Pembrolizumab Plus Lenvatinib Active in Endometrial Cancer

Vicky Makker, MD

The incidence of endometrial cancer continues to rise in the United States. The prognosis for patients in the recurrent and advanced settings is particularly poor, said Vicky Makker, MD, and options remain limited.

Updated phase Ib/II results of the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) in patients with endometrial cancer were presented at the 2018 ASCO Annual Meeting. The activity was encouraging regardless of microsatellite instability or mismatch repair deficient status, with an objective response rate of 39.6% (21/53) and a median progression-free survival of 7.4 months (95% CI, 5.0—not estimable).

“This disease is sharply on the rise; it is a clearly a disease that we need to develop more rational therapeutics for,” said Makker, a medical oncologist at Memorial Sloan Kettering Cancer Center. “This is a very exciting time in the world of endometrial cancer.”

A phase III study of this combination in patients with recurrent endometrial cancer is currently in the planning stages, she added.

OncLive: What was the rationale to explore the combination of lenvatinib and pembrolizumab in endometrial cancer?

In an interview with OncLive^®, Makker, who was also lead author of the study, discussed the combination and the future of endometrial cancer treatment.Makker: Endometrial cancer is the most common gynecologic malignancy in the United States. The problem with this cancer type is that compared with other gynecologic cancers, the incidence and mortality of this disease is sharply on the rise. When they are early stage, endometrial cancers can often be cured and have a very good prognosis. However, in the recurrent or advanced settings, the prognosis is very poor. The other limitation is that, unlike other cancers, we don't have a lot of options in terms of treatment. This is particularly true for what we call the microsatellite-stable (MSS) population, which makes up the majority of the recurrent cases in this cancer.

We know from prior work that elevated levels of VEGF are associated with aggressive disease and can portend for prognosis in this particular cancer. There has been prior activity demonstrated with antiangiogenic agents that target this pathway. Particularly, there is a drug called bevacizumab (Avastin), which has shown modest response rates of around 14%. That serves as a background. There are other agents that have looked at the antiangiogenic pathway and have sort of shown reproducible but modest activity; some are limited by toxicity, others are more tolerable.

With regard to immunotherapy in endometrial cancer, we know that based on The Cancer Genome Atlas data and other publications that this is a heterogeneous disease with various molecular phenotypes. Some are more immunogenic and, therefore, are more likely to respond to immunotherapy agents. This is because they have genetic instability that can make them more favorable responders to agents like pembrolizumab, for example. There have been studies that have investigated immunotherapy agents, such as pembrolizumab, in endometrial cancers in an unselected patient population. The response rates were modest, but there was activity.

This serves as a background of this current trial, which was a multicohort, open-label, nonrandomized phase Ib/II trial looking at multiple diseases. We tested this combination of lenvatinib, an oral multikinase inhibitor, in combination with pembrolizumab, which is a PD-1 inhibitor. Lenvatinib targets multiple proteins, including VEGF1-3, FGFR1-4, and PDGFR-alpha. All of these are pathways that are known to promote oncogenesis in some fashion. It also inhibits oncogenes, such as RET and KIT. Clearly, it is the antiangiogenic pathway.

There are a lot of preclinical data that have looked at these drugs as single agents as well as in combination. What we know from early preclinical data is that lenvatinib appears to have antitumor activity as well as immunomodulatory effects. This agent in vivo has shown to decrease the tumor-associated macrophage population. We believe that is how this drug mediates its activity as a single agent. Recent updates to the preclinical data, and biomarker results for 37 patients in the endometrial cancer cohort that were presented at the 2018 ASCO Annual Meeting, showed that when these 2 drugs were combined, they actually stimulate the interferon gamma pathway. Interferon gamma is upregulated as are interferon gamma-regulated chemokines. It appears that the 2 drugs together mediate their efficacy that way.

How is the tolerability?

What are the next steps?

Do you foresee there being more combinations of PD-1 and VEGF inhibitors?

Lenvatinib is approved in radioactive iodine—refractory differentiated thyroid cancer, as well as in advanced renal cell carcinoma in combination with everolimus (Afinitor) in patients who have had prior antiangiogenic therapy. The drug has been evaluated in endometrial cancer in heavily pretreated patients and showed a modest response rate of 14%. Pembrolizumab has already been evaluated in endometrial cancers across the board, showing a modest response rate of around 13%. There were no new safety signals identified, which was very encouraging. The side effects are predicted and anticipated. The most common toxicities that we saw were high blood pressure, which again is an on-target effect of lenvatinib. We also saw fatigue, diarrhea, hypothyroidism, and loss of appetite. Those are the most common side effects that we saw on this study. We saw that with supportive care, dose holds, and dose reductions of lenvatinib, that the toxicities were generally very well managed. That was encouraging to see.The data that we have acquired so far are highly encouraging. It is also great to see that there were no new safety signals identified. We believe that this combination warrants further investigation in endometrial carcinomas—specifically in the MSS populations, which make up the majority of the recurrent disease cases. A phase III, international, randomized, clinical trial of pembrolizumab plus lenvatinib versus physicians’ choice chemotherapy in the advanced endometrial cancer setting will soon be activated and open to accrual.I do. Right now, the investigative ground is ripe, and there are a lot of very interesting ideas that are being generated. I anticipate that there will be additional antiangiogenic combinations with immunotherapy. Cabozantinib (Cabometyx) is looking interesting in combination with immunotherapy.

Outside of immunotherapy, there is interest in evaluating drugs that target the PI3K/AKT/mTOR pathway in combination with PARP inhibitors. There were data presented at the 2018 ASCO Annual Meeting looking at those 2 combinatorial approaches.

Makker V, Rasco DW, Vogelzang NJ, et al. Lenvatinib + pembrolizumab in patients with advanced endometrial cancer: updated results. J Clin Oncol. 2018;36 (suppl; abstr 5596).