Immunotherapy May Address ‘Huge Need’ in Advanced Endometrial Cancer

Immunotherapy May Address ‘Huge Need’ in Advanced Endometrial Cancer

Later-stage presentations of endometrial cancer intensify the urgency for novel therapies to treat this disease, highlighting the demand for less toxic alternatives to traditional chemotherapy, an expert said.

Recent FDA approvals, notably pembrolizumab (Keytruda) and lenvatinib (Lenvima) combinations, mark a turning point, offering hope in the landscape of advanced endometrial cancer treatment, said Amanda Duck, PA-C, RD, a physician assistant in the division of gynecology oncology at Texas Oncology Fort Worth Cancer Center, said during a Community Case Forum event discussing the evolution of immunotherapy for advanced endometrial cancer. This case discussion underscored the complexities faced by patients, emphasizing the need for tailored approaches amidst evolving therapeutic paradigms.

Endometrial Cancer Rates

The incidence of endometrial cancer is increasing globally, but specifically in the US. There were 66,000 new cases of uterine cancer projected for 2022, with an increased projection of 122,000 in 2030.^1,2 In addition, in 2020, there were 417,000 new cases of endometrial cancer and 97,000 deaths from the disease worldwide.³

“We’ve had so many gynecologic oncologists mention that they never, ever thought that uterine cancer mortality would surpass that of ovarian cancer,” Duck said. “And we have a lot of doctors that are like, ‘You know what? ‘It’s going to happen.’”

Many women with endometrial cancer are presenting with late-stage and metastatic disease, Duck added, nothing that as years go by, this has been worsening.

“There’s a huge need to come up with new therapies, and I think all of us can echo [that] since we’ve all been in oncology for some time,” Duck said. “We need more [immuno-oncology] therapies and more things that aren’t as toxic, as we know [that] chemo can be very, very tough to handle.”

Over the past 7 years, there have been several FDA approvals that have made it “a really, really interesting time for both ovarian cancer and uterine cancer,” Duck said.

In May 2017, pembrolizumab was approved with a pan-tumor indication for microsatellite instability high (MSI-H). This was followed by an approval of lenvatinib plus pembrolizumab in September 2019 for advanced endometrial cancer that is not MSI-H or mismatch repair deficient (dMMR) with progressive disease after systemic therapy. In 2021, dostarlimab (Jemperli) received FDA approval for dMMR recurrent or advanced endometrial cancer. Pembrolizumab was also approved in 2022 for advanced endometrial cancer that is MSI-I or dMMR. Most recently, in 2023, dostarlimab plus carboplatin and paclitaxel was approved by the FDA for advanced or recurrent disease.

“Lots of cool [FDA] approvals, and more to come,” Duck said.

Case Discussion

Duck detailed the case of a 71-year-old woman who presented with postmenopausal bleeding, increasing frequency, and nausea/cramping for approximately 6 months. Her physical exam was considered notable for an enlarged uterus and right lower quadrant abdominal tenderness on palpation. A CT scan showed uterine and bladder masses, and her CA-125 level was slightly elevated at 38.6 U/mL. An endometrial biopsy revealed that she had grade 3 (poorly differentiated) endometrioid adenocarcinoma with certain notable molecular features including p53 wild type, MMR proficient, ER negative, MSS, and HER2-negative.

Since the patient has bladder masses, she is considered to have stage 4A uterine cancer that is not amenable to surgery due to her age and comorbidities. She received first-line therapy with carboplatin and paclitaxel chemotherapy, which was well tolerated other than grade 1 peripheral neuropathy and vomiting.

Four months after treatment initiation, the patient was determined to have no evidence of disease on PET scan and had complete resolution of symptoms. Twelve months later, her CA-125 level was increasing, and she had intensely FDG-avid lesions in her lungs, peritoneum, and para-aortic lymph nodes. A biopsy confirmed that she had a recurrence.

The recurrence was treated with lenvatinib, a VEGFR kinase inhibitor, and pembrolizumab, a PD-L1 receptor blocking antibody.

The KEYNOTE-775/Study 309 Trial

Duck discussed the design and findings from the KEYNOTE-775/Study 309 trial (NCT03517449), which included patients with advanced endometrial cancer, who had measurable disease by blinded, independent central review (BICR), and who were previously treated with 1 or more prior platinum-based chemotherapy regimen in any setting, including adjuvant and neoadjuvant.⁴ Of note, patients with endometrial sarcoma, including carcinosarcoma, were excluded from this trial.

