番茄社区

Results from two phase III trials (NRG-GY018 and RUBY01) presented earlier this year at the Society of Gynecologic Oncology (SGO) annual meeting demonstrated that immunotherapy combined with standard chemotherapy significantly improved progression-free survival in patients with advanced or recurrent endometrial cancer.

Two oral presentations were given at the recent American Society of Clinical Oncology (ASCO) meeting, and physicians were still buzzing about how NRG-GY018 and RUBY01 will change the future of treatment for their patients, along with the implications for second-line care.

番茄社区 brought together three expert leaders in the field -- moderator , from the Dana-Farber Cancer Institute in Boston, is joined by , of Mass General Cancer Center at Massachusetts General Hospital in Boston, and , also from the Dana-Farber Cancer Institute -- for a virtual roundtable discussion. This first of four exclusive episodes focuses on the strengths and potential weaknesses of both of these studies, and the clinical implications for the future.

Following is a transcript of their remarks:

Campos: Hi, good morning, my name is Susana Campos. I'm a medical oncologist at Dana-Farber Cancer Institute, and I'm joined today by two of my colleagues, Dr. Penson and Dr. Lee. I'll let them both introduce themselves, Dr. Penson.

Penson: I'm a medical oncologist at Mass General in Boston, and it's fabulous to be here. Great to be thinking about some of the highlight moments from ASCO.

Campos: Thank you so much. And Dr. Lee.

Lee: Hi, I'm Elizabeth Lee. I'm a medical oncologist in the gyn oncology group at Dana-Farber, and I'm also a liaison within our early-phase trials group here as well.

Campos: Thank you so much for joining us this morning. And I think in the next hour or so, we're going to be actually reviewing some of the data that was presented at the American Society of Clinical Oncology meeting. And I think we'd all agree that it's been a really exciting year in gyn in terms of some updates in uterine cancer, some very key pivotal trials, some very interesting overall survival data in cervical cancer. And, most recently, some really very innovative data in terms of platinum-resistant ovarian cancer. So we do have our work cut out for us this morning.

So we're going to start off what made the biggest hit in the [SGO meeting] back in March, as well as at the American Society [of Clinical Oncology] meeting. And that really is our concentration in uterine cancer. For many years, we've had many studies that actually allowed us to treat patients with uterine cancer, but I think most recently with immunotherapy, we've had two pivotal trials that have actually really changed the management of uterine cancer going forward. And what I'm hoping to do is talk a little bit about it, talk about the strengths of both of these studies, and then perhaps some weaknesses of the trial, and maybe some implications for the future.

So, Dr. Lee if you'd start us off, if you could just give us a little briefing perhaps on what was presented at ASCO, the RUBY, and perhaps then we can dive into the NRG-018 [NRG-GY018] please.

Lee: Sure. So we've had a lot of exciting data presented both at the [Society of Gynecologic Oncology] conference as well as at ASCO in regards to uterine cancer. And this was two studies looking at the addition of immunotherapy, so immune checkpoint inhibition to chemotherapy. For both of these trials, these were looking at stage III or stage IV or recurrent endometrial cancer, looking at the combination of carboplatin and paclitaxel [Taxol], so chemotherapy with or without an immune checkpoint inhibitor. With RUBY, this was with dostarlimab [Jemperli], with GY018 this was with pembrolizumab [Keytruda]. And with that immune checkpoint inhibitor continued as maintenance therapy following.

I think there were some very exciting results for both of them, especially within the mismatched-repair [MMR]-deficient/microsatellite instability-high [MSI-high] population, and I think a little bit more of a discussion and a debate within the mismatch repair-proficient group. But overall, very exciting results.

Campos: Indeed, and in these two trials, the NRG-018 and the RUBY01, in many ways they're similar because they asked the question of immunotherapy, granted one with pembrolizumab and one with dostarlimab. And they really did highlight the benefit into deficient MMR. But they also, to our surprise, gave us very inviting data in terms of the proficient [group]. In the NRG-018 there were two endpoints. They looked at progression-free survival, both in the deficient MMR, as well as in the proficient. And in the RUBY01 using dostarlimab, they utilized a different design. They looked at the progression-free survival with the deficient MMR, and they looked at the group as a whole. And the RUBY01 does have overall survival benefits.

What do you see as potential advantages or disadvantages in either one of those studies? Like, what are some of the questions, are you happy with the design? What are some of the questions that you're thinking about as these results have emerged?

Penson: So I do think it's very exciting when there's two New England Journal [of Medicine] papers that come out as companions to the SGO meeting, and then I think unprecedentedly two oral presentations at ASCO on the RUBY trial. And so this is high-impact, practice-changing, and we anticipate this particular expansion of indication to be approved at the end of the year. So exciting, it makes a difference for patients.

