Dr. Shannon Westin and her guests, Dr. Michael Atkins, Dr. Adil Daud, and Dr. Gary Schwartz, discuss a definitive work: The DREAMseq Trial.

TRANSCRIPT

The guests on this podcast episode have no disclosures to declare.

Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast that gets in-depth on articles that have been published in the Journal of Clinical Oncology. And it is my great pleasure to be your host. I'm Shannon Westin, GYN oncology, and I serve as the social media editor for the Journal of Clinical Oncology.

Today, we're going to be discussing a very exciting article describing "The DREAMseq Trial—ECOG-ACRIN EA6134, Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients With Advanced BRAF-Mutant Melanoma." This article was published in the JCO on January 10^th, 2023.

And I am joined today by the lead author, Dr. Michael Atkins, who is Deputy Director, Georgetown Lombardi University Hospital, and Scholl Professor and Vice Chair of Oncology at Georgetown University Medical Center. Welcome.

Dr. Michael Atkins: Thank you. Nice to be here.

Dr. Shannon Westin: In addition, we are also accompanied by two experts in the field, Dr. Adil Daud, Professor in the Department of Medicine at the University of California San Francisco, and Director of Melanoma Clinical Research at UCSF Helen Diller Family Comprehensive Cancer Center. Welcome, Dr. Daud.

Dr. Adil Daud: Hi, great to be here.

Dr. Shannon Westin: And with Dr. Daud is Dr. Gary Schwartz, the Division Chief of Hematology Oncology and Deputy Director of the Herbert Irving Comprehensive Cancer Center in Columbia, New York. Thank you for being here.

Dr. Gary Schwartz: Delighted to be here.

Dr. Shannon Westin: So I'm surrounded by experts, and I'm very excited as a GYN oncologist to hear all of what you all have learned in melanoma because we're always excited to take that back into our field. So I think first, though, for those of us that aren't melanoma experts, Dr. Atkins, can you just level set for us and tell us what was the standard of care for melanoma when you began this study?

Dr. Michael Atkins: Sure. Well, first of all, this was a study for patients with BRAF V600 driver mutations in their melanoma, which represents about 50% of the patients with metastatic melanoma. And at the time the study was launched in 2015, two BRAF/MEK inhibitor combinations were FDA approved and shown to produce significant progression-free survival and overall survival benefits relative to BRAF inhibitor monotherapy. In addition, combination checkpoint inhibitor therapy with nivolumab and ipilimumab was shown to be superior to ipilimumab and, in particular in patients with BRAF-mutant melanoma, also to nivolumab monotherapy based on the results of the CheckMate 067 study, leading to its FDA approval. So we had these two regimens there that were approved. Of note, despite the many debates and attempts to garner real-world evidence at the time—the study actually reported out in 2021—marketing data showed that half of all patients in the US with metastatic BRAF-mutant melanoma were receiving BRAF/MEK inhibitors, and only one-quarter received nivo-ipi as initial therapy. So there remained a confusion throughout the course of the study as to which regimen was best in the US and around the world.

Dr. Shannon Westin: Tell me, what led to the current study? Was it really trying to drive at that very question?

Dr. Michael Atkins: These were the best treatment available at the time. And they really had changed melanoma patient outcomes in ways that we could have only dreamed about just five to 10 years prior, when median survival for patients with metastatic melanoma was six to nine months. Hence, the DREAMseq trial, this doublet, randomized evaluation of advanced melanoma sequencing, was really an apt acronym for the trial. But we had these two regimens of BRAF/MEK inhibitors tending to display the overall survival curve, while immunotherapy tended to raise the tail. And at the time the study was launched, it was really unclear which treatment was preferred in general or for particular subsets of patients. And given that patients would likely have the option to receive both approaches, was there a preferred sequence? So the DREAMseq trial was a launch to address these questions.