In the trial, patients were randomized 1:1 to receive either 200 mg of pembrolizumab intravenously every 3 weeks for a maximum of 24 months plus 20 mg of lenvatinib orally once per day (n = 411), or investigator’s choice of doxorubicin or paclitaxel (n = 416). Primary end points of this trial were progression-free survival (PFS) by BICR and overall survival (OS).

Although researchers excluded patients with sarcomas, patients with other types of endometrial cancer were enrolled including serous carcinoma, clear-cell carcinoma, high-grade disease, and low-grade disease.

In the proficient mismatch repair population, the median PFS was 6.6 months (95% CI, 5.6-7.4) in patients assigned pembrolizumab plus lenvatinib compared with 3.8 months (95% CI, 3.6-5.0) in those assigned chemotherapy (HR = 0.60; 95% CI, 0.50-0.72; P < .001). For all patients in the trial, median PFS was 7.2 months (95% CI, 5.7-7.6) in the pembrolizumab plus lenvatinib group vs 3.8 months (95% CI, 3.6-4.2) in the chemotherapy group (HR = 0.56; 95% CI, 0.47-0.66; P < .001).

“Results are obviously favoring lenvatinib and [pembrolizumab] together,” Duck said.

The median OS for all patients was 18.3 months (95% CI, 15.2-20.5) in the lenvatinib plus pembrolizumab group and 11.4 months (95% CI, 10.5-12.9) in the chemotherapy group (HR = 0.62; 95% CI, 0.51-0.75; P < .001).

“That was pretty exciting, and this really put Lenvima and [pembrolizumab] on the map,” Duck said.

Adverse events of any cause occurred in at least 25% of patients in the trial. Of note, any-grade adverse events occurred in 99.8% of patients assigned lenvatinib plus pembrolizumab and in 99.5% of those assigned chemotherapy. Grade 3 or higher adverse events occurred in 88.9% of patients in the lenvatinib-pembrolizumab group and in 72.7% of those in the chemotherapy group.

As lenvatinib is “hard to tolerate,” Duck said, she asked the participants about how they approach dosing to address adverse events.

“I know we were a little nervous at first a couple years ago when we first started using [lenvatinib],” she added. “And then we’ve gotten more and more creative as time has gone on. But I have seen, obviously, thyroid issues, … diarrhea, nausea, I have seen a ton of joint pain, like really intense joint pain from [lenvatinib]. I’ve seen hoarseness, patients with mouth sores. It’s just all over the map.”

One participant recalled their patient with mixed carcinosarcoma experiencing hypertension and Steven Johnson syndrome.

“[We] came to find it was very, very early,” they said. “Admittedly, we were not well experienced. We had to get the [medical science liaison] from the company involved and everything. Turns out she was [of] Asian descent, and if you look in the data, the Asian population is at a higher risk for those [adverse events]. But it was horrendous, the mouth ulcers, the head-to-toe blistering rash. It was awful.”

Lenvatinib Dosing

In the presentation, Duck mentioned that the recommended dosage of lenvatinib is 20 mg orally once a day plus 200 mg of pembrolizumab every 3 weeks until unacceptable toxicity or disease progression. Lenvatinib comes in capsule form in both 4 mg and 10 mg doses. In addition, the recommended dosage reductions of lenvatinib for adverse reactions in endometrial carcinoma is a starting dose of 20 mg once a day, reduced to 14 mg once a day, then 10 mg once a day, followed by 8 mg once a day.

Duck asked the participants in the event at what dose they start their patients on lenvatinib with. “I don’t think many people are starting at 20 [mg],” she added. Several participants mentioned 14 mg and 10 mg.

“No one’s staying on 20 [mg], nobody can tolerate 20 [mg],” one participant commented. “I think there’s clear definition when you lower the dose and the efficacy. So, the goal would be to maximize the dose as much as you can, but I don’t know. It’s quality of life. If they have horrendous diarrhea, they’re not taking anything.”

Another participant said, “The goal is to keep people on treatment. So if you have to lower the dose to where you have compliance, in my personal opinion, that’s what you do.”

References

1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7-33. doi:10.3322/caac.21708
2. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States [published correction appears in Cancer Res. 2014 Jul 15;74(14):4006]. Cancer Res. 2014;74(11):2913-2921. doi:10.1158/0008-5472.CAN-14-0155
3. Endometrial cancer statistics. World Cancer Research Fund International. Accessed March 21, 2024. https://www.wcrf.org/cancer-trends/endometrial-cancer-statistics/
4. Makker V, Colombo N, Casado Herráez A, et al. Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. N Engl J Med. 2022;386(5):437-448. doi:10.1056/NEJMoa2108330