Adjuvant Vs. Neoadjuvant Therapy in Melanoma

This transcript has been edited for clarity.

Hello. I’m Dr. Jeffrey Weber. I’m a medical oncologist at the Laura and Isaac Perlmutter Cancer Center at NYU Langone Health in New York City. Today, I’ll be reporting on a couple of abstracts related to adjuvant and neoadjuvant therapy in melanoma. Also, I’m going to quote, very briefly, a recent publication that also talks about neoadjuvant therapy, which is a coming thing in the treatment of melanoma and many other cancers like lung, head and neck, and renal cancer.

Sapna Patel presented the first abstract, and it was a follow-up on some very nice work from the SWOG 1801 trial, which was a clinical trial in which patients in a phase 2 style were randomly allocated to receive either neoadjuvant pembrolizumab times three cycles, then surgery, then adjuvant pembrolizumab, or just go straight to surgery and then have adjuvant pembrolizumab.

Adjuvant pembrolizumab, of course, is standard-of-care, FDA-approved therapy in resected stage III melanoma. All patients in that original trial, SWOG 1801, had clinically detected disease either radiologically or palpably. At 2 years, the event-free survival was 72% vs 49%, which is a very impressive difference, with a p value of .004 and a hazard ratio of 0.58.

The presentation made at the 2023 European Society for Medical Oncology (ESMO) meeting showed that the concordance in the pathological assessment was pretty close to 90%. In the real world you’re going to have individual institutions doing pathological assessment of neoadjuvant specimens — which I think, as has become evident over the past couple of years, is clearly prognostic for outcome.

The recurrence-free survival by pathological response was also assessed in this trial. You had a very nice 87%-89% 2-year recurrence-free survival if you had a pathological complete response (CR), a 90% CR, or > 50% pathological CR. If it was a past nonresponse, meaning < 50%, those patients did not do as well, and their recurrence-free survival was about 70% at 2 years.

Again, if you look at major pathological response — meaning ≥ 90% necrosis up to 100% vs not having a major pathological response — there was a clear difference, at 88% to 2 years vs 80% in terms of event-free survival.

Interestingly, if you look at the actual Response Evaluation Criteria in Solid Tumors (RECIST) response on CT scans before and at the time of surgery, that’s actually about 50%, whereas the actual pathological response rates are somewhat higher. If you look at the recurrence-free survival by RECIST response, there is a clear association. The patients who have a CR do the best. The patients who have progressive disease or no change are the ones who do the worst at 24 months.

What do we know? A significant portion of the specimens from this large, randomized phase 2 cooperative group trial — I think it was 73% of the specimens — were looked at, and the concordance was very good with central pathology and individual institutions. The major pathological response rate was 53%, which I think is quite respectable. There is no question that at 2 years, both event-free and recurrence-free survival are segregated by RECIST response and by pathological response.

As opposed to some other trials, there was a finite recurrence in the event rate that occurred by 2 years, even if you had a major pathological response. I think it was something like 88% event-free survival at 2 years, even with a major pathological response. If you didn’t have a major pathological response, of course, it was significantly higher, with about 70% if you had ≤ 50% necrosis. Again, more grist for the mill of neoadjuvant therapy in melanoma, which to some degree has become almost a standard of care in the community.

I reported an update on the KEYNOTE-942 trial, which was the first randomized trial of a neoantigen mRNA vaccine with pembrolizumab vs pembrolizumab alone. Again, many of the data have been presented. We know that the immune-related adverse event rate of grade 3/4 is actually no different in the pembrolizumab control arm than in the pembrolizumab vaccine arm. In fact, it was 10% for the combo arm and 14% for pembrolizumab alone, which is quite favorable, although the overall toxicity, as we know, is higher.

To refresh your memory, the recurrence-free survival rates were clearly superior for the combination, with a hazard ratio of 0.56 and a two-sided p value of .052. The distant metastasis-free survival rate was superior for the combination again, with a hazard ratio of 0.34 — a highly favorable 66% reduction in distant metastases.

There was a press release a couple of months ago suggesting that at 3 years of follow-up, as opposed to the 2 years of follow-up that I presented at the American Association for Cancer Research (AACR) and ESMO meetings, the recurrence- free survival superiority for the combination now has a p value of .019 — a lot better p value — and the distant metastasis-free survival benefit is maintained.

What we now showed at ESMO is that, regardless of whether you were ctDNA positive or ctDNA negative, it was still better to get the combination vs a single agent, both in terms of distant metastasis-free and recurrence-free survival. With ctDNA, you had three patterns. Some patients were negative all the way through, which was about 12%-15% of the patients. Those patients did very well in terms of recurrence-free survival. You could be a nonresponder, meaning you either were negative and then became positive or were positive all the way through, and those patients did very poorly.

You could be a molecular ctDNA responder, where you were positive at baseline and then became negative or were negative, then positive, then negative again. Those patients had an intermediate recurrence-free survival and distant metastasis-free survival, which has been shown in other cancers.

We also showed that if you were BRAF mutated or BRAF wild-type, you still benefited from combination vs single agent therapy in terms of recurrence-free survival. Interestingly, the mutated patients seemed to have a better separation with a better hazard ratio. Whether you were mutated or wild-type, you still did better with combination than with single-agent pembrolizumab therapy in this randomized phase 2 study.

Finally, there’s the NeoACTIVATE study, which was a very small, single-arm neoadjuvant study just published in Nature Communications. I’ll mention it for a minute because even though it was a very small pilot study with 20 BRAF-mutated patients who had vemurafenib, cobimetinib, and a programmed death-ligand 1 (PD-L1) antibody, atezolizumab, it showed about a 70% pathological CR rate in the mutated population. It was very impressive.

There was approximately a 70%-80% RECIST response rate, whether you were BRAF mutated or BRAF wild-type, among those who got cobimetinib plus atezolizumab (ie, without vemurafenib). Of course, no BRAF mutation so no reason to give a BRAF drug Those patients did very well, with a very nice RECIST response rate, and > 60% pathological CR rate in those who were BRAF mutated and about a third pathological CR rate in those who were BRAF wild type. Those patients didn’t do quite as well, but again, these were very nice data.

There were some correlative marker studies, surprisingly showing that in patients who were PD-L1 positive or negative, there was no association with pathological response as measured by immunohistochemistry or soluble PD-L1 assay. Again, raising the bar in the neoadjuvant space, suggesting that if you are BRAF mutated, you could get BRAF/MEK inhibitors, plus atezolizumab, and you’d probably have a higher pathological CR or near-CR rate. We’ll see what the recurrence-free survival rates show when those data become available.

This is Dr Jeffrey Weber. Please call in with comments, questions, and concerns. Thank you very much for your attention.