Evolving Treatment Paradigms in Endometrial Cancer - Episode 12

Novel Targets of Interest in EC

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Experts in endometrial cancer comment on novel targets of interest that are currently being investigated.

Brad Monk, MD, FACOG, FACS: Dave, I want you to discuss this point: If PARP inhibitors work in this DNA damage-repair pathway, there’s emerging evidence that maybe WEE1 inhibition might be effective in treating serous cancer. A novel agent is pushing the envelope—it’s so much fun. Tell us about that as an opportunity.

David O’Malley, MD: It’s really interesting from a WEE1 standpoint. Joyce Liu presented at last year’s ASCO [American Society of Clinical Oncology Annual Meeting] on an agent—I believe it’s pronounced adavosertib. I’ll say that faster and try not to butcher it that badly.

Brad Monk, MD, FACOG, FACS: AZD1775. It is 1 of the few instances in which I can remember the number. Keep telling the story.

David O’Malley, MD: The fun part is that I give Brad these entertaining pronunciations, so we always get a good laugh. We just talked a lot about the activity with the lenvatinib-pembrolizumab approach—about 30% in the recent AZD1775 trial. The WEE1 inhibitor, which was used to treat 34 patients, is something we have to take this with a grain of salt—34 patients who Joyce presented had a response rate of 29% with a duration response at 9 months. Everybody had to have 1 regimen of prior systemic chemotherapy, but it’s very interesting because this is an extremely heavily pretreated group of patients with 3 prior regimens. Three prior regimens with a response rate of 29%—in these patients with serous cancers, that’s a very impressive response. This is a very exciting opportunity that we are going to continue to see develop in the future.

Brad Monk, MD, FACOG, FACS: The sponsor of that trial is continuing the study. There are at least 2 other WEE1 inhibitors, which are in the clinic. I don’t know if those studies are in the public domain, but there’s going to be an accelerated approval opportunity: Enroll 100 patients, show that there’s a response rate, and then we would design and execute the randomized phase 2 trial. I’m excited about that. I’m just going to roll through these new agents. We’ve already talked about 2. Ketta, CDK4/6 inhibitors really have revolutionized the ER [estrogen receptor]–positive landscape in breast cancer, but you have knowledge of a European trial and some other studies that have generally used an aromatase inhibitor plus CDK4/6. Tell me what you know about that.

Domenica Lorusso, MD, PhD: It was really exciting to see the results of the ENGOT-EN3-NSGO/PALEO trial last year during ESMO [European Society for Medical Oncology Congress]. We’re taking the opportunity with the lesson we learned in treating breast cancer. Mansoor Mirza was the PI [primary investigator], and he performed this randomized phase 2 trial. It was a small trial, but there was a strong proof of concept suggesting that when we combine the aromatase inhibitor—letrozole, in this case—with palbociclib, a CDK4/6 inhibitor, we are able to increase response rates and progression-free survival [PFS] with respect to letrozole alone. Particularly, the subgroup analysis suggests that the benefit is higher in patients who were pretreated with hormonal treatment. We are designing the phase 3 confirmatory trial, and if these results are be confirmed in the future, we may have this combination to treat all receptor-positive tumors.

Brad Monk, MD, FACOG, FACS: This is 1 of the 4 groups of the molecular staging, so it all comes together. It’s really exciting.

David O’Malley, MD: I want to make 1 correction. I may be wrong, but I don’t believe there’s a difference in the response rates, and these agents don’t seem to shrink tumors. They slow the growth. It is much different from when we discussed lenvatinib-pembrolizumab when we discuss these WEE1 inhibitors. In the future development of these drugs, a patient who is not symptomatic, a patient who does not have a rapidly growing tumor, is going to be impacted. So it’s very important, as we develop and look at these drugs, to know that is the problem. The CDK4/6 inhibitors don’t seem to shrink tumors when you combine them with AIs [aromatase inhibitors]; they keep disease stable.

Brad Monk, MD, FACOG, FACS: That’s a great point. In breast cancer, they shrink tumors. Go ahead, Ketta.

Domenica Lorusso, MD, PhD: I just have a comment on the toxicity of this drug. In the ENGOT-EN3-NSGO/PALEO trial, we have a huge percentage of patients who discontinue treatment because of toxicity. We’re talking about a fragile population. These are older patients with several comorbidities, so this aspect should be taken into account in the next trial.

Brad Monk, MD, FACOG, FACS: I’ll get to you in a minute, Nicoletta. Dave, I wanted to highlight you because you’re working on the POD1UM study, FGF/IDO1. Tell us about that.

David O’Malley, MD: This was an interesting umbrella study. They are taking 2 parallel groups of patients: those who have been exposed to previous I/O [immuno-oncology] therapy and those that are not. Those who have not been exposed are using their PD-1 inhibitor, looking at both patients with high MSI [microsatellite instability] as well as the patients with deficiency, as a single-agent therapy. Those that have been exposed are taken out, and we are looking at the unselected population, which is the PD-1 inhibitor, plus the IDO1 inhibitor vs a select population of those with amplified or mutated in the FGFR1, FGFR2, and FGFR3 domain. When they add that, then they’re adding an additional agent that’s specific to the FGFR1, FGFR2, and FGFR3 patient population. We’re being smarter and more personalized in taking that molecular signature to the next level—which is not just TP53, not just deficient or proficient MMR [mismatch repair], but taking it and utilizing next-generation sequencing on the tumor to have more rational therapeutics.

Brad Monk, MD, FACOG, FACS: We talked about dostarlimab. Dostarlimab should be the seventh checkpoint inhibitor in the clinic. This 1 that you’re talking about, which was used in POD1UM, is called retifanlimab. Retifanlimab has been submitted to the FDA for approval for treatment for patients with anal cancer, especially HPV [human papillomavirus]–positive anal cancer, so that will be seven and then eight. That’s a very congested landscape, but it’s interesting.