麻豆传媒

A second-line combination of anti-PD-1 immunotherapy plus VEGF inhibition improved survival outcomes compared with single-agent chemotherapy in advanced or metastatic endometrial cancer, the phase III KEYNOTE-775/Study 309 trial showed.

Among more than 800 patients previously treated with platinum-based chemotherapy, the median progression-free survival (PFS) reached 7.2 months with pembrolizumab (Keytruda) plus lenvatinib (Lenvima), as compared with 3.8 months with physician's choice of chemotherapy (HR 0.56, 95% CI 0.47-0.66, P<0.0001), reported Vicky Makker, MD, of Memorial Sloan Kettering Cancer Center in New York City.

At a median follow-up of 11.4 months, an interim overall survival (OS) analysis demonstrated a median OS of 18.3 months with pembrolizumab-lenvatinib compared with 11.4 months with doxorubicin or paclitaxel (HR 0.62, 95% CI 0.51-0.75, P<0.0001), according to findings presented at the virtual Society of Gynecologic Oncology (SGO) annual meeting.

"Benefits with regards to PFS and OS were observed across all analyzed subgroups, including histology and number of prior therapies," Makker noted during her presentation. "And lenvatinib plus pembrolizumab had a manageable safety profile that is generally consistent with the individual monotherapies."

In 2019, the FDA to pembrolizumab-lenvatinib based on overall response rate (ORR) for patients with advanced mismatch repair (MMR)-proficient endometrial cancer who are ineligible for curative surgery or radiotherapy following systemic therapy.

Among patients with MMR-proficient tumors in the current study (84% of the total population), median PFS was 6.6 months with pembrolizumab-lenvatinib versus 3.8 months with chemotherapy (HR 0.60, 95% CI 0.50-0.72, P<0.0001), while OS was 17.4 months versus 12.2 months, respectively (HR 0.68, 95% CI 0.56-0.84, P<0.0001).

"When you have a randomized trial that shows overall survival benefit in the second-line setting, I think it's kind of hard to argue that this shouldn't be the standard of care," Alexander Melamed, MD, MPH, of Columbia University Vagelos College of Physicians and Surgeons in New York City, told 麻豆传媒.

"I think my one caution would be, are these additional months that you're giving these patients of life, are these high-quality months?" he added. "I don't think just from this presentation I can make my mind up on that."

Melamed, who was not involved in the study, pointed to the higher toxicity and treatment discontinuation rates in the study arm, and said that patient-reported quality-of-life outcomes will be key.

Grade ≥3 treatment-emergent adverse events (AEs) occurred in 90% of patients on pembrolizumab-lenvatinib versus 73% of those on chemotherapy. And 66.5% of those in the study arm needed dose reductions compared with just 12.9% in the chemotherapy arm. Overall, one-third of patients on pembrolizumab-lenvatinib stopped one or both agents due to toxicity (31% lenvatinib, 19% pembrolizumab, 14% both).

"In my clinical experience, some patients do just fine on this regimen, [while] a lot of patients do need dose reductions and have a hard time on it," said Melamed. "There will definitely be some degree of patient selection that will be required."

Melamed also noted the deep degree of benefit with pembrolizumab-lenvatinib for patients with MMR-deficient tumors (PFS: HR 0.36, 95% CI 0.23-0.57; OS: HR 0.36, 95% CI 0.22-0.62), but questioned whether that was largely driven by the checkpoint blockade.

"Do you really need the lenvatinib for the people who are MMR deficient? Are they just going to have a good enough response from the pembrolizumab alone?" he said.

"This is indeed practice changing for mismatch repair-proficient endometrial cancer," said SGO Discussant Ursula Matulonis, MD, of Dana-Farber Cancer Institute in Boston. "However, pembrolizumab alone remains the standard for recurrent mismatch repair-deficient endometrial cancer."

Matulonis pointed out that pembrolizumab-lenvatinib is the first endometrial cancer-specific treatment to be FDA approved since 1971, and the combination has now shown improvements in OS, PFS, ORR, and duration of response versus single-agent chemotherapy.

Study Details

The KEYNOTE-775/Study 309 trial randomized 827 patients with advanced, metastatic, or recurrent endometrial cancer to IV pembrolizumab (200 mg every 3 weeks) plus oral lenvatinib (20 mg daily) or physician's choice of IV doxorubicin (60 mg/m² every 3 weeks) or IV paclitaxel (80 mg/m² every 3 weeks of 28-day cycles). The dual primary endpoints were OS and PFS.

Patients had a median age of 64-65 and had all previously received at least one line of platinum-based chemotherapy, with 20.2% in the study arm and 24.3% in the control arm having received two or more. About two-thirds had endometrioid carcinoma, about one-fourth had serous carcinoma, and the remaining had clear cell or mixed histology. Patients were stratified by history of pelvic radiation therapy (about 41%), MMR status, and region.

ORRs with pembrolizumab-lenvatinib were 30.3% in the MMR-proficient subgroup and 31.9% in all comers, including complete responses in 5.2% and 6.6%, respectively. ORR was 15% in both chemotherapy groups, including complete responses in 2.6% each.

Median time to response was 2.1 months with pembrolizumab-lenvatinib (in both the MMR-proficient subgroup and all comers) versus 3.5 months with chemotherapy in the MMR-proficient group and 2.1 months with chemotherapy in all comers. With pembrolizumab-lenvatinib, the median duration of response was 9.2 months in the MMR-proficient group and 14.4 months in all comers, as compared with 5.7 months with chemotherapy (in both groups).

Common grade ≥3 treatment-emergent AEs with pembrolizumab-lenvatinib included hypertension (37.9%), decreased weight (10.3%), decreased appetite (7.9%), diarrhea (7.6%), anemia (6.2%), asthenia (5.9%), proteinuria (5.4%), and fatigue (5.2%). With chemotherapy, the most common grade ≥3 treatment-emergent AEs included neutropenia (25.8%) and anemia (14.7%).

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