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Two new immunotherapy-chemotherapy options are now approved for patients with primary advanced or recurrent endometrial cancer, the FDA announced.

On Monday, the agency approved the PD-1-directed immune checkpoint inhibitor (Keytruda), in combination with carboplