Advanced Endometrial Cancer - Episode 13

Endometrial Cancer: Chemo-Free Regimens on the Horizon

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Bradley J. Monk, MD, FACS, FACOG: Let’s talk about some novel targets. One of the questions I always have is chemotherapy versus hormonal therapy. I know, Brian, you’ve been a passionate advocate for everolimus, letrozole, one of the chemotherapy-free regimens beyond pembrolizumab, lenvatinib—that’s a second one. Now the third one is an aromatase inhibitor, a CDK4/6. Tell us about this third chemotherapy-free combination. You’ve got letrozole, mTOR everolimus; you’ve got pembrolizumab, lenvatinib; and now you have CDK4/6, AI. Tell us about that.

Brian M. Slomovitz, MD: There are many different options for endometrial cancer. Katie alluded toward this. Right now, we’re doing it mostly on trial, it’s tough to get off trial. But there was a recent study presented at ESMO [the European Society for Medical Oncology annual meeting] by the ENGOT [the European Network for Gynaecological Oncological Trial] group, the PALEO trial, looking at a CDK4/6 inhibitor plus letrozole, versus letrozole alone. They really did significantly better as far as progression-free survival [PFS] in the CDK4/6 plus letrozole group. Within the GOG [Gynecologic Oncology Group], we have a single-arm activity trial opening up.

Again, this mimics what we’re learning in breast cancer, where it’s an FDA approved indication, that a CDK4/6 plus letrozole is likely going to be, we saw it in PALEO and we’re likely going to confirm it, an active regimen for patients with endometrial cancer. It has a different set of adverse events, a different toxicity profile. But it provides more options, which is great when we’re talking about treating our patients with endometrial cancer.

Bradley J. Monk, MD, FACS, FACOG: Yes, we talked about trastuzumab adding to chemotherapy to treat serous patients who are HER2positive. I’m hoping that a CDK4/6, AI would get compendium listing, which the HER2 opportunity is. Did your everolimus, letrozole ever get compendium listing?

Brian M. Slomovitz, MD: Yes, it did. That’s everolimus, letrozole versus what Dave alluded to, the progestin, tamoxifen in GOG-3007, and it got listed in the NCCN [National Comprehensive Cancer Network] guidelines. The key there, we saw a similar response rate to hormones, but our progression-free survival in the chemotherapy-naive patients was 24 months. It’s an active regimen, very tolerable. Not to forget in this age of COVID-19 [coronavirus disease 2019], which we keep hoping to talk about in past tense, but we’re not, oral regimens could keep patients out of the infusion center.

Bradley J. Monk, MD, FACS, FACOG: Yes. Krish, you’ve had the pleasure of training under Dr Desai. I can remember talking to you about some of these patients who were treated initially with antihormonal therapy and lived for a long, long time, particularly with lung metastases in his patients. Do you ever use hormonal therapy before chemotherapy?

Krishnansu S. Tewari, MD: No, but I use it after.

Bradley J. Monk, MD, FACS, FACOG: OK.

Kathleen N. Moore, MD: To your point, I love to use it first. I love trials, but that’s exactly the patient population, these patients who come in with recurrent disease in their lungs. You put them on tamoxifen, Megace [megestrol], or I actually like Brian’s regimen now better. They can cruise for years without chemotherapy. I don’t know what it is about the lung metastases, although I have seen benefit in abdominal metastases, as well, in older patients who don’t want chemotherapy. It’s a very important thing to remember when you have a lot of these patients who are frail and have medical comorbidities. For endometrioid cancers, this is a really effective set of combination options in which patients can just cruise.

If they don’t, just like to your point earlier Krish, try it. If it doesn’t work, you can go to chemotherapy. That’s fine. You’re not going to lose that much ground over 2 months potentially. That’s an important thing that I think people forget in endometrial cancer, even though they’re so used to it in breast cancer.

Brian M. Slomovitz, MD: Real quick, cross-trial comparison. We’re not allowed to do it. But GOG-209 was reported: measurable disease, 52% response rate, as Katie mentioned earlier, 24-month PFS. Chemotherapy, you lose your hair, toxicity, tingling, everything. Everolimus, letrozole, chemotherapy naïve, get the prescription, take it home: 53% response rate, 24-month PFS. Same outcome, different profile.

Bradley J. Monk, MD, FACS, FACOG: Interesting, lower extremity edema. Wee1 inhibitors, Krish. Tell us about that, I saw these data presented on the Wee1 inhibitor AZD1775 [adavosertib] in the serous tumors. I’m not very familiar with that.

Krishnansu S. Tewari, MD: It’s another checkpoint inhibitor, but it’s not an immunologic checkpoint. This is a cell cycle checkpoint inhibitor. This is a novel mechanism of action. It inhibits the molecule that shuttles cells into the mitotic phase. This is about 30 patients, 34 patients with serous cancers. Response rates were about 30% with this drug, with a median PFS of 6 months. It’s an active drug in this group of patients. I can’t remember how many prior lines of therapy they had, but they were pretty heavily pretreated.

Kathleen N. Moore, MD: It was a median of 3.

Bradley J. Monk, MD, FACS, FACOG: Wow.

Krishnansu S. Tewari, MD OK.

Bradley J. Monk, MD, FACS, FACOG: I came to Arizona in 2010, and we were doing the same agent with chemotherapy in cervical cancer. It sounds like this is the best opportunity. It took us a decade to figure it out. But I hope that they take it forward.

Krishnansu S. Tewari, MD: Yes, me too. I remember John Farley, MD, was looking at that with cervical cancer, through the GOG.

Transcript Edited for Clarity