Round 2: Treatment for Patient Case 2

In the second round, panelists debate whether patients with BRAF-mutant melanoma should start with targeted therapy or combination immunotherapy, weighing durability of response, toxicity, and sequencing strategies.

To hear arguments related to treatment for patient case 1, see Round 1.

To hear arguments related to treatment for patient case 3, see Round 3.

Dr Jose Lutzky: So let's move on to the second round. This is Case 2, a 55-year-old man presented to his dermatologist with a pigmented lesion on the left thigh. On physical exam, there was a palpable nodule on the left groin. ECOG-performance status was 1. Biopsy of the primary skin lesion showed a melanoma, Breslow depth at 3.1, ulcerated with a mitotic rate of 5 per square millimeter. A fine needle aspiration of the left groin mass showed metastatic melanoma in the lymph node. This patient harbored a BRAF V600E mutation. LDH within normal range. CT scans of the chest, abdomen, and pelvis reveal evidence of metastatic disease in the lung, 3 on the left and 2 on the right lung. The MRI of the brain was negative.  

So the question obviously here is: Should we start treatment of this patient whose tumor harbors a BRAF V600E mutation—which is mutating in almost 50% of melanomas—should these patients be treated with a combination of BRAF and MEK inhibitors, or should they be treated with combination immunotherapy? 

Dr Tarhini thinks they should treat with immunotherapy, and Dr Smithy is going to argue for targeted therapy.

Dr Ahmad Tarhini: Thank you, Dr Lutzky, for giving me the easy task for this part. All right, so it is really hard to argue against immunotherapy in the first-line for patients with metastatic melanoma. So this was a case of metastatic melanoma, lung metastases, BRAF mutant disease, no brain metastases. And the argument here for immunotherapy in the first-line comes primarily from the DREAMseq study. This is the ECOG-ACRIN study, 6134, led by Mike Atkins, which randomized patients 50:50, or 1:1, to either starting with IPI + NIVO combination or to the BRAF-MEK inhibition, with dabrafenib and trametinib, and then cross over at progression into the other treatment option. The primary endpoint was 2-year overall survival, which was, this study was actually, the accrual was halted early before it completed accrual because the DSMC seeing significant difference in overall survival in favor of immunotherapy. The difference at 2 years at the time was 21%, and Mike just presented the 5-year data at ASCO that now, we have a 5-year update from this analysis. 

The difference at 2 years eroded a little bit; it's 14%, but then the curves continue to separate. Now, at 5 years, it’s almost a 30% difference in survival in favor of immunotherapy first, so significant improvement in overall survival. We see parallel benefits in terms of progression-free survival, also significantly better early on at 2 years and then at 5 years in favor of immunotherapy.  

One thing to note as well is the durability of the responses with immunotherapy as compared to those who respond to targeted therapy. So at 5 years, almost 80% of patients who responded to immunotherapy stayed in response, compared to only about 14% or so of those who responded to targeted therapy, so if they respond to targeted therapy, a significant proportion of these patients lose their response by the time they reach 5 years. And this is a major issue to have patients who come to the clinic who start first-line treatment and they respond very well. So looking, the long term, the likelihood of these patients staying in response is very important. It is obviously there with immunotherapy, but it is concerning with targeted therapy. I've been practicing as a faculty since 2006, and when these drugs started getting approved, we were very excited about target therapy in the first-line. We had these patients who had complete responses, and then 9 months later, you get burned when a young lady comes with 30 brain metastases after a complete response. This comes into question what to do next for those that we have to start with targeted therapy.  

And then I'll pass on to Dr Smithy.

Dr James Smithy: Great. So it's a tall, tall order to argue with a randomized phase 3 trial, as Dr Tarhini just presented. But I think I want to point out some of the limitations of those data and then also just broadly thinking about BRAF/MEK inhibition as a combination. 