Dr. Gary Schwartz: I can echo Michael's statement about that. There was also—having been at the beginning of immunotherapy and targeted drug therapy, the transformation of cancer medicine in melanoma was extraordinary. Over a very short amount of time, we transformed a disease that's incurable to curable. And I don't think anybody, at least not in my lifetime, that ever think we'd ever see—or I'd see that type of transformation. But the debate in the community was what should be the first therapy. Should it be a targeted drug combination targeting RAF and MEK for BRAF-mutant melanoma, or should it be immunotherapy? And actually, there was a trend favoring immunotherapy, I think, at the time of the start of the study. It was actually an unresolved issue that many of us were continuing to debate up to the publication of this data, which certainly has now solidified the role of immunotherapy as a starting point for patients with BRAF-mutant melanoma.

Dr. Michael Atkins: Thanks, Gary.

Dr. Shannon Westin: I would love for you—because it is a complex design, and I feel like a lot of times, as drug developers, we're often discouraged to do too many lines in a row. And I was just so intrigued at how well this was laid out to really understand those very questions of superiority as well as sequence, which we don't often assess. Dr. Atkins, will you just summarize the design so that all of the very smart researchers on the line can utilize that for their own cancer types?

Dr. Michael Atkins: Yeah, it was complicated to execute, but the design was pretty simple. Patients with treatment-naive BRAF-mutant metastatic melanoma were stratified according to ECOG performance status and LDH normal and high and randomized in step 1 to receive either combination nivo-ipi induction for 12 weeks, followed by nivo monotherapy maintenance for up to 72 weeks—that was arm A, and that was standard of care for that regimen—or dabrafenib-trametinib continuously, and that was arm B. And if patients experienced disease progression and met the step 2 eligibility criteria, they were able to cross over to the alternative sequence: arm C, dabrafenib-trametinib, or arm D, nivo-ipi. And we followed the patients and chose two-year overall survival as the primary endpoint.

Dr. Shannon Westin: And we kind of got a little hint. So what was the primary finding?

Dr. Michael Atkins: Yes, because of the anticipated distinct shapes of the overall survival curves, with the BRAF/MEK inhibitors tending to have their benefit early and the immunotherapies tending to raise the tail of the curve, we thought there'd be non-proportional hazards and that the overall survival curves might cross. And therefore, we chose as a primary endpoint two-year landmark overall survival, with an estimate that the nivo-ipi first sequence would have a 70% overall survival rate compared to 50% for the dab-tram first sequence. And with 300 patients enrolled and 270 evaluable, there was about a 90% power to show this difference in two-year overall survival rate, with a two-sided type one error rate of 0.05.

Dr. Shannon Westin: And it met its primary endpoint?

Dr. Shannon Westin: Yes, the study was opened in July of 2015, and it was set up that there would be Data Safety Monitoring Committee meetings after the first 100 patients were accrued every six months and that the data cutoff used for the fourth interim Data Safety Monitoring Committee meeting, which was a median follow-up of a little over two years, 265 patients had enrolled in step 1—those were evenly split between the two arms—and 73 had enrolled in step 2, with nearly two-thirds of those being on arm D, second-line nivo/ipi. And the two initial arms were balanced for most of the characteristics and was randomized for the important characteristics.

And from an efficacy standpoint, once again, we chose landmark two-year overall survival as a primary endpoint. And the overall survival curves for the combined sequences showed the anticipated biphasic pattern; they actually crossed around 10 months, and 100 patients had died, with 62 of them on the sequence beginning with dab-tram. And the two-year overall survival rate was 72% for patients who started on nivo/ipi and 52% for those who started on dab-tram. And that was a pretty significant difference; P equals about 0.01 by log-rank test. And so this 95% repeated confidence intervals, along with the 20% difference in overall survival, ranged from 3% to 38%, and the O'Brien-Fleming boundary had been crossed based on this estimate. Interesting, as we published, the three-year overall survival difference was even greater, approaching 24%. So that was the main study endpoint. And because the Data Safety Monitoring Committee felt that that difference was clinically significant even though we had only had about 59% information, they recommended at that point that the study be closed early and that patients who were on arm B, dabrafenib-trametinib, be given the option to cross over to immunotherapy before disease progression.

So that was the primary endpoint. I'm going to pause there. There were some secondary endpoints that I think were interesting, but maybe Gary or Adil have comments about this.

