Treatment Strategies in Non-Responders to Chemotherapy


Bradley J. Monk, MD, FACS, FACOG, and Christian Marth, MD, PhD, share treatment approaches to patients with endometrial cancer with a low response rate to chemotherapy, highlighting a biomarker-based approach.


Bradley J. Monk, MD, FACS, FACOG: To summarize, today, [we discussed] second-line dMMR [mismatch repair–deficient], dostarlimab or pembrolizumab; second-line pMMR [mismatch repair–proficient], pembrolizumab/lenvatinib. And then you said, “Well, let‘s make the chemotherapy go away, taking that same paradigm to the front line.”

Christian Marth, MD, PhD: Yes.

Bradley J. Monk, MD, FACS, FACOG: DMMR, checkpoint vs chemo [chemotherapy], 2 studies. PMMR, pembro [pembrolizumab]/lenvatinib vs chemotherapy. So I’m hoping that we get there. I really am. Now, let’s talk about response rate. The response rate in the dMMR patient population in the RUBY trial [phase 3; NCT03981796] was only slightly improved by the addition of dostarlimab because chemotherapy works so well. The response rate to chemotherapy was 69% in the dMMR subset in RUBY. When chemotherapy was added, it went up to 78%, so 69% to 78%. Not a big jump. So we’re all so excited, this was published in the New England Journal of Medicine, adding it to chemotherapy, making chemotherapy go away as you’ve done in colorectal cancer. For colorectal cancer dMMR, you can use checkpoint inhibitors. But what do we do about the 25% of dMMR patients who don’t respond to chemotherapy? The questions are getting harder. What do you do with that patient who gets 6 doses of chemotherapy with checkpoint, which is now the standard and going to get approved? What do you do with that patient?

Christian Marth, MD, PhD: That’s a very hard question because we did a lot of very nice second-line trials with checkpoint inhibitors. But those data are not any more valid because the patients are coming already pretreated. So the question is, ‘Can we re-treat the patient with a checkpoint inhibitor?’ Or should we do something else? But the situation is hard. We know that chemotherapy is not a very good option, there is not a great response rate with chemo. The complete GOG [Gynecologic Oncology Group] experience is approximately 15% over the response rate in second-line chemotherapy. So that’s not really working. We know that IO [immuno-oncology therapy] in the IO-naïve patient is working very well. So both pembrolizumab and dostarlimab showed in the dMMR group approximately 46% to 48% over response rate. In the pMMR, it is going down, to [approximately] 10% to 15%. The same as chemo. Chemo in those patients is, for sure, not a very good option. We know that a platinum rechallenge frequently used is not a very good option. It’s not ovarian cancer. It’s a different disease. And…the platinum-free interval is not predictive of platinum.

Bradley J. Monk, MD, FACS, FACOG: Like ovarian....

Christian Marth, MD, PhD: It’s not, and it’s a prognostic factor. Those with a long platinum-free interval have a better prognosis, but they don’t respond better to a platinum rechallenge. These agents are not really working. In the next trial, the question will be, ‘What can we give those patients?’ Maybe if a patient got chemo and a checkpoint inhibitor, the combination of pembrolizumab plus lenvatinib is still validated, maybe. But this has to be confirmed by further trials.

Bradley J. Monk, MD, FACS, FACOG: Although I said only 75% or so respond in the dMMR [group], it’s really progression that should cause you to do something, right?

Christian Marth, MD, PhD: Yes.

Bradley J. Monk, MD, FACS, FACOG: Most of the patients who don’t progress, who have stable disease, those patients can still transition to maintenance checkpoint. But once they progress, just as you said, don’t be so fast to abandon that, because you don’t have a lot of stuff sitting there on the shelf waiting to treat this patient. So like PARP inhibitors, what I’ve done on occasion if a patient has a dramatic response and starts to progress in an oligometastatic setting, maybe I radiate that lesion. Do you ever radiate oligometastatic progressive disease?

Christian Marth, MD, PhD: Yes, or we remove it surgically.

Bradley J. Monk, MD, FACS, FACOG: We’re surgeons. You got me on that one. Yes, that’s right. And the way we do surgery today is minimally invasive and pretty slick. And then back on the treatment.

Christian Marth, MD, PhD: Yes. I think the data from RUBY are clearly telling us that the response rate is not a very good surrogate for the outcome.

Bradley J. Monk, MD, FACS, FACOG: That’s right.

Christian Marth, MD, PhD: We have to continue. The response rate is important for us to look for, but in IO trials this might not be the right end point to look for. It’s the long-term outcomes because we are doing something else. We’re not killing the cells immediately. We are teaching the immune system to kill the cells, and this takes time and maybe it’s not that fast. Maybe we can also achieve more, living together with the tumor and living longer with this treatment. And this is showing us the outstanding long-term survival and this flattening of the curves without any events, although there is disease there.

Bradley J. Monk, MD, FACS, FACOG: It’s individualized, obviously, and radiation is still on the table. I’m interested in what the community is doing in breast cancer with antibody-drug conjugates, the anti–Trop-2 and the anti-HER2 antibody-drug conjugates. I’m not sure, but I’m trying to advocate for studying those in our patients with endometrial cancer, particularly in that second-line setting, because we do not have anything better. What do you think about antibody-drug conjugates?

Christian Marth, MD, PhD: …This is the future because we have some targeted therapy that is going directly to the target, and what we are aiming for. And we can use very toxic chemo as a payload on this antibody. Still, we have toxicity. We see toxicity.

Bradley J. Monk, MD, FACS, FACOG: I know.

Christian Marth, MD, PhD: It’s not biotherapy. It’s not chemo-free. It is some kind of chemotherapy. We see new adverse effects, which we have to learn about. Nobody else saw some eye complications before we applied these antibody-drug conjugates, so we have to learn. We have to live with this. But I think it’s really the future, and the results presented recently really are very encouraging.

Bradley J. Monk, MD, FACS, FACOG: Agreed. Thank you for that and thank you to the investigators and sponsors that are doing antibody-drug conjugate studies in endometrial cancer.

Transcript edited for clarity.

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