For me, the similarities of the studies were a bit greater. So a hazard ratio of of 0.3 roughly, for their [MSI-high]. That's absolutely staggering. That's a 70% reduction in the risk of recurrence of death in the RUBY study. And then in the proficient tumors, the more common tumors, in RUBY it was like 20%, 25% of the participants had [MSI-high tumors].

And there were sort of two things [that] were important. Clearly they did much better, a massive improvement in outcomes. The second thing was that the dostarlimab was given for up to 3 years, and yet the progression-free survival curve, so really sort of disease-specific outcomes, really went flat at 1 year. There was a little bit of a gap that with longer follow-up the curves went flat.

So the idea is the concurrent 500 mg, and then the six weekly 1,000 mg afterwards, you may not even need that for longer than that first year. It's absolutely fabulous that patients are doing so well. So a year of immunotherapy transforms chemotherapy. Some people may say well, in Taxol/carbo [carboplatin], a third of people are still around at 5 years. But this is really groundbreaking. This is when immunotherapy changes outcomes for patients.

Campos: No, I agree. And Dr. Lee, your take on this, please.

Lee: I fully agree with Dr. Penson. And I think something that has not yet been explored that I am very eager to hear about eventually is looking at the subgroup of patients within the mismatch-repair proficient group who are part of that tale on the survival curves. I don't think we yet have any translational data suggesting if there's particular molecular features within the mismatch repair-proficient group that lends them to having these durable responses

Penson: With Vicky Makker's data on lenvatinib [Lenvima]/pembrolizumab altering the microenvironment particularly for the patients with the mismatch repair-proficient tumors, the more common garden endometrial cancer, that's exactly where we're headed. We're headed to try and get every patient to do as well as patients with Lynch syndrome or mismatch-repair deficiency, where they clearly do a ton better -- more antigen expression, activation of the sort of pathways that really sort of frame the setting where you're going to do well with immunotherapy. That's the next horizon, but this is a milestone. Very exciting.

Campos: Yeah, I completely agree. We haven't had something like this in a very, very long time. And to Dr. Lee's point, looking at the proficient MMR, in many ways I think that's probably the most exciting cohorts, probably the most heterogeneous cohort. So I too have these questions like, who lies within the proficient? What translational elements will come to light that will allow us to understand why some do and some do not? For example, in the proficient, how many of these patients had POLE mutations? How many of these individuals had a high mutational burden? And how about those that did not? Did they fare as well? So I think as time goes forward, we'll get a little bit more information.

We're also going to get a little bit more information about the subgroups because as we know, RUBY01 did include uterine pap [papillary] serous and also included the carcinosarcomas, which are rarely included in any of these trials. So I do agree, NRG-018 and certainly RUBY01 certainly has changed things around. Dr. Lee, do you want to talk a little bit about RUBY01, as some of the data presented at ASCO?

Lee: Sure, I'm happy to talk about that. So the RUBY01 study, this was the combination of carboplatin and Taxol with dostarlimab. So using dostarlimab as immune checkpoint inhibitor continuous maintenance for up to 3 years following completion of chemotherapy.

As you noted, this was a trial that allowed very unusual and aggressive subtypes of uterine cancer that we typically do not see. And I think that is a point where I would be very interested in looking at the results based on histologic subtype. So carcinosarcoma was allowed, mixed clear cell uterine serous, they were all allowed. These patients were randomized in a 1:1 fashion to receiving either the chemotherapy with placebo or chemotherapy with dostarlimab and the continuation of either the placebo or dostarlimab as maintenance.

I do think it was important to note these patients were stratified by their mismatched-repair status. It ended up being fairly well balanced between the two arms of treatment, as well as by receipt of previous radiotherapy. And again, that was pretty well balanced as well.

I think some of the data we've already talked about that has been quite striking is based on the median progression-free survival and the reduction in the risk of progression or death, particularly in the mismatch repair-deficient group. And this was notably pretty concordant between investigator assessment as well as the BICR, the blinded independent central review. So there was good concordance there, that was one of the findings from the presented RUBY study.

I think the early OS [overall survival] data is very intriguing, but wanting to acknowledge that it is not mature, it's not fully mature. And so even though it is a trend towards a very intriguing overall survival signal we do have to take that with a grain of salt.

Campos: Yeah, agreed, absolutely. And only time will tell, hopefully time will pass quickly so we can actually get that overall survival benefit.

Now, in the practical terms, we know the studies, we know the hazard ratios, we know the patient population, the stratification. But when it comes down to the clinic, understanding that these regimens are not FDA approved at this point in time, understanding they are a category I on the NCCN [National Comprehensive Cancer Network] guidelines. What do we do practically in our clinic? So I'm going to pivot to Dr. Penson and, Dr. Penson, in your clinic you have a patient that comes in proficient MMR, are you offering pembrolizumab or dostarlimab to all of your patients, or are you considering those that you should or should not?

