Recent Developments in Management of Gynecologic Cancers - Episode 12

Standard Frontline Therapy for Endometrial Cancer


Bradley Monk, MD, FACOG, FACS: The standard frontline treatment for endometrioid or serious tumors has been carboplatin-paclitaxel. Endometrial cancer is clearly a very heterogeneous disease. One of the rare histologies is carcinosarcoma. The traditional treatment has been unknown. There was a study here at this meeting, the American Society of Clinical Oncology Annual Meeting, from the NCI [National Cancer Institute] and GOG [Gynecologic Oncology Group], GOG-0261. Jubilee, tell us about that.

Jubilee Brown, MD: Yeah, gladly. Matt Powell presented this information on GOG-0261 that looked at both ovarian and uterine carcinoma sarcomas. It was a large study, over 600 patients enrolled with a primary endpoint of overall survival. And what this trial did was to compare paclitaxel with ifosfamide and mesna, which historically has been relatively toxic and difficult to administer. So not a lot of enthusiasm for giving that, to paclitaxel and carboplatin, which of course we have a lot experience with.

Interestingly, progression-free survival [PFS] and overall survival [OS] were both improved on the paclitaxel, and carboplatin didn’t reach significance. But the toxicity of course was, as expected, worse with the ifosfamide-containing component. What this does is give us a new standard for paclitaxel and carboplatin.

Thomas Herzog, MD: Thank God.

Bradley Monk, MD, FACOG, FACS: What did you say?

Thomas Herzog, MD: Thank God—I hate ifosfamide.

Bradley Monk, MD, FACOG, FACS: And the statistics were noninferior.

Jubilee Brown, MD: Correct.

Bradley Monk, MD, FACOG, FACS: Krish, does that change your treatment?

Krishnansu S. Tewari, MD: It changed it awhile ago.

Bradley Monk, MD, FACOG, FACS: So you’re already doing it?

Krishnansu S. Tewari, MD: Well, when we designed the trial, a lot of these drugs were available—carboplatin, paclitaxel—and we definitely need the trial to validate these things. But the trouble with ifosfamide-paclitaxel is, as you said, it’s difficult to administer and difficult to tolerate.

Bradley Monk, MD, FACOG, FACS: So it joins the graveyard of intraperitoneal chemotherapy?

Krishnansu S. Tewari, MD: Yup, there you go.

Michael J. Birrer, MD, PhD: And it got into the treatment primarily because IFOS [ifosfamide] was used for soft-tissue sarcomas.

Bradley Monk, MD, FACOG, FACS: Which this is really epithelial.

Jubilee Brown, MD: It’s not a sarcoma.

Thomas Herzog, MD: Great point.

Bradley Monk, MD, FACOG, FACS: So we talked about the opportunity for pembrolizumab in mismatch repair deficient tumors. Probably the other biomarker, other than mismatch repair deficiency, is HER2. Tell us about HER2 testing and trastuzumab, Tom.

Thomas Herzog, MD: Brad, I think you said it well. If you look at cervical cancer, you’re looking at PD-L1 [programmed death-ligand 1] and you’re looking at HER2 now. Now with endometrial cancer you’re looking at an MSI [microsatellite instability] and HER2. And there have been data that have been evolving. There were several abstracts at the SGO [Society of Gynecologic Oncology Annual Meeting], a couple by Dr Haider Mahdi looking at cell lines, both in UPSC [uterine papillary serous carcinoma] as well as endometrioid showing an advantage despite what strategy you use of going after the overexpression, whether an antibody drug conjugate or more of a global inhibitor.

And I think all this preclinical work has led to the recognition that a clinical trial was indicated and was published. Amanda Nickles Fader published in JCO [Journal of Clinical Oncology] in July of last year. And just as a randomized phase II trial with 61 patients. But it combined with CARBO [carboplatin]-paclitaxel in HER2 over expressors, UPSC, and it was 8 versus 12.6 months in terms of the difference.

Bradley Monk, MD, FACOG, FACS: For trastuzumab.

Thomas Herzog, MD: Yeah, which was a hazard ratio of 0.44. By adding the trastuzumab it reduced the risk of progression by nearly 60%.

Bradley Monk, MD, FACOG, FACS: This is a big deal. Test your cervical cancer for PD-L1 and EGF-activating mutations as we talked about. And HER2 neuro overexpression or amplification in MSI-high in endometrial cancer. Finally we’re getting close—because of Dr Birrer, because you’re the biomarker guru. Finally, we’re getting biomarkers in our tumors.

Michael J. Birrer, MD, PhD: Yeah, it’s going to clearly help the patients maximize effect—you know, the efficacy of our drugs and minimize toxicity.

Bradley Monk, MD, FACOG, FACS: I want to talk about 2 final topics. One is adding a checkpoint to chemotherapy. Well, maybe we can do that now. Tom, is checkpoint being added to chemotherapy frontline? Because that’s the idea.

Thomas Herzog, MD: There are a number of trials out there. It makes sense from preclinical rationale. The science is there to support it, and we await the data.

Bradley Monk, MD, FACOG, FACS: We have it with atezolizumab and nab-paclitaxel in breast cancer, and platinum taxane in lung cancer, so I like that. Michael, tell me about this idea that we can use anti-VEGF therapy to improve I/O [immuno-oncology]. The highest unmet need now in second-line endometrial cancer is those patients who are not mismatch repair deficient. There’s this whole idea that we can add anti-VEGF to PEMBRO [pembrolizumab] in the microsatellite stable group.

Michael J. Birrer, MD, PhD: That’s right. Again, from a biologic standpoint, there’s a lot of rationale to do that. Tumors have essentially, for lack of a better description, messed up vessels from high levels of VEGF. And that means that immune cells can’t necessarily traffic. So if you give BEV [bevacizumab] and you normalize those vessels, then it’s easier for the TILs [tumor-inflating lymphocytes] to get access. VEGF itself is a very immunosuppressive agent.

Bradley Monk, MD, FACOG, FACS: That’s the point.

Michael J. Birrer, MD, PhD: We haven’t really explored all that, but I think those are the basis and the rationale for combining these 2. I think it needs settings. Also, we know BEV is active as a single agent. We also know I/O is active, maybe not as much in the stable group. We can debate that. For all those reasons it makes a lot of sense to do that. It may be that BEV isn’t the best drug. Maybe a TKI is.

Bradley Monk, MD, FACOG, FACS: To that point, PEMBRO-lenvatinib is an opportunity for an oral anti-VEGF, anti-PDGF, with pembrolizumab. So that’s being studied in multiple tumor types. Recently published in Lancet Oncology was this single-arm phase II. And as a result, it got breakthrough designation.

That is being studied in a prospective fashion, second-line endometrial: PEMBRO-lenvatinib versus physician’s choice chemotherapy. I don’t know what second-line treatment is in endometrial cancer, but that study included weekly paclitaxel and doxorubicin. Also being studied frontline in a chemotherapy-free option are carboplatin, paclitaxel versus PEMBRO-lenvatinib.

You were talking about breakthrough designation. We got breakthrough designation in the mismatch repair proficient endometrial group with PEMBRO-lenvatinib. You told me we got a TIL in cervical cancer just a few weeks ago, and then I was thinking, “Has it ever happened before?” And the only other time we’ve had breakthrough is ARIEL2 with rucaparib. So breakthrough designation in both of those settings—the TIL, and also in the PEMBRO-lenvatinib—again, it doesn’t guarantee FDA approval but facilitates it.

Transcript Edited for Clarity