This transcript has been edited for clarity.
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.
There are some significant points to remember with more follow-up in the KEYNOTE-716 stage IIB/IIC adjuvant trial. It is now with longer follow-up. We are at 39 months. The hazard ratio for the primary endpoint of RFS of pembrolizumab vs placebo is maintained. It's 0.62. The difference in RFS is very nicely seen for both IIBs and IICs, and very similar in terms of hazard ratio.
Again, for patients with resected stage IIB/IIC melanoma with now 39 months of follow-up, there is a definite difference in distant metastasis-free survival, which many folks think is a surrogate for overall survival. The benefit for pembrolizumab compared with placebo had a hazard ratio of 0.56, reflecting a 44% reduction in the risk for distant metastases. That difference was seen for IIB and IIC disease and no new toxicity signals emerged with longer follow-up.
We also heard longer follow-up from the RELATIVITY-047 study, which was a different kind of study. This was a study of metastatic melanoma among patients who received either the PD-1 antibody nivolumab with the LAG-3 antibody relatlimab or nivolumab alone. It was a straight one-to-one, double-blind, randomized phase 2/3 trial with 714 total patients. The primary endpoint was PFS.
We now have updated PFS data, which still show a significant separation. The hazard ratio is 0.81, and the projected 36-month absolute difference in PFS was 31 vs 27 with follow-up that's now at about 25.5 months. Again, the median PFS was reached at the initial assessment, which led to the registration of nivolumab-relatlimab for patients with metastatic unresectable melanoma, and that was 10.2 vs 4.6 months. Those medians haven't changed.
What's changed is now longer follow-up with the curve of the combination clearly continuing to be above the curve of single-agent nivolumab. If you look at the survival data, now seen for the first time, there's also clearly a difference. The curve of nivolumab-relatlimab is always above nivolumab and breaks apart literally within the first 6-12 weeks. At a projected 36 months, now, with 25 months of follow-up, we're looking at 54% vs 48% overall survival with a hazard ratio of 0.82. Again, it's looking like it's still considerably different.
If you look at what we call PFS2, that is, the PFS after the first progression, there's interestingly and almost surprisingly a clear benefit for the combination of nivolumab-relatlimab compared with nivolumab alone. At a projected 36 months of follow-up on the Kaplan-Meier curve, it's 46% vs 36%, so a 10-percentage point absolute number of patients who survive without progressing; that is PFS2. If you look at the median PFS2, it's 28 vs 20 months for the combo vs the single agent, with a hazard ratio of 0.79.
That was a secondary endpoint but was very interesting data showing for the first time that if you were on the combination and you relapsed or progressed, you will have a longer time to progression with the next regimen if you had gotten the combo compared with the PD-1 nivolumab alone.
Points to remember for the RELATIVITY-047 update are that all of the outcomes examined still favor the combo vs nivolumab alone; the PFS hazard ratio is 0.81; the 3-year PFS rate is 31 vs 27; the overall survival now, for the first time, hazard ratio is documented at 0.82. The 48-month survival of 52% for the combo is clearly superior to 42% for nivolumab alone.
The response rate — again, no big surprise because we heard about that previously — is maintained at 44% for the combination vs 34% for nivolumab alone. Interestingly, the PFS2 with subsequent therapy is superior if you got the combination initially at 42% vs 35% projected at 48 months. These are very interesting data.
Please feel free to call in with comments, concerns, or questions. This is Dr Jeffrey Weber reporting. Thank you very much for your attention.
Jeffrey Weber, MD, PhD, is deputy director of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center and co-director of its Melanoma Research Program. His research, which has been continuously funded by the NCI for more than 20 years, focuses on experimental therapeutics and drug development, particularly in immunotherapy.
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Cite this: Melanoma Updates From ASCO 2023: PD-1 and LAG-3 - Medscape - Oct 24, 2023.
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