Factors Influencing Treatment Post-Chemo in dMMR Endometrial Cancer

Bradley Corr, MD

Associate Professor, Department of Ob/Gyn-Gynecologic Oncology

LeBert-Suess Family Endowed Professorship in Ovarian Cancer Research

Director of Clinical Research for Gynecologic Oncology

University of Colorado School of Medicine

Aurora, CO

DISCUSSION QUESTIONS

• Please review the systemic therapy options for patients with metastatic dMMR/MSI-H (mismatch repair deficient/microsatellite instability-high) endometrial cancer.
• What are your determining factors in selecting next-line therapy for a patient who relapsed less than 12 months after a complete response to frontline carboplatin/paclitaxel? What if the patient had a partial response?

BRADLEY CORR, MD: [Systemic therapy options include] chemotherapy rechallenge with the platinum doublet therapy. Hormonal therapy is our mainstay, that’s what’s been known for years as the only therapy. Immune checkpoint inhibitors [include use of] the single-agent therapy. We don’t use tyrosine kinase inhibitors such as lenvatinib [Lenvima] as a single agent, but that would [fall under the] pembrolizumab [Keytruda]/lenvatinib combination.

What’s determining our selection of the next line, and would it change if a patient’s prior response to the carboplatin/paclitaxel was a partial response rather than a complete response? Would you order repeat molecular testing for that patient?

ARIEL SORIANO, MD: From my standpoint, if the disease recurred [in less than 12 months means that] after multiple therapies, I want to give as much as I can, so immunotherapy plus lenvatinib would be my choice.

SHIVEN PATEL, MD: I don’t think there are any wrong answers. The textbook answer would probably be single-agent immunotherapy. Anyone who has the ability to get immunotherapy should get it as early in their disease course is possible, because sometimes it takes time to work. I’ve seen it kick in even when I move on to the next therapy. [However], if single-agent immunotherapy is going to work, there’s no reason pembrolizumab plus lenvatinib wouldn’t work, and I think it’s a better regimen that might be synergistic. Even though that might not be the textbook answer, that’s what I would go to. I don’t know of any data where [adding] lenvatinib it would make it work less well in MSI-H disease. I’m curious to see what you think of that.

CORR: I think it’s a great point.… We will go in depth about KEYNOTE-775 [NCT03517449], which was the trial of pembrolizumab/lenvatinib vs provider’s choice of chemotherapy. Your point is well taken…does the combination of lenvatinib with pembrolizumab work better than pembrolizumab? We don’t know whether it works better, but what we know is for FDA approval and therapeutic benefit, you can certainly go with a single-agent checkpoint inhibitor. [The dMMR/MSI-H population is] what they are FDA approved for. We know that it works very well in that patient population.

But you bring up a point that is often lost in the results of KEYNOTE-775. We use [lenvatinib/pembrolizumab] for patients who have proficient MMR [pMMR] because it did show benefit and it’s [becoming] the standard of care for the pMMR patients. We also know it works better in the dMMR group [than the pMMR group]. Although that trial was not only trying to look at pMMR—about 20% of the patients had dMMR, and they did exponentially better than the pMMR patients.¹

You’re absolutely correct that if you want to use both, you can. [The concern is] more about the toxicity profile. We can all agree that single-agent immunotherapy is going to have a better toxicity profile than the combination of lenvatinib and pembrolizumab. I’m also happy to hear that some physicians aren’t afraid of lenvatinib due to the toxicity profile, because I do hear a lot of that. I hope to [assuage] that because it is a great doublet agent for the right patient.

I probably wouldn’t use a platinum doublet chemotherapy in a patient who has recurred after fewer than 12 months. We don’t talk about platinum-free interval too much in uterine [or endometrial] cancer, but it is still significant. When we have an active therapy with a better adverse event profile and less bone marrow toxicity, [it suggests that] something based on immunotherapy should be the next line of therapy.

As far as repeat molecular testing, if you already [determined] dMMR status, you would [only retest if you are] looking for some other targeted therapy. Whether you [test for] that now or at another time, you should be basing your therapy at this point on some sort of immunotherapy.

Then, if the patient had a partial response to previous carboplatin/paclitaxel, they probably would have moved on to another therapy a bit sooner and you probably would have included immunotherapy.

PATEL: In a patient like this, if I started on pembrolizumab and they started subtly progressing, given that they are dMMR, would you add on lenvatinib in that case?

CORR: Great point. Yes, I do that commonly. If I start a patient on single-agent immunotherapy, and they’re having no toleration issues, and they start to progress on it, I will add lenvatinib and I have seen amazing responses. I’ve gotten complete responses off that combination when the [disease failed to respond to pembrolizumab, more than] just a slight progression. That’s an excellent point, and I definitely see the synergy when that happens in an optimal treatment regimen.

DISCUSSION QUESTION

• What factors influence your preferred immune checkpoint inhibitor for a patient such as this?

CORR: I have had physicians say they’ve gotten nivolumab [Opdivo] approved [by insurance], but nivolumab, durvalumab [Imfinzi], and avelumab [Bavencio] haven’t reached [FDA] approval yet for [endometrial cancer]. Dostarlimab [Jemperli] and pembrolizumab by far have the most data in uterine and endometrial cancer. I would use either one of those, and they’re equally effective.

I don’t have anything specific that influences me on either one. For me, it is the data for which the patient most fits into what I think would work. The prior trials for the single-agent therapies…the KEYNOTE-158 [NCT02628067] and GARNET [NCT02715284] trials looked at dostarlimab [and] pembrolizumab [respectively], and both had pretty equal efficacy.^2,3 We’re not supposed to compare trials head-to-head [since they had] different patient populations, but when you look at the duration of response and rate of complete response, partial response, and stable disease, they’re all remarkably similar, even with slightly different patient populations, in the dMMR group. So for me, none of the [trial outcomes] factor into this.

The one factor would be with pembrolizumab, [the ability to use] every-6-week dosing. Some physicians have considered that, but there are less data on it currently. There are more coming out about every-6-weeks dosing in uterine cancer.

_References:

_{1. Makker V, Colombo N, Casado Herráez A, et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med. 2022;386(5):437-448. doi:10.1056/NEJMoa2108330}

_{2. O’Malley DM, Bariani GM, Cassier PA, et al. Pembrolizumab in patients with microsatellite instability-high advanced endometrial cancer: results from the KEYNOTE-158 study. J Clin Oncol. 2022;40(7):752-761. doi:10.1200/JCO.21.01874}

_{3. Oaknin A, Gilbert L, Tinker AV, et al. Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET-a phase I, single-arm study. J Immunother Cancer. 2022;10(1):e003777. doi:10.1136/jitc-2021-003777}