Penson: So it's not approved actually in this indication right now. It's just for the single-agent treatment that's coming up at the end of the year. But we absolutely are offering it. The pembrolizumab and dostarlimab are amazing agents, and this was instantly practice-changing. There's a famous old rule at the New England Journal of Medicine from one of the GI [gastrointestinal] docs ages ago, that if something came across his desk as the editor, it should go out in the next edition if it should change [practice] for patients, and this is that. Patients should have access to this.

Campos: Excellent. And Dr. Lee, we tend to practice in the same microenvironment. So your thoughts on [this], we're clearly offering these two agents to patients with deficient MMR status, but the proficient, Dr. Lee, how are you feeling about that particular group?

Lee: So, I completely agree. So for patients with mismatch-repair deficient, I think it is just without a doubt something that needs to be discussed and offered. And it's a little bit more of a nuanced discussion that I have with my patients with mismatch-repair and molecular alterations, more predictive of response to immune checkpoint inhibition with mismatched repair-proficient disease. So I do try to say there is evidence of some benefit, but I also have to walk all of my patients through the potential toxicities. There are sort of the anticipated toxicities related to chemotherapy, certainly, that span across both groups receiving chemotherapy, but the addition of potential immune-related adverse events that have to be talked about as well. Whether that's endocrine or cutaneous or GI toxicities being the most common, it is important to note there.

Campos: Agreed. And the million dollar question is, let's say we adopt pembrolizumab or dostarlimab in stages III/IV recurrent disease and then the patient recurs. And I think this is a subject that's coming to light. What is our data? Where are we going after IO [immunotherapy]? Dr. Penson highlighted the KEYNOTE-775 study, and basically the benefit of pembrolizumab and lenvatinib, that was in an era where we were not using prior IO. But our world has just changed.

And I know this is not data that we have, and we do not have a study to draw from, but at the end of the day, let's think practically in terms of, we are all clinicians. And what if you have your patient on pembrolizumab or dostarlimab and then they recur? So Dr. Penson, I'm going to make this up, but let's pretend that it's a year and a half out, even better, 2 and a half years out, you've chosen pembrolizumab. Would you go back to pembrolizumab and add the lenvatinib? What are your thoughts on that?

Penson: So I think it's an example of when the armamentarium of the oncologist is sort of augmented -- and within sort of really underlined in terms of the potency of immunotherapy -- we are trying to get ARID1A [AT-rich interaction domain 1A] or [MSI-high], or clear cell ovarian cancers to sort of really respond, but it's not a sort of hot tumor, not even a warm tumor where we see better outcomes.

Endometrial cancer is completely different. Immunotherapy has arrived and has transformed the care of our patients. So if a patient is reasonably fit, doesn't have another autoimmune disease, doesn't have a pressing sort of visceral crisis, isn't slipping clinically with failing health, then I think a second-line immunotherapy is absolutely reasonable.

What you're alluding to, and I completely agree, is that this completely requires that we re-benchmark the outcomes. We can no longer sort of talk about the great outcomes for lenvatinib/pembrolizumab because almost all of our patients are going to be previously treated with another PD-1 inhibitor.

So I think the lenvatinib/pembrolizumab sets the stage for clinical trials to sort of change what we're doing, add in other agents we've been looking at: PARP inhibitors, angiogenics, Cytoxan [cyclophosphamide] may have a role altering T-cell subsets. But we don't know what the effective second-line therapy is now that the agents have moved up to frontline therapy.

Campos: Yeah, I agree completely. And Dr. Lee, anything to add on that note?

Lee: So if there is a patient who, let's say is progressing on first-line maintenance dostarlimab for example, going by the review treatment paradigm, I don't think that we have data at this point to suggest that they would not subsequently respond to pembrolizumab and lenvatinib. There's a potential if we think mechanistically that perhaps adding an anti-VEGFR [vascular endothelial growth factor receptor] agent may be able to rescue some sort of an immune response and alter the tumor microenvironment a bit more. But because of this data being so new, we don't have that data yet of sequential IO to IO plus anti-angiogenic.

So I would say that if I had a patient in clinic who had progressed on maintenance immunotherapy, I would not deprive them of the chance to try, certainly with a caveat of making sure they are clinically stable and able to do so, of trying pembrolizumab and lenvatinib subsequently.

Campos: Yeah, I completely agree. I think it's uncharted waters, but I agree and perhaps resurrecting another response by carrying over the pembro [pembrolizumab] and adding lenvatinib. The lenvatinib is a very strong contender in that particular ground. Or perhaps a different combination of immune therapy could be an alternate contender.

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