Pembrolizumab in dMMR Recurrent EC: Data From KEYNOTE-158


Shared insight on the utilization of pembrolizumab in dMMR recurrent endometrial carcinoma in the context of the KEYNOTE-158 clinical trial.


Robert L. Coleman, MD, FACOG, FACS:Let me get into the data that support that recommendation. There are 2 studies. KEYNOTE‑158 is a very large study with multiple arms. This was a trial that was looking at patients who met the criteria for a MSI [microsatellite instability] high or a dMMR [mismatch repair–deficient] tumor type. In this case, it was endometrial cancer, and 90 patients were enrolled in these 2 cohorts: 11 patients in D and 79 patients in the K cohort. They saw patients responding in this regimen. That was the primary end point of the trial. But they’re also interested in duration of response and some other standard end points.

As you can see, patients enrolled in the trial had that feature that we’d expect to see. This is broken down by the all-comers population and the efficacy population. There was a lot of use of radiation, and almost all these patients had had a previous operation. Then there’s PD-L1 status; most weren’t assessed. But half the patients had a prior line of therapy. The other half had more lines of therapy, with 2 or more lines of treatment. The objective response is almost 50% in the efficacy population. It was somewhat lower in patients who had multiple priors, but we still saw a 44% response rate in patients with 2-plus priors. That’s pretty impressive.

For these patients, their time to response was around the time of the first assessment cycle. Some had a complete remission. Remember, these are patients who’ve had chemotherapy and then progressed, so seeing another complete response is impressive. Obviously, the progression-free survival [PFS] was unexpected. It was nice to see a progression-free survival of 13.1 months. An overall survival at this point had not been registered.

We don’t have the graphic, but this was 1 of those situations in which we had a very L-shaped curve. It’s instructive to look at that PFS curve because it’s very L-shaped, so in this setting gets to the median around 13 months. It goes down fast and then flattens. It takes a long time to get to that median time point. But in the first 6 months, you see this shoulder. Sometimes in trials we’re looking for an efficacy population, and we’ll see is that there’s no progression. Then when people get their CT scans, they show progression; the curve is a stairstep.

In this study, and in the next study that we’ll talk about, it was fairly rounded, which means that there patients were having hyperprogression—a small number of those—or were just sicker. They are getting unscheduled CT scans, or they’re taken off a study early because of that rapid deterioration. Mike, how often do you see hyperprogression with immune checkpoint inhibitors in solid tumors? It’s very different with different tumors, but have you seen much in the gyn [gynecology] space with hyperprogression?

Michael J. Birrer, MD, PhD:To be honest, not in the gyn space. We see it more with other tumors, with pseudoprogression. With my own patients, I can’t say I’ve seen it. I will note that the len/pem [lenvatinib/pembrolizumab] is a little more confusing because you have the len in there. But for the responders, it takes awhile for you to see it. That’s typical for immunotherapy. The other issue is that this study demonstrates that a subset of patients really benefits from this regimen. The challenge is that PD-L1, at least in endometrial [cancer], is a crummy marker. We don’t know how to identify them.

Robert L. Coleman, MD, FACOG, FACS:Exactly.Outside the dMMR status, we haven’t seen much improvement with using something else, like a PD-L1 marker. Kimberly, by the time this study was published, we’d had a lot of experience with single-agent immune checkpoint [inhibitor], but when we started this study, we didn’t have that much. When we were starting new patients on this regimen, when they had any kind of diarrhea, we put them in the hospital because we were afraid that if it was a Friday event, on Monday patients were going to be out. So we got better. I’m curious, when you counsel a patient who’s going to get a single-agent immune checkpoint inhibitor, what kind of strategy do you use to help inform them about what to expect?

Kimberly Halla, MSN, FNP-C:It’s about managing what those are, because [an immune checkpoint inhibitor is] different from chemotherapy. At this point, patients think they know what their adverse effects are because they’ve been through round after round of chemotherapy. We have to educate them that this isn’t chemotherapy. It works differently. There are different adverse effects. We have to list what those adverse effects are for patients, what they could be and what they come across as. We have to encourage them to call us. As a nurse practitioner, I want to know if they have this rash because it might be completely different from a rash from chemotherapy. I want to know the ins and outs of what’s going on with them and then be available to make this better for them.

Robert L. Coleman, MD, FACOG, FACS:That’s sage advice. I’m glad our clinics have people like you who are able to spend the time to make sure they’re comfortable and feel like they’re not disappointing us by calling with adverse events when they occur. Fortunately, at this point, with this particular study, the discontinuation rates for adverse events were relatively low, around 7%. But there are definite ones that we see. Even though many of them are low grade, they still need attention. Hypothyroidism is 1 of the more common ones. Krish, what are the more problematic adverse events you see with a single-agent immune checkpoint inhibitor?

Krishnansu S. Tewari, MD:Hypothyroidism is the big thing. We’re checking TSH [thyroid-stimulating hormone] monthly. I set up expectations with the patients. I tell them the 2 things I’m most worried about: a grade 3 colitis with abdominal pain, fever, and 7 or more bowel movements a day, or grade 3 pneumonitis if they’re in the ED [emergency department] and need oxygen. I tell them that the chance that’s going to happen is really low—5% of patients, maybe less. Those are the 2 things I’m concerned with. Everything else I can manage. We’re going to check your thyroid every month. If you’ve got preexisting autoimmune disease, you shouldn’t flare. Speak generally, but I’ve learned over the last 4 years that I’m much more comfortable with immune checkpoint inhibitors and the adverse events that can manifest. I just explain that to patients I’m really only worried about grade 3 colitis and pneumonitis.

Robert L. Coleman, MD, FACOG, FACS:I had a couple of patients who ended up having adrenal insufficiency. It was like 1 of those diagnoses of exclusion. We went down and handled the fatigue thing and worked up to the hypothyroidism and then ultimately ended up getting cortisol and ACTH [adrenocorticotropic hormone] and then we’re able to make that diagnosis. But that could be a problem.

Krishnansu S. Tewari, MD:I had 1 of those also.

Robert L. Coleman, MD, FACOG, FACS:Also, the diabetes sometimes is lifelong. So it’s a new state and they have to deal with that.

Transcript edited for clarity.

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