Dr. Shannon Westin: I hope they do, yeah. I'm going to give over my podcast hosting to you.

Dr. Adil Daud: Mike, congratulations on that study. I mean, that's transformative. I mean, I think there was a feeling, like Gary was saying, that immunotherapy might be better in the long term. But I remember a lot of discussions, and I think you answered them in 2015 or 2014 and 2013 because you've been working on this design for a while, that the people who were treated with BRAF inhibitor therapy were just different. And a lot of people would say that when somebody walks into the clinic, the folks who are BRAF-mutant, they just have rapidly progressive disease, like something really bad is going on. And that's why the results on BRAF/MEK inhibitor therapy just looked different than immunotherapy. Immunotherapy was for slower-growing tumors, and I think your study kind of puts maybe a different spin on that, basically suggesting differently. Would you comment on that?

Dr. Michael Atkins: Yeah. So, Adil, I think early on, people thought that the BRAF/MEK inhibitor was for patients who had rapidly progressive disease, and you needed to get a response to get the disease under control. But over time, as those studies were followed out, it appeared that the BRAF/MEK inhibitors tended to work best in patients who had less aggressive disease—performance status 0, M1a or b disease, and normal LDH. And so it was still confusing as to who should get which therapies. And when you compared the results using retrospective data between those who got immunotherapy and those who got targeted therapy, it was really difficult to be sure that these were the same patient population. So the only way you could really know whether immunotherapy was truly better was to do prospectively randomized studies where the two arms were balanced, which is what we set out to do in DREAMseq.

Dr. Adil Daud: Yeah, I think there's a lot of areas in oncology where people think whether you should give somebody a CAR T-cell or whether you should give somebody myeloma therapy or—people think, well, these are just totally different. Or in melanoma, I think, the TIL therapy, there's this question about, can you really compare that to anything else? And I think your study, which perhaps wouldn't be done by a pharmaceutical company and perhaps wouldn't be— outside of the cooperative groups, I feel that it's hard to really do a study of that type.

Dr. Michael Atkins: I agree.

Dr. Gary Schwartz: Yeah. First, I want to say congratulations on really an extraordinary study, Michael. I think it really answers some critical clinical and biological questions that have been subject to debate in the melanoma and the medical oncology community for the last five or more years.

There were a couple of things that surprised me. One was the fact that patients that started on dab-trame, when crossed over to immunotherapy, the outcomes were pretty poor. And that was a biological outcome, I guess, we kind of thought about. But this study certainly suggests that there's something about prior targeted drug therapy that may affect outcome and immunotherapy. And also, the other thing that was surprising was the number of dropouts that developed and couldn't cross over because of the rapid progression on the first-line study. Do you want to comment on both of those points and maybe share some thoughts about what that means for the medical care of patients who get this type of treatment?

Dr. Michael Atkins: Sure. First of all, response rates were similar between the step 1 regimen and for dab-tram, whether used in step 1 or step 2. In contrast, as you said, nivo-ipi appeared to be less effective after progression on dab-tram than in the first line. It was like a 46% response rate in the first line, and about 30% in the second line. The median PFS in the first line was about 11+ months, and in the second line, was only about three months. And I think there was some feeling in the community—probably wishful thinking and also based on what I think are some flawed preclinical and translational studies—that BRAF/MEK inhibitors might cause some immunogenic cell death and cause new antigens to be expressed and activate the immune system, be synergistic with immunotherapy given afterwards, while I think other data suggested that the resistance mechanism to the dabrafenib-trametinib was immunosuppressive, leading to upregulation of VEGF and things like that.