So, I think DREAMseq is a very compelling story. I think it compares 1 BRAF/MEK regimen against NIVO + IPI, which is 1 combination ICI regimen; we don't know, per se, that those results are applicable to patients getting NIVO + RELA or PD-1 monotherapy in the first line. There are 2 other FDA-approved BRAF/MEK combinations as well, like encorafenib and binimetinib, and then vemurafenib and cobimetinib as well. So as you know, these are all FDA- and NCCN-listed options for patients, and I think it's a little bit of a misconception that every patient treated with BRAF/MEK inhibitors is going to have secondary progression within the first year, and there aren’t patients with durable responses.  

If you look at the COLUMBUS trial, which was the randomized phase 3 trial of encorafenib and binimetinib against either encorafenib monotherapy or vemurafenib monotherapy, there are actually, with the 7-year update, 20% of patients had not progressed by year 5. So, there is a subset of patients who can actually have durable responses to upfront BRAF/MEK. These tend to be patients with normal LDHs, with fewer organ sites involved, like less than 3 sites. I do think there's some group of patients, maybe not the average patient, where you could have a really great durable response with a target therapy. So patients in my practice who have been on BRAF/MEK for over 7 years, which is pretty incredible. And I think the flip side is what is the toxicity profile of these look like and how is it different than what we might encounter with combination checkpoint blockade.  

So, as mentioned before, the rates of severe IREs with IPI + NIVO are considerable, and they can be lifelong or life-threatening as well. So any endocrinopathy you cause with NIVO + IPI could be something that affects the patient for the rest of their life, especially if they're young. And then there are non-insignificant rates of treatment-related fatalities, too, with encephalitis and myocarditis, so these are all things to consider for each patient individually. The thing with BRAF/MEK therapy is that all of the toxicities, while there are still considerable rates of grade 3-4 toxins, they are titratable with dose and dose interruptions, de-escalations, and intermittent dosing as well.  

So I think you have a better shot at a lot of patients who are maintaining an adequate toxicity profile with careful titration, it takes a lot of communication. But I think, just thinking about that patient who may be likely to have a durable long-term response to BRAF/MEK is someone to think about, and what are the costs or downsides of using NIVO + IPI for a patient who may have underlying autoimmune disease or borderline performance status and balancing those risks and benefits, I think it is important for each patient. So hard to say what the right answer is for every patient, but there are definitely possibilities of using targeted therapy in the first line as well. 

Oh, sorry, I didn't talk about the SECOMBIT trial. Apologies. One last thing. So SECOMBIT, this slide is actually really important as well, and I almost left this out, but I think DREAMseq is a really powerful 2-arm study comparing keeping each therapy until the time of progression and then switching at the time of progression. This European, phase 2 trial I think was a really interesting, novel application of BRAF/MEK in the first line, where they have 2 arms, Arm A and Arm B, that more or less mirror the DREAMseq arms, so starting with either BRAF targeted therapy or IPI + NIVO until progression, then switching. But the kind of innovation of this trial is the Arm C, where patients were on 8 weeks of encorafenib and binimetinib at the beginning, and then at 8 weeks, electively switching over to IPI + NIVO prior to progression. And then if they progress again, then switching them back to encorafenib and binimetinib. So in Arm C, this is represented in the red line on this overall survival curve. It very much resembles the curve of the patients who start on IPI + NIVO, in green. So it seems that by starting with a limited duration of encorafenib and binimetinib, you don't lose the durability of your immunotherapy response either. I think this blue arm of the people who stayed on ENCO + BINI until progression does recapitulate what we know from DREAMseq, and those patients do tend to do worse. But for a patient who has a heavy disease burden or is not necessarily the one that we were talking about in our case, but someone you need to get an early, rapid response on, this is a very appropriate first-line option as well. This has been recapitulated also in the brain; there's some data here, too. So this is looking at the 5-year brain metastasis-free survival, and both Arm B and Arm C have improved brain metastasis-free survival over the patients who stayed on ENCO + BINI until progression. 

EBIN is another phase 2 randomized study that reflects a similar approach. They're on a little bit longer induction course in this trial, but starting with encorafenib and binimetinib until switching to IPI + NIVO. And here, this more or less reflects the results from SECOMBIT, but it's also going into details. 

Those are some novel applications of first-line BRAF/MEK, which I think, beyond what I said earlier, also speak for the role of these types of drugs in the first-line setting.