Immunotherapy vs TKIs in BRAF+ Metastatic Melanoma


Sanjiv S. Agarwala, MD: The metastatic melanoma has similar issues and discussions. And we’ll start with the whole BRAF and BRAF-mutant wild-type story. I’ll turn to you, Caroline, as well, to start this. [

They’re similar debates. What do you choose? We don’t have randomized data to tell us which way to go. Let’s start with efficacy—efficacy of immunotherapy versus targeted therapy. Is there a difference in survival rates? Two years, 3 years? Whatever data we have, looking at the latest ASCO [American Society of Clinical Oncology Annual Meeting], [from] which 1 of the abstracts is yours.

Caroline Robert, MD, PhD: Yes, we have some results. We have long-term results. We know the response rate is much higher with BRAF/MEK than with anti—PD-1 [programmed cell death protein 1] monotherapy. And the difference is a bit smaller with anti–PD-1, but still 70% of response rate with anti-BRAF, anti-MEK for the first evaluations, usually very early responses. However, as we said before, we know that the curves cross each other at about 15 months, or after 15 months, and we have the PD-1 continuing curve that gets on top. So if you have the choice at the beginning, if you don’t have a patient with a very high tumor burden, and you’re afraid the patient is not going to be alive in 2, 3 months, usually we would initiate with immunotherapy. But we know that, I think it’s important to remind everybody that immunotherapy also has a lot of resistance mechanism that can be up front or can appear secondarily. And that’s important because a lot of patients—and the media, and everybody—talk almost only about immunotherapy. But we also know…that recently, we presented at ASCO that we also have a long-term benefit with anti-BRAF/anti-MEK first line with 20% of the patients free of progression at 5 years and one-third of the patients alive. It’s less than what we see with immunotherapy, but still it means that some patients really benefit further for a long time. And I have some patients who have had this therapy without any adverse events for a long time. The truth is that we don’t dare to stop, and this is a big difference because a big revolution that we lived through was that we learned that we could stop the treatment and keep the patients in response and complete response. And this was a wonderful news that was quite recent in our field which we could not obtain with targeted therapy today. We are afraid to stop.

Sanjiv S. Agarwala, MD: Not yet, yeah.

Caroline Robert, MD, PhD: No.

Sanjiv S. Agarwala, MD: Can you comment on KEYNOTE-006? You presented the updated results at ASCO. The survivals are looking, for monotherapy because always a choice between monotherapy and combination and KEYNOTE-006...

Caroline Robert, MD, PhD: Yes. With anti—PD-1, if you look at the patients in first line, you have 43% of patients alive at 5 years.

Sanjiv S. Agarwala, MD: Five years, yeah.

Caroline Robert, MD, PhD: For the patients who have done the treatment, who went through the 2 years of treatments, we have stopped after 2 years. And the patients benefited, so there are complete responders, partial responders, or stable disease. I think a lot of the partial responders and the stable disease are hidden complete responders, because sometimes you cannot really make sure that you still have a scar or something. But these patients, when you stop therapy, must have remained.

Sanjiv S. Agarwala, MD: In the same condition.

Caroline Robert, MD, PhD: Yeah.

Sanjiv S. Agarwala, MD: Dirk, CheckMate-067 had updated data, mostly, at ESMO [European Society for Medical Oncology], and then you presented a quality-of-life analysis at this meeting. Can you comment on the combination? What are we looking at in terms of long-term benefit and quality of life as well?

Dirk Schadendorf, MD, PhD: Yeah. I think what we have seen and learned is what was actually also seen in the KEYNOTE-006, that the monotherapy using a PD-1 antibody has long-lasting tumor control in a substantial fraction of patients, starting actually to stabilize after 2 to 3 years. And we are expecting to see 5-year survival data and PFS [progression-free survival] data at ESMO in autumn this year. If you look at the tumor control in comparison with a combination, there is even an increase that is statistically significant for the PFS in favor of the combination, which is not significant. If you look at the overall survival, it’s around 6% to 7% in favor of the nivolumab-ipilimumab combination, with an overall survival rate at 4 years, about 50%. So median overall survival is still not reached at 4 years.

I think this comes to a price, which is a toxicity that we have discussed several times, with roughly one-third of the patients dropping off very early within the first 6 to 10 weeks. The good news, I think, is that a lot of these patients—also, it’s cumbersome to treat all these toxicities—stay free of disease and free of further treatment. I think if we look at the 4-year landmark, you see that a substantial fraction of these patients, roughly more than 100 patients at that point, have not seen any further treatment.

Sanjiv S. Agarwala, MD: Treatment-free interval.

Caroline Robert, MD, PhD: Yes.

Dirk Schadendorf, MD, PhD: Treatment-free interval and the proportion of patients who never needed any further treatment. And I think that’s a quality we have not seen in oncology.

Sanjiv S. Agarwala, MD: It’s very interesting.

Dirk Schadendorf, MD, PhD: I think that quality of life was going with it, and this is a very ambitious project as part of CheckMate-067. Quality of life was measured not only during the treatment period but also now up to 4 years.

Caroline Robert, MD, PhD: Yes.

Dirk Schadendorf, MD, PhD: And I think there is clear indication that this suffering through the toxicity is worthwhile for the patients.

Caroline Robert, MD, PhD: But I think it’s very important what you said, because very up front we have patients referred to us or colleagues asking us, “We have this huge toxicity. Do you think we can rechallenge?” And we always say, “Wait, look at the patient.” Evaluate your patient with a CT [computed tomography] scan before even considering rechallenging. And that’s also very nuanced. Very often we don’t need to go back to the treatment.

Dirk Schadendorf, MD, PhD: Absolutely.

Caroline Robert, MD, PhD: So that’s great.

Sanjiv S. Agarwala, MD: Alex, you’re going to make a comment, but I want to ask you 1 more as you think about it. There was an ASCO abstract about depth of response in terms of that correlating with outcome or benefit. Do you think that’s important? You’re a surgeon; obviously you get a complete response every time you operate. What do you think about depth of response? And in terms of the toxicity as well, if you could comment, please.

Alexander Eggermont, MD, PhD: Well, there is a good correlation with PET [positron emission tomography] scans, but PET scans are still not showing some inflammatory activity. They’re underestimating the pathologic complete response rates. Although there is some linearity, there is still quite a distance between the PET readout and the pathologic readout. We underestimate the responses. There are many more complete responders than we think, and we find out only because of the survival curves. The point I wanted to make is that in general, in discussions, the 3-year, the 4-year, the 5-year survival rates between BRAF/MEK combos and between immunotherapy are compared.

Whereas you are comparing a BRAF-mutant population with the overall population in the immunotherapy population, which is incorrect. You must realize that the BRAF-mutant patient population has much better survival curves than the BRAF wild-type patients. And so the real difference at 3 years is that for BRAF/MEK combo, it’s 45% overall survival at 3 years. But for the nivolumab, low-dose ipilimumab or pembrolizumab, low-dose ipilimumab combination, it is—for the monotherapy with anti—PD-1—already 59%. Sorry, that’s already 14% higher, and it’s 68% for the combo. That is 25% higher than the BRAF/MEK combination for the same patient population.

We should stop comparing overall populations with BRAF-mutant populations. When we make a comparison, we make the comparison between the 2 BRAF-mutant patient populations. And this is why we brush over the difference. No, the difference is huge. It is at 3 years, a whopping 25% overall survival difference. And already monotherapy with anti—PD-1 is distinctly better than BRAF/MEK combo. I’m sorry. So we must stop making the wrong comparisons and only make the right comparisons.

Transcript Edited for Clarity

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