFS was prolonged versus vemurafenib and cobimetinib alone. We need to watch those trials to see what the long-term data show because the real question will be, “How does this triplet therapy compare with combination immunotherapy such as nivolumab (Opdivo) and ipilimumab (Yervoy), for example?” That question has not been answered yet.

There may be a subset of patients where triplet therapy is useful, but we have yet to define that. We need longer-term data.

What other melanoma abstracts that were presented at the 2020 ASCO Virtual Scientific Program were exciting to hear about?

A couple of highlights were presented during the Virtual Scientific Program. We saw 5-year adjuvant data from the COMBI-AD trial. It was great to see that the benefit in relapse-free survival (RFS) with dabrafenib combined with trametinib versus placebo persisted out to 5 years. The hazard ratio was 0.5, translating to a 50% reduction in the risk of recurrence with adjuvant dabrafenib/trametinib in stage III resected melanoma. The landmark 5-year RFS rate was 52% for dabrafenib/trametinib and 36% for placebo. That is a persistent benefit.

We also saw 3-year data with adjuvant pembrolizumab (Keytruda) in the same patient population. This trial is a little behind COMBI-AD, but the 3-year RFS rate was 64% with pembrolizumab and 44% with placebo. Now, that placebo arm is doing well compared with what we saw [from the placebo arm] in the COMBI-AD trial. The reason for that is when you look at the BRAF-mutant subpopulation of patients within the adjuvant pembrolizumab trial, you can see that the placebo arm is very similar to COMBI-AD. When BRAF-mutant patients are diagnosed with stage III melanoma, they have a higher chance of recurring than BRAF wild-type patients. That is why the placebo arms look a little different. Interestingly, the effect of pembrolizumab at 3 years was exactly the same for BRAF wild-type and BRAF-mutant patients.

There were also some data on autologous [tumor]-infiltrating lymphocytes. They are a work in progress, which is great.

Also, there was a large retrospective study of ipilimumab alone or in combination with an anti–PD-1 inhibitor for patients who progress on anti–PD-1 therapy. The take-home message from that trial was that it looks like the combination of ipilimumab plus a PD-1 inhibitor may be better and more efficient at inducing responses compared with ipilimumab alone in the setting of PD-1 progressors. Again, it was a retrospective trial, so there are some biases within that analysis.

There were also some updated data with encorafenib (Braftovi) and binimetinib (Mektovi), as well as some interesting data in mucosal melanoma with VEGF inhibition. We’ll have to watch these areas as the data mature.

References:

1. Long GV, Lebbe C, Atkinson V, et al. The anti–PD-1 antibody spartalizumab in combination with dabrafenib and trametinib in advanced BRAF V600–mutant melanoma: efficacy and safety findings from parts 1 and 2 of the phase III COMBI-i trial. J Clin Oncol. 2020;38(suppl 15):10028. doi:10.1200/JCO.2020.38.15_suppl.10028

2. Dummer R. Biette K, Gusenleitner D, et al. Effect of first-line spartalizumab + dabrafenib + trametinib on immunosuppressive features detected in peripheral blood and clinical outcome in patients (pts) with advanced BRAF V600–mutant melanoma. J Clin Oncol. 2020;38(suppl 15):10034. doi:10.1200/JCO.2020.38.15_suppl.10034