Key Considerations for Detecting and Targeting BRAF Mutations - Episode 8

Trials and Treatment in Advanced Melanoma


Hussein A. Tawbi, MD, PhD: COMBI-AD was a large, randomized, global phase III trial that took patients with nodal involvement, so stage III patients—it was patients with stage IIIa, IIIb, and IIIc in the AJCC [American Joint Committee on Cancer Cancer Staging Manual] 7th edition—and randomized them to dabrafenib and trametinib as active therapy versus placebo. Treatment was conducted for a year. Over 800 patients were randomized, and the study actually had a very long follow-up.

I can tell you that in the field, we have waited very patiently to see the results of that study. It was really useful to see the results, because after a prolonged follow-up—I believe it was over 22½ years at the time of first reporting—the combination of dabrafenib and trametinib was highly effective and decreased the risk of recurrence with a hazard ratio of 0.47, which is almost a 53% reduction in the risk of relapse. There was also an improvement in overall survival.

I was careful not to say significant, because it had a really low P value. It was 0.000-something, but it hadn’t hit the primary level for significance for that study. That was set originally by the statistical design and then, with a longer follow-up that was reported in the Journal of Clinical Oncology, it was interesting to see that based on a cure-rate model, the combination is actually capable of curing patients—up to almost 17% of patients.

We really do think this is effective adjuvant therapy. And again, it’s relatively tolerable. About 26% of patients actually stopped treatment because of toxicity. Yet those patients still benefited. They were kind of analyzed in an intention-to-treat analysis, and they also derived the clinical benefit that was seen across the board. Again, we think it’s relatively safe and tolerable and definitely effective therapy.

Immunotherapy had already proven its ability to cure patients in the metastatic setting, and it made a lot of sense to test that in the adjuvant setting. Again, patients with stage III melanoma were randomized in a large phase III trial to either nivolumab or ipilimumab. Ipilimumab was used at a dose of 10 mg/kg. I just want to highlight that, because that’s known to be a relatively toxic regimen.

When the study was designed, the idea was to use it in patients who were at a higher risk for recurrence. It actually took patients who were stage IIIb, IIIc, and resected stage M1a as well that were treated on this study.

Nivolumab proven to be superior to ipilimumab in terms of decreasing the risk of recurrence. The hazard ratio was 0.65, so it decreased the risk of recurrence by 35%. This is fascinating because ipilimumab alone was actually effective against placebo when it was used in the EORTC [European Organisation for the Research and Treatment of Cancer] trial. Ipilimumab alone had a hazard ratio of about 0.72, meaning that it decreased the risk of recurrence by 28%. Yet nivolumab actually was more effective and beat it to the hazard ratio of 0.65. I think that’s really relevant because if you look at the rate of toxicities, ipilimumab at 10 mg/kg has a grade 3/4 toxicity rate upward of 40%. Whereas in nivolumab, it was only 15%. Again, it was a safer and definitely more effective therapy. Based on the results of that study, nivolumab was FDA approved for the treatment of patients with stage III melanoma in the adjuvant setting. The treatment, by the way, was for 1 year.

The International Neoadjuvant Melanoma Consortium is a consortium that was established in the last couple of years to define the way we need to perform clinical trials in the adjuvant setting. The idea was to harmonize the study design, so we treat patients with the same duration of therapy before they go to surgery, or that we treat them in a relatively homogenous way, so we can really understand the differences and the similarities between the different trials.

I can take a step back and tell you that neoadjuvant therapy is appropriate for patients who present with bulky nodal disease. That’s a population that is extremely high-risk. If you take them to surgery alone, obviously surgery can be performed. People go through completion lymph node dissections. However, after surgery, their risk of relapse is extremely high—upward of 60%, and sometimes as high as 70%. And so the idea of using effective therapy that we now have at our disposal ahead of surgery— dabrafenib, trametinib, BRAF inhibition, or immunotherapy with single or combination therapy—makes a lot of biological sense because you can kind of cytoreduce the tumor, decease the size of the tumor, maybe improve outcomes of surgery, but most importantly, biologically, especially in the case of immunotherapy, induce a better, more sustained immune response if you treat when the tumor is in place.

That’s kind of the concept behind doing the therapy. There were several clinical trials that were done at multiple institutions, mostly a single center of clinical trials. For instance, we had performed 2 at The University of Texas MD Anderson Cancer Center. Our collaborators in Australia had performed a couple of trials with targeted therapy and immunotherapy. The same thing was done in Europe. We all came together as a group to learn from one another, discuss best practices, and try to harmonize the way we designed and analyzed those trials.

What was really interesting is that we did find a lot of similarities among our trials. Then we decided that, given that most of them were conducted with the same approach or at least a similar approach, it was actually safe to consider putting all the data together, pooling all that data so that we could understand better the patterns of response, the patterns of progression, and whether we could start gaining more information with more patient numbers.

The analysis that was presented at the 2019 ASCO [American Society of Clinical Oncology] Annual Meeting was of about 188 patients. I personally presented this as, “This is the totality of all the adjuvantly treated patients in the world at this point.” That included data from MD Anderson Cancer Center, Europe, and Australia. It also included data from the University of Pennsylvania, with some data from the University of Pittsburgh as well. It was all the studies that were ongoing with immunotherapy, anti—PD-1 [programmed cell death protein 1] and anti-CTLA4 blockade, and targeted therapy.

What was really interesting to see is that we had managed and induced a high rate of pathological complete response. What does that mean? That’s a very important marker. It means that at the time of surgery, after treatment for sometimes 8 weeks—some of the studies were 12 weeks—there’s actually no viable tumor in the tumor bed, right? That’s what’s called a compete pathologic response, or path CR.

Path CRs occurred at a pretty high rate. It was over 50%. It kind of depends on the specific study. When we started looking at the patterns of recurrence, especially in the postsurgical space—the relapse-free survival—it was really remarkable to see that the patients who had a pathological complete response had a great outcome, and they had a much lower rate of relapse. Patients who did not achieve a path CR had a higher rate of relapse, which is what you would expect. It means that there was some viable tumor there.

The interesting part is that when we started looking at the differences between targeted therapy versus immunotherapy, remarkably, about 51 patients had a path CR with immunotherapy. Not a single 1 of them has recurred, so it’s almost a 100% relapse-free survival.

There were recurrences with immunotherapy with patients who had no path CR, but even those patients still looked better than what you would expect for this population in relapse-free survival. With targeted therapy, path CR was associated with a really great relapse-free survival, but there were still some relapses, even if you had achieved a path CR. And if you looked at those curves, you would see that the patients who did not achieve a path CR with targeted therapy are those patients who actually did worse in this pooled analysis.

Altogether, I think it points to the fact that neoadjuvant therapy is safe and reasonable, and it doesn’t compromise the ability to do surgery, which is 1 of the concerns with neoadjuvant therapy. Most importantly, it actually can predict longer-term outcomes.

Transcript Edited for Clarity