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 here at NYU Langone Health in New York City. I'd like to report to you today on three important oral melanoma abstracts presented at the 2024 ASCO meeting in Chicago.
The first and clearly important abstract was presented at the plenary session. This was the first report by Dr Christian Blank of the primary endpoint of event-free survival in the NADINA study, which was a randomized, phase 3 study of 420 patients with clinically detected and/or palpable stage III melanoma. They were randomly allocated 1:1 to either get surgery followed by adjuvant therapy, or they would receive two cycles of fixed-dose ipilimumab-nivolumab (ipi-nivo), roughly at 1 mg/kg ipilimumab and 3 mg/kg of nivolumab, depending on the weight of the individual.
They would receive that for two cycles, then go to surgery for a total lymph node dissection, and then get adjuvant therapy. If they had a significant level of necrosis of 90% or more, they would get no further adjuvant therapy. If they had less than 90% but more than 50%, they would continue on immunotherapy. If it was less than 50% and they were BRAF mutated, they would be receiving adjuvant dabrafenib-trametinib.
The primary endpoint of event-free survival was defined as the time from randomization until recurrence, progression, or death due to melanoma or their treatment. This is a little different from what we saw as the definition of event-free survival in the previously described SWOG S1801 trial.
For the primary endpoint of event-free survival, there was a very impressive difference for the neoadjuvant arm compared with the surgery/adjuvant-only arm, with a 26–percentage point absolute difference in event-free survival (83% vs 57%) at a projected 12 months of follow-up. Please keep in mind the median follow-up here is only about 9.9 months, so it's still early days, but the hazard ratio is a very healthy 0.32 with a P value of.0001 for the difference. This is a very impressive event-free survival difference favoring neoadjuvant therapy.
If you look at BRAF wild-type vs BRAF mutated, for the BRAF-mutated population, there was a very impressive 31% difference. There was a 21% difference if you're BRAF wild-type, but still a clearly statistically significant difference, with an excellent hazard ratio in the 0.3 range.
As has been seen in other trials of this type, a 90% pathologic response or more gave a very low rate at 1 year of recurrence of 4%-5% at most, whereas it significantly dropped off if you had less than a 50% level of pathologic response. With less than 50% necrosis, there was 57% event-free survival at a year, and it was 76% if you had between 50% and 90% necrosis. Those are the patients who probably would benefit from further adjuvant therapy.
There was a 29% rate of grade 3/4 side effects during the neoadjuvant phase, which is not so different from what has been seen in prior studies.
The conclusion is that clearly, neoadjuvant therapy is here to stay. For that modest proportion of maybe 15% of patients with clinically detectable and/or palpable stage III melanoma, two cycles of ipi-nivo, to me, is the way to go. I think this is an excellent advance, which will decrease the risk that patients who get a 90% pathologic response or more will ever have recurrence and probably will eliminate the need for further surgery. Again, with only 9.9 months of follow-up, time will tell.
The second very interesting abstract was presented as one of the orals, and this was by Dr Paolo Ascierto, from Napoli, who talked about the results of the RELATIVITY-048 study. This was a Phase 2 study of 46 patients who received, now for the first time, triplet immunotherapy with ipilimumab, nivolumab, and relatlimab. They received nivolumab and relatlimab at the usual fixed dose of 480 mg and 160 mg every 4 weeks, respectively. Every 8 weeks, they got 1 mg/kg ipilimumab out of concern that if that interval had been shorter or the dose higher, more toxicity would have been seen.
The primary endpoints were safety, response, and duration of response. Progression-free survival was a key secondary endpoint. We now have 49 months of median follow-up. It was a very healthy and respectable group of patients, with a significant rate of elevated lactate dehydrogenase in about 37%; 52% had M1c disease. This was a really good, representative group of stage IV melanoma patients that were unresectable and had metastatic disease.
The investigator-called response rate was a very nice 59%. Interestingly, if one looks at progression-free survival, it was 52% at 3 years and 52% at 4 years. Amazingly, there is a plateau, and it looks like the median will not be reached at 4 years. That is a phenomenal median survival compared with something like 11 months for CheckMate 067, or 10.2 months in the flipped-dose ipi-nivo arm in CheckMate 511.
Again, these are very nice data suggesting clear clinical benefit, in my opinion, for that triplet therapy, with a 39% rate of grade 3/4 immune-related adverse events. This is still a very significant rate, but again, survival of 72% at 3 years and 72% at 4 years beats the 59% survival seen in CheckMate 511 with a flipped dose of ipi-nivo.
