Rationale for Combination Therapy in Advanced EC


Kathleen Moore, MD: I just finished talking about monotherapy immunotherapy and how landscape changing and world changing it has been for women with mismatch repair deficient [dMMR] recurrent endometrial cancer, which is about 30% of women who present. You see that across the board in studies. That’s really important, but what about the other 70% who don’t have mismatch repair deficiency? Are they just left with our standbys of doxorubicin and weekly paclitaxel with expected response rates of 15%? That hardly seems fair. Fortunately, they are not left with that. They actually have an equally good option, also accelerated approval, and hopefully will be confirmatory approval very soon with the combination of pembrolizumab and lenvatinib.

This is a really interesting combination. Dr Vicky Makker from Memorial Sloan Kettering Cancer Center has led developments of this combination in endometrial cancer. This originally was an investigator-initiated trial. Those of you who run IITs [investigator initiated trials] know that they can sometimes result in tremendous opportunities for our patients; this is an example. Congratulations to Dr Makker, who recognized that both drugs individually had some efficacy. Lenvatinib, just to remind you, is an oral tyrosine kinase inhibitor that targets a number of things: VEGF1, VEGF2, VEGF3, FGFR, PDGFR, BIK, and MEK. I may be even forgetting 1. It’s kind of a dirty tyrosine kinase inhibitor, mainly acting in an antiangiogenic space. We know from prior studies that antiangiogenic agents have efficacy in endometrial cancer. A very large, over 100-patient, single-arm phase 2 was done with single-agent lenvatinib with a response rate of 14%. It has some activity, certainly, but it’s not overwhelming.

Similarly, if you look at pembrolizumab in microsatellite-stable patients, or those patients who don’t have mismatch repair deficiency, you see a similar response rate. It’s about 10% to maybe 15%. There is some efficacy with each drug, but it’s not great in a microsatellite-stable population.

There’s a lot of rationale for combining them. When you think about that VEGF, it is a drug that promotes angiogenesis, and that’s how we all think about it, but it’s also incredibly immunosuppressive. If you have high levels of VEGF around your tumor, you’re creating a microenvironment that is incredibly immunosuppressive with high levels of immunosuppressive macrophages or Tregs but not a lot of cytotoxic CD8 cells. When you block VEGF with tyrosine kinase inhibitors—cediranib is very good at this, lenvatinib actually may be a little better—you’ll not only block the antiangiogenic effect but also convert this immunosuppressive environment into a less immunosuppressive environment, allow more CD8 T cells to come in, and by doing so enhance the efficacy of immune agents such as pembrolizumab.

This was demonstrated in elegant animal models and then moved into IIT that I talked about, which was a single-arm study that launched in a few centers in the United States and used the combination of lenvatinib and pembrolizumab in patients who had disease that had recurred after frontline paclitaxel and carboplatin. So many patients were enrolled who were mismatch repair deficient, but most of the patients were mismatch repair intact. They found a remarkable response rate in this group of patients who heretofore had nothing active in their toolbox. They had an overall response rate of almost 40%, several standard deviations above what would be expected with standard options.

In addition to this, about 11% of patients had complete response rates, which is something we had never talked about in this disease space. Suddenly, we’re putting patients into some kind of a remission, which is pretty remarkable. At the time this was presented, the duration of response had not been reached, but it’s right about a year, with most responders going well beyond 6 months.

When you look at the breakdown among the different histologies—and these are small numbers, so we can’t hang too much on it— it is quite exciting. There were 5 patients who had clear cell tumors and each of them had a reduction in their tumor size. Not all of them were a RECIST response of a 30% reduction, but all of them had a reduction in their tumor size. If you looked at the patients who were classed by the serous, their response rate was even higher than the overall group. So this combination appeared to be synergistic in a group of patients who would not be expected to respond to immune checkpoint inhibitors alone.

This got very quickly accelerated approval, not only in the United States, but simultaneously in Australia and Canada as well through a very interesting program. As with all accelerated approvals, there was an ongoing confirmatory trial that compared the combination vs standard medicines, but we have not seen the data. We hope to see it in spring, but the press release has just come out and stated that it met the primary end points and was superior. The anticipation is that this will receive confirmed approval and then hopefully will be available outside the United States as a global approval as well, which is an incredibly important advance for women with recurrent disease. We have 2 options now based on molecular subtypes, both of which with a high likelihood of helping patients for a durable period of time. That’s a world of difference from where we were a few years ago.

Transcript Edited for Clarity

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