So this result suggested that immunotherapy didn't work as well in the second line. There are probably several reasons for that. It could be biologic changes, which I think we don't pay enough attention to when we think about what we're doing in the first and the second line. But also the type of patients who progressed on BRAF/MEK inhibitors. when you stop those drugs, the disease tends to accelerate. Many of them probably had subclinical CNS disease, and it was just not a good time for them to be going on immunotherapy, while in the front line, you didn't have to deal with those type of issues. And with regard to crossover, one of the things that we looked at as a secondary endpoint in this study was feasibility of doing the crossover. Because in clinical practice, we found that if you waited until disease progression on BRAF/MEK inhibitors and then tried to cross them over, oftentimes, patients progressed really rapidly, and you weren't able to get the immunotherapy in to large degree, while in patients who got immunotherapy, they had a lot of toxicity often, which caused them to stop therapy. And if they had toxicity at the time they were progressing, it might be complicated to add new drugs in.

And so I think the community was a bit surprised that only about half the patients were able to successfully cross over. But I think that's reality, that if you use these drugs to progression and then have eligibility criteria, which you have to have in a clinical trial for patients to go on the second-line treatment, you're going to have a lot of dropouts. One of the major reasons for dropouts on dab-tram was progression in the CNS, and dabrafenib-trametinib doesn't work as well in the CNS as it does systemically, while immune therapy actually appears to work as well for patients with asymptomatic or undetected CNS metastases as it does systemically. And I think that was an important reason why immunotherapy was better.

Dr. Gary Schwartz: I've looked at your paper now multiple times, Michael, and I can't think of any reason why anybody would want to start a targeted therapy for BRAF-mutant melanoma. I mean, I think this really becomes a definitive study declaring that immunotherapy is where all medical oncology should begin in the treatment of BRAF metastatic melanoma. Is that too much of a statement to make, or would you agree with that as well? I've been trying to think of all the reasons why not to give immunotherapy first. I can't think of one now, after your paper, that would suggest otherwise.

Dr. Michael Atkins: Well, I've been chastened by a lot of reviewers, as you know, to say that these results only definitively apply to the patients who were eligible for this study. And patients who had poor performance status or active brain mets or who required steroids and needed to be in the hospital or had to have a response were not eligible for this study. And so I think there are some patients where the disease is just on fire, where you may need to give BRAF/MEK inhibitors to try to cool it off before you start immunotherapy, particularly if patients need to be on immunosuppressive drugs to control edema in their brain, or because of bone mets pressing on the spinal cord or things like that, I think that it's important to have that other option. But as soon as you can, as soon as you've created enough window to get patients off immunosuppressive drugs or improve their performance status enough so that they can be an outpatient, you probably should switch to immunotherapy and give them the chance for a long-term benefit.

Dr. Adil Daud: I have doctors call me outside of academia and say, "Hey, I've got a patient walking in. I'm trying to decide, should I do the triple therapy, or should I do…"—which triple therapy in melanoma refers to dabrafenib plus trametinib plus a PD-1 drug like pembrolizumab or, in some cases, like a PDL-1 inhibitor—and they're questioning whether that's an appropriate place to start. Or sometimes people say, "Well, what about doing a sandwich regimen where we start off with dabrafenib-trametinib and then switch over to something else without waiting for progression just to give people…" And I give a long-winded answer to that, but I'm curious to hear what you think, what you both think.

Dr. Michael Atkins: So my view is—I've always thought, based on some of our early translational studies, which were presented at ASCO and hopefully we'll be able to publish soon, that the BRAF/MEK inhibitor data that showed that there was an influx of immune cells and potential synergy was actually an artifact, that it was not increasing immune cells in the tumor microenvironment, but actually loss of tumor cell in the tumor microenvironment that was causing the impression that the tumors were more inflamed. And I felt that when it came to immunotherapy, BRAF/MEK inhibitors were not ipilimumab and were not going to add to the benefit that we see with immunotherapy of durable responses the way you can see with nivo/ipi.

So I've stayed away from those triplet regimens, and I think we've seen with the studies that have been published so far that they tend to have sub-additive benefit when you add an anti-PD-1 to BRAF/MEK inhibitors. You see some prolongation of PFS, but you don't see the same tail of the survival curve. And even at two years, the tail of the survival curve for those triple regimens is below where it is for nivo/ipi in the BRAF-mutant population all the way out at five years. And the nivo/ipi population—I'm talking about the progression-free survival curve—and that nivo/ipi population can still get BRAF/MEK inhibitors if they progress. So I think that triple regimen, I can't think of a patient where I would use that. But the sandwich regimen, as I was just describing, may be useful in some patients who just aren't in appropriate shape to start with immunotherapy.

