Kyle Doherty

The combination of lenvatinib (Lenvima) plus pembrolizumab (Keytruda) induced durable responses with a manageable safety profile in adults with previously treated, advanced endometrial cancer, according to a long-term follow-up analysis of a phase 1b/2 study (NCT02501096) presented by Vicky Makker, MD, during the 2021 Society for Immunotherapy of Cancer (SITC) Annual Meeting.

“With extended follow-up, this updated analysis continued to show durable responses, as well as [survival] benefits in patients with challenging to treat, advanced endometrial cancer who received lenvatinib plus pembrolizumab,” said Makker, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York. “The safety profile [for the combination] was generally consistent with that of the individual monotherapies.”

At the August 18, 2020, data cutoff, the total population of the analysis included 108 patients. The objective response rate (ORR) was 39.8% (95% CI, 30.5%-49.7%), including 9 (8.3%) complete responses (CRs). The median progression-free survival (PFS) was 7.4 months (95% CI, 5.2-8.7) and the median overall survival (OS) was 17.7 months (95% CI, 15.5-25.8). The median duration of response (DOR) was 22.9 months (95% CI, 10.2-not evaluable [NE]).

To be eligible for the open-label, single-arm trial, patients needed to have histologically confirmed and metastatic endometrial carcinoma measurable by immune-related RECIST. A maximum of 2 prior systemic therapies were permitted and patients needed to have an ECOG performance status of 1 or less. The study required patients have a minimum life expectancy of at least 12 weeks.

Investigators administered oral lenvatinib at a dose of 20 mg per day; 200 mg pembrolizumab was administered intravenously every 3 weeks. Pembrolizumab could be given for a maximum of 35 cycles and lenvatinib could continue beyond this point as long as benefit was observed. The primary end point of the trial was ORR at week 24. Key secondary end points included overall ORR, disease control rate (DCR), DOR, and progression-free survival (PFS).

The mean age of the total population was 65.1. Most patients (50.9%) had an endometroid carcinoma and 32.4% had a serous adenocarcinoma. The vast majority of the population (98.1%) had previously been treated for endometrial cancer with a platinum plus taxane combination and 49.1% of patients were PD-L1 positive.

The end points of the follow-up analysis included ORR, PFS, DOR, OS, and safety. The median follow-up duration was 34.7 months (95% CI, 30.9-41.2). The analysis population included 94 patients who were MMR proficient (pMMR) and 11 patients who were MMR deficient (dMMR).

In the pMMR cohort, the mean age was 65.4 and 48.9% of patients were PD-L1-positive. An even number (50%) of patients received 1 or 2 prior treatments for endometrial cancer. Common histological subtypes included endometrioid adenocarcinoma (48.9%), serous adenocarcinoma (35.1%), and clear cell adenocarcinoma (5.3%). Nearly all (98.1%) had been previously treated for endometrial cancer with a platinum plus taxane combination.

In the dMMR group, the mean age was 62.4 and most patients were PD-L1-positive (63.6%). All patients had been previously treated for endometrial cancer with a platinum plus taxane combination and 36.4% had undergone 2 prior treatment regimens. The most common histological subtype was endometrioid carcinoma (72.7%), of which 36.4% of patients were FIGO grade 2.

Among the patients who were pMMR, the ORR was 38.3% (95% CI, 28.5%-48.9%) and 8 patients achieved a CR. The median DOR was 25.0 months (95% CI, 8.5-NE) and the mean time to response was 3.2 months. The median PFS was 7.4 months (95% CI, 4.4-7.6) and the median OS was 17.2 months (95% CI, 15.0-28.5).

In the dMMR cohort, the ORR was 63.6% (95% CI, 30.8%-89.1%). The median DOR was 21.2 months (95% CI, 7.33-NE). Notably, the median OS was NE (95% CI, 7.4-NE) and the median PFS was 26.4 months (95% CI, 4.0-NE).