These are very nice data. This, of course, was a moderately sized phase 2 study. It needs to be subjected to further verification, and those studies are now ongoing.
Finally, we heard about the long-term follow-up of COMBI-AD, which was a randomized trial in the adjuvant mode in resected patients with stage IIIA/B/C disease, according to AJCC Seventh Edition criteria, of oral dabrafenib-trametinib for 1 year vs placebo. We've seen the 3-year, 4-year, and 5-year follow-ups. Now, we have a minimum of 100 months of follow-up.
This was essentially the final report on recurrence-free survival, which was the primary endpoint, and it's 50% at 100 months, with a plateau where it really looks like the recurrence-free survival levels out. If you look at distant metastasis-free survival, it was 64% at 100 months; at 5 years, it was 65%. I think that's a real plateau.
If you look at overall survival, there is a difference at 100 months, at 71% vs 65%. The P value just misses at 0.063, but the hazard ratio is 0.8 and the curves come apart early and stay apart all the way through that 100 months of follow-up.
Interestingly, and almost bizarrely, if you look at the forest plot of different factors, for those who are BRAF V600E mutated, again there's a clear benefit in terms of recurrence-free survival and overall survival. If you look at the BRAF V600K mutations — which only represent somewhat less than 10% of the total BRAF-mutated population, which of course is 100% of the patients in this trial — it goes the other way. The hazard ratio is 1.95, suggesting that the placebo group actually did better than the group that got dabrafenib-trametinib. This is really hard to understand, given that for recurrence-free survival, there's a benefit both for BRAF V600E and BRAF V600K.
If you look at melanoma-specific survival, there were similar data to the overall group, at 76% at 100 months vs 70%, which I think clearly establishes that dabrafenib-trametinib is an impressive standard-of-care adjuvant therapy in patients with stage IIIA/B/C disease by AJCC Seventh Edition criteria who are candidates for adjuvant therapy and are BRAF mutated, whether BRAF V600E or BRAF V600K.
This is Dr Jeffrey Weber, reporting to you on this most recent ASCO meeting's melanoma abstracts. Thank you for your attention.
COMMENTARY
Drug Combinations Improve Survival in Melanoma
Jeffrey S. Weber, MD, PhD
DISCLOSURES
| July 25, 2024This 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 here at NYU Langone Health in New York City. I'd like to report to you today on three important oral melanoma abstracts presented at the 2024 ASCO meeting in Chicago.
The first and clearly important abstract was presented at the plenary session. This was the first report by Dr Christian Blank of the primary endpoint of event-free survival in the NADINA study, which was a randomized, phase 3 study of 420 patients with clinically detected and/or palpable stage III melanoma. They were randomly allocated 1:1 to either get surgery followed by adjuvant therapy, or they would receive two cycles of fixed-dose ipilimumab-nivolumab (ipi-nivo), roughly at 1 mg/kg ipilimumab and 3 mg/kg of nivolumab, depending on the weight of the individual.
They would receive that for two cycles, then go to surgery for a total lymph node dissection, and then get adjuvant therapy. If they had a significant level of necrosis of 90% or more, they would get no further adjuvant therapy. If they had less than 90% but more than 50%, they would continue on immunotherapy. If it was less than 50% and they were BRAF mutated, they would be receiving adjuvant dabrafenib-trametinib.
The primary endpoint of event-free survival was defined as the time from randomization until recurrence, progression, or death due to melanoma or their treatment. This is a little different from what we saw as the definition of event-free survival in the previously described SWOG S1801 trial.
For the primary endpoint of event-free survival, there was a very impressive difference for the neoadjuvant arm compared with the surgery/adjuvant-only arm, with a 26–percentage point absolute difference in event-free survival (83% vs 57%) at a projected 12 months of follow-up. Please keep in mind the median follow-up here is only about 9.9 months, so it's still early days, but the hazard ratio is a very healthy 0.32 with a P value of.0001 for the difference. This is a very impressive event-free survival difference favoring neoadjuvant therapy.
If you look at BRAF wild-type vs BRAF mutated, for the BRAF-mutated population, there was a very impressive 31% difference. There was a 21% difference if you're BRAF wild-type, but still a clearly statistically significant difference, with an excellent hazard ratio in the 0.3 range.
As has been seen in other trials of this type, a 90% pathologic response or more gave a very low rate at 1 year of recurrence of 4%-5% at most, whereas it significantly dropped off if you had less than a 50% level of pathologic response. With less than 50% necrosis, there was 57% event-free survival at a year, and it was 76% if you had between 50% and 90% necrosis. Those are the patients who probably would benefit from further adjuvant therapy.