Dr. Gary Schwartz: Now, I would agree with Michael. I think the clinical trial data would really discourage the use of triplet therapy. They really lean—again, the benefit of triplet therapy for all the published papers we've seen so far in that area. But I guess you're right. The idea, if you have one of those patients that comes in and who's really on fire with rapidly progressive disease, on steroids, and needs a very quick benefit, perhaps initiating targeted therapy first for a short time would be reasonable in the treatment of those patients. But beyond that, I really think there probably are not going to be many exceptions to starting immunotherapy first because your data, to me, strongly would suggest that starting targeted therapy is going to diminish the benefits of immunotherapy to follow. And that, to me, is an important take-home point of the study and sort of validates some of the preclinical data. I mean, depends what you look at. But there is preclinical data suggesting that MEK inhibition will diminish T-cell responsiveness, and I think this supports that biological effect. So I think we have to be cautious about upfront targeted drug therapy now and have to find what are those opportunities where it may be appropriate. But I think they're really diminishingly few.

Dr. Michael Atkins: And I would just emphasize the flip side of that, which is that targeted therapy is equally effective in the second line for patients who don't respond to immunotherapy. And I think that was also a critical component of why the immunotherapy first sequence was better than the targeted therapy first sequences. You had better salvage.

Dr. Gary Schwartz: That's a very good point.

Dr. Shannon Westin: Well, I personally just want to thank the three of you. I learned a ton today, and I fully intend to take that back to the work that we're doing in gynecologic malignancies, combining immune therapies and targeted therapies, and I hope our listeners will do the same.

Further, I agree with you, Dr. Schwartz. I think this is a practice-changing study. I appreciate you, Dr. Atkins, in being a little cautious. I appreciate the editors that reviewed it as well. But this is as clear a definitive trial as we can get and a testament to your hard work through the cooperative groups, which we all know can be a struggle in itself to get this type of trial through. So congratulations again.

Dr. Gary Schwartz: And I think the lessons learned in melanoma are going to be applicable to all solid tumors. So melanoma is about so far ahead of many other tumors, but what we learned here isn't just impacting melanoma, but will impact all cancer medicine. And I think that what's so important about this trial is that lessons learned here really are broadly based and have clinical applications to many patients getting immunotherapy, targeted drug therapies today. So congratulations, Dr. Atkins. I think you hit a home run on this one. The medical oncology community is indebted to you and to your group to making this possible. And thank you for bringing it to JCO as well. I think that itself speaks to the success of the journal and the impact these types of studies have on reaching a large segment of the medical oncology community.

Dr. Michael Atkins: Well, thank you very much, Gary. I do want to emphasize the point you made, that I think this result does impact how we think about the use of targeted therapies or chemotherapies or antiangiogenic therapies in other tumors in coordination with immunotherapy. And I'm sort of on a mission to make the point that if you want to get the most benefit out of immunotherapy, you should give it first, and you should give it unencumbered by other things that might interfere with its activity.

Dr. Gary Schwartz: I think that's the last word, Shannon.

Dr. Shannon Westin: I believe it is. I believe it is. Thank you all so much for being here. And thank you to our listeners for being here for another episode of JCO After Hours. Again, we were discussing "Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients With Advanced BRAF-Mutant Melanoma: The DREAMseq Trial—ECOG-ACRIN EA6134," published in January 10^th, 2023, in the JCO.

Please do check out our other podcast offerings. You can check them out on the JCO website or anywhere you get your podcasts. Until next time, be well.

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Sequencing Matters – Combination Dabrafenib/Trametinib Versus Nivolumab/Ipilimumab for Advanced BRAF-Mutant Melanoma: The DREAMseq Trial

Journal of Clinical Oncology (JCO) Podcast

Sequencing Matters – Combination Dabrafenib/Trametinib Versus Nivolumab/Ipilimumab for Advanced BRAF-Mutant Melanoma: The DREAMseq Trial