In terms of safety, 96.3% of the total population experienced any treatment-related treatment-emergent adverse events (TEAEs). Most patients (74.1%) experienced a TEAE that lead to study-drug interruption and 21.3% had a TEAE that lead to study-drug discontinuation. TEAEs of grade 3 or higher were reported in 71.3% of patients.

Common TEAEs of any grade included hypertension (60.2%), diarrhea, fatigue (both 53.7%), decreased appetite (50%), and hypothyroidism (46.3%). Grade 3 or higher TEAEs included hypertension (33.3%), fatigue (8.3%), and diarrhea (7.4%).

“Study 309/KEYNOTE-775 (NCT03517449), a confirmatory study of lenvatinib plus pembrolizumab vs treatment of physician’s choice in advanced endometrial cancer, further supports the lasting clinical benefits observed in this follow-up study,” concluded Makker.

On July 21, 2021, the FDA granted a full approval to lenvatinib plus pembrolizumab for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high or dMMR, who have disease progression after previous systemic therapy in any setting, and who are not candidates for curative surgery or radiation based on data from the KEYNOTE-775 trial.

This article was initially published by our sister publication Onc Live. 

Makker V, Aghajanian C, Cohn AL, et al. Lenvatinib and pembrolizumab in advanced endometrial carcinoma: long-term efficacy and safety update from a phase 1b/2 study. Presented at: 2021 Society for Immunotherapy of Cancer (SITC) Annual Meeting; November 10-14, 2021; Washington, DC. Abstract 354.

FDA grants regular approval to pembrolizumab and lenvatinib for advanced endometrial carcinoma. News release. FDA. July 22, 2021. Accessed September 6, 2021. https://bit.ly/3wRB9Sw

Articles

The combination of lenvatinib plus pembrolizumab induced durable responses with a manageable safety profile in adults with previously treated, advanced endometrial cancer, according to a long-term follow-up analysis of a phase 1b/2 study (NCT02501096).

Lenvatinib plus pembrolizumab displays efficacy in advanced endometrial cancer

The accelerated approval of the tissue factor–directed antibody and microtubule inhibitor tisotumab vedotin-tftv (Tivdak) bolsters the treatment portfolio for patients with recurrent metastatic cervical cancer. The FDA granted the approval to tisotumab vedotin on September 20, 2021, specifically for patients in this population who have disease progression on or after chemotherapy.

The approval was based on results from the phase 2 innovaTV 204 trial (NCT03438396), which showed that tisotumab vedotin elicited an overall response rate (ORR) of 24% (95% CI, 15.9%-33.3%), including a 7% complete response rate, among 101 treated patients. The median duration of response was 8.3 months (95% CI, 4.2-not reached).

® Robert L. Coleman, MD, chief scientific officer of The US Oncology Network in The Woodlands, Texas, discussed the need to add new agents to the treatment portfolio of recurrent or metastatic cervical cancer and how the approval of tisotumab vedotin may help to fill this void.

®: What are the clinical implications of the FDA approval of tisotumab vedotin in cervical cancer?

: This new agent adds to our armamentarium for patients with recurrent metastatic cervical cancer. That’s the bottom line. We have very few effective options. I include immunotherapy in that statement because the vast majority of patients with cervical cancer don’t benefit from immunotherapy. There is certainly a cohort of patients who do remarkably well. We have seen that [immunotherapy is] better than standard chemotherapy in a recent randomized phase 3 trial [KEYNOTE-826, NCT03635567], but that does not close the book. The need for effective therapies, ones that act rapidly, is desperately present in our day-to-day care of patients with advanced metastatic cervical cancer.

The clinical rationale was [primarily] based on the need for effective therapy in patients with recurrent disease post chemotherapy, but also [on the need] to explore a new class of agent. This [agent] is an antibody-drug conjugate that takes advantage of the near-universal expression of tissue factor, which is seen across many solid tumors but is especially high in patients with cervical cancer, [and presents an] opportunity to take advantage of a biological expression of a target and incorporate a targeted smart bomb, so to speak, with chemotherapy that is effective on the cells in the microenvironment.

