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Melanoma Updates From ASCO 2023: PD-1 and LAG-3 [Video]

Skin Cancer

Melanoma Updates From ASCO 2023: PD-1 and LAG-3

Jeffrey S. Weber, MD, PhD, discusses updates related to melanoma practice and care from ASCO 2023.

This is Dr Jeffrey Weber. I’m a medical oncologist at the Laura and Isaac Perlmutter Cancer Center at New York University Langone Health in New York City. Today, I’d like to report to you about three abstracts presented at this year’s American Society of Clinical Oncology (ASCO) meeting in Chicago, which I think have significance and importance as they relate to melanoma practice and care.

The first one was a phase 1/2 trial of the new lymphocyte-activation gene 3 (LAG-3) antibody, fianlimab, with the established programmed cell death protein 1 (PD-1) antibody cemiplimab. This was an interesting study with an initial dose escalation with a rapid accrual of patients and two expansion cohorts, where 40 patients were treated in one cohort who could have been PD-1 experienced and another 40 patients were treated who could not have seen prior PD-1 or PD-1–cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) therapies. Finally, there was a third cohort of another 18 patients, for a total of 98, where patients could have seen PD-1 but had significant negative prognostic factors.

The amazing thing was that in this PD-1–LAG-3 trial, the response rates were fantastic. The response rates in the initial and in the second cohort, each of about 40 patients, were very high: 63% in both of those cohorts as evaluated by the investigators. You even had a 56% response rate in the PD-1–experienced cohort that had negative prognostic factors like liver metastases or prior brain metastases.

And there was a 13% rate of complete responses in the first two cohorts comprising 80 patients, which is not a trivial number.

The median progression-free survival (PFS) has not been reached. At 12 months of follow-up, it’s 52% PFS, and the projection is about a 14- or 15-month median PFS.

When you think about it, the LAG-3 antibody fianlimab with the PD-1 antibody cemiplimab had an impressive response rate and pretty impressive PFS in newly diagnosed melanoma patients.

If you look at the toxicity, the grade 3, 4, or 5 immune-related adverse events are only about 13%, which is not much more than you would expect with the PD-1 antibody alone; although interestingly, it looked like there were, relatively speaking, more endocrinopathies.

The cemiplimab plus fianlimab performed well in the poorer outcome patients within the smaller 18-patient cohort, including those who had high lactate dehydrogenase (LDH) or liver metastases, where PD-1 antibodies alone tend not to do very well.

Clearly, this combination has promise, and it’s now involved in a randomized phase 3 study vs either some cemiplimab or pembrolizumab alone. It’s also involved in an adjuvant study in stage III/IV resected patients who will receive the combination vs standard pembrolizumab.

We then heard an update on the KEYNOTE-716 trial. This is, again, a trial that led to the registration of pembrolizumab for resected stage IIB and IIC melanoma. This is a multicenter, randomized, double-blind, placebo-controlled, phase 3 study of over 950 patients who were randomly allocated one-to-one to receive either pembrolizumab for 17 cycles over 1 year at the standard dose of 200 mg every 3 weeks intravenously or a placebo for the same number of cycles. In this trial, if you recurred, you could get a guarantee of going back on pembrolizumab, especially if you were on the placebo arm.

The updated data that were presented were distant metastasis-free survival data. At a median follow-up at 39 months, the hazard ratio for distant metastasis-free survival is a very nice 0.59. At 36 months, the distant metastasis-free survival rate was 84% vs 74%; that’s an absolute difference of 10 percentage points.

If you look at the distant metastasis-free survival by stage, we’re looking at 86 vs 78 for the IIB disease and 80 vs 68, which again, is a pretty healthy difference at 36 months, for those who have IIC disease. The hazard ratios were 0.62 or 0.57, respectively, which again, I think are very nice and would suggest that there’s clear benefit for adjuvant pembrolizumab in resected stage IIB and IIC melanoma.

If you look to the primary endpoint of recurrence-free survival (RFS), now at 36 months, the hazard ratio is 0.62, with an RFS rate of 76% vs 63%, which is a healthy 13-percentage point absolute difference. Again, if you break it down by stage IIB or IIC, it’s 79% vs 66% and 71% vs 58%, with the lower figures obviously coming from the IICs compared with the IIBs, who will always do better. These are still very nice, consistent data, with hazard ratios of 0.58 and 0.65 for the IIBs and the IICs, respectively.

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