There was a 29% rate of grade 3/4 side effects during the neoadjuvant phase, which is not so different from what has been seen in prior studies.
The conclusion is that clearly, neoadjuvant therapy is here to stay. For that modest proportion of maybe 15% of patients with clinically detectable and/or palpable stage III melanoma, two cycles of ipi-nivo, to me, is the way to go. I think this is an excellent advance, which will decrease the risk that patients who get a 90% pathologic response or more will ever have recurrence and probably will eliminate the need for further surgery. Again, with only 9.9 months of follow-up, time will tell.
The second very interesting abstract was presented as one of the orals, and this was by Dr Paolo Ascierto, from Napoli, who talked about the results of the RELATIVITY-048 study. This was a Phase 2 study of 46 patients who received, now for the first time, triplet immunotherapy with ipilimumab, nivolumab, and relatlimab. They received nivolumab and relatlimab at the usual fixed dose of 480 mg and 160 mg every 4 weeks, respectively. Every 8 weeks, they got 1 mg/kg ipilimumab out of concern that if that interval had been shorter or the dose higher, more toxicity would have been seen.
The primary endpoints were safety, response, and duration of response. Progression-free survival was a key secondary endpoint. We now have 49 months of median follow-up. It was a very healthy and respectable group of patients, with a significant rate of elevated lactate dehydrogenase in about 37%; 52% had M1c disease. This was a really good, representative group of stage IV melanoma patients that were unresectable and had metastatic disease.
The investigator-called response rate was a very nice 59%. Interestingly, if one looks at progression-free survival, it was 52% at 3 years and 52% at 4 years. Amazingly, there is a plateau, and it looks like the median will not be reached at 4 years. That is a phenomenal median survival compared with something like 11 months for CheckMate 067, or 10.2 months in the flipped-dose ipi-nivo arm in CheckMate 511.
Again, these are very nice data suggesting clear clinical benefit, in my opinion, for that triplet therapy, with a 39% rate of grade 3/4 immune-related adverse events. This is still a very significant rate, but again, survival of 72% at 3 years and 72% at 4 years beats the 59% survival seen in CheckMate 511 with a flipped dose of ipi-nivo.
These are very nice data. This, of course, was a moderately sized phase 2 study. It needs to be subjected to further verification, and those studies are now ongoing.
Finally, we heard about the long-term follow-up of COMBI-AD, which was a randomized trial in the adjuvant mode in resected patients with stage IIIA/B/C disease, according to AJCC Seventh Edition criteria, of oral dabrafenib-trametinib for 1 year vs placebo. We've seen the 3-year, 4-year, and 5-year follow-ups. Now, we have a minimum of 100 months of follow-up.
This was essentially the final report on recurrence-free survival, which was the primary endpoint, and it's 50% at 100 months, with a plateau where it really looks like the recurrence-free survival levels out. If you look at distant metastasis-free survival, it was 64% at 100 months; at 5 years, it was 65%. I think that's a real plateau.
If you look at overall survival, there is a difference at 100 months, at 71% vs 65%. The P value just misses at 0.063, but the hazard ratio is 0.8 and the curves come apart early and stay apart all the way through that 100 months of follow-up.
Interestingly, and almost bizarrely, if you look at the forest plot of different factors, for those who are BRAF V600E mutated, again there's a clear benefit in terms of recurrence-free survival and overall survival. If you look at the BRAF V600K mutations — which only represent somewhat less than 10% of the total BRAF-mutated population, which of course is 100% of the patients in this trial — it goes the other way. The hazard ratio is 1.95, suggesting that the placebo group actually did better than the group that got dabrafenib-trametinib. This is really hard to understand, given that for recurrence-free survival, there's a benefit both for BRAF V600E and BRAF V600K.
If you look at melanoma-specific survival, there were similar data to the overall group, at 76% at 100 months vs 70%, which I think clearly establishes that dabrafenib-trametinib is an impressive standard-of-care adjuvant therapy in patients with stage IIIA/B/C disease by AJCC Seventh Edition criteria who are candidates for adjuvant therapy and are BRAF mutated, whether BRAF V600E or BRAF V600K.
This is Dr Jeffrey Weber, reporting to you on this most recent ASCO meeting's melanoma abstracts. Thank you for your attention.
Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
TOP PICKS FOR YOU