What are the key data points from the innovaTV 204 study you wish to highlight?

The headline that catches most individuals' attention is that we have a relatively high response rate. The response rate is in the mid-20s, [which is] usually considered an area that would represent a real clinical advance. That’s why this was submitted under the accelerated approval program. We felt that this was substantially better than our experience with second-line chemotherapy agents in this setting.

The ORR of 24% was felt to be remarkable in this 101-patient trial. The other component of this that sometimes gets lost is that when we treat patients in the clinic, we will make decisions of continuing therapy in the presence of nonprogression. For instance, if a patient comes in who has had a stability in their tumor that we’ve been able to document by exam or by CT scan and symptoms have not accelerated, our strategy at that point is not to change [treatment].

If you look at the proportion of patients for which their best response was progression, it was a really low number. This translates into clinical benefit, which captures the stable disease rate along with all responses. That’s what is meaningful in the clinic. Then, for those patients who respond, the duration of response being more than 9 months or so is substantially meaningful, especially since our life expectancy for this patient population can be quite muted. Of course, we must balance [these advantages] against the toxicity that was observed.

What are the toxicities clinicians need to be aware of?

The toxicity that we saw with this treatment was not dissimilar to what we see with chemotherapy, although there were a few notable differences. Common adverse effects that we see with chemotherapy in this setting are things such as asthenia and fatigue, bone marrow suppression, alopecia—various adverse effects that we can see with any kind of cytotoxic agent.

The unique toxicities that we saw with [tisotumab vedotin] were ophthalmologic toxicities. Conjunctivitis and neurotoxicity observed with this class of agent are not dissimilar from other antibody-drug conjugates in the literature.

We were also very concerned early on about bleeding during the phase 1 and phase 2 expansion trial because tissue factor is an element that’s present in the clotting cascade. Our concern was that if we were interrupting this process, we were potentially increasing bleeding events. We were happy to see that that wasn’t the case, and we did monitor it very carefully. So, it would be considered a special interest adverse effect.

Fortunately, most of the bleeding events that we saw were epistaxis and others that we’ve seen with [agents such as] bevacizumab [Avastin]. Most of the bleeding that we saw was grade 1 and most of it was resolvable in a short period of time. Overall, we were reassured, but it doesn’t [change] the fact that the optimal logical component of this needs to be addressed. It’s a unique toxicity that, if investigators have not had experience with it, it certainly would be one that they need to pay attention to when they administer the drug.

What does the future hold for tisotumab vedotin?

The agent was brought into the clinical domain under accelerated approval, which means there needs to be a confirmatory trial. That trial has already launched [innovaTV 301, NCT04697628]. [Tisotumab vedotin has] been matched with several different compounds, not only chemotherapy, but also other antiangiogenic agents and immunotherapies that are being investigated to see what might fit best and where in the clinical domain.

[Additionally, we would like to] see it in an earlier line of therapy where we would have an opportunity to provide benefit to more patients in a broader spectrum. It would be logical to assume that an effective second-line agent or third-line agent could be moved up into earlier lines of therapy, where more patients would have access.

This article was initially published by our sister company OncLive.

FDA grants accelerated approval to tisotumab vedotin-tftv for recurrent or metastatic cervical cancer. FDA. Updated September 21, 2021. Accessed September 29, 2021. bit.ly/3upkVAr

Tivdak. Prescribing information. Seagen Inc; 2021. Accessed September 29, 2021. bit.ly/3ij3rAW

The accelerated approval of the tissue factor–directed antibody and microtubule inhibitor tisotumab vedotin-tftv bolsters the treatment portfolio for patients with recurrent metastatic cervical cancer.

Kyle Doherty

Articles

Lenvatinib plus pembrolizumab displays efficacy in advanced endometrial cancer

Tisotumab vedotin displays efficacy, tolerability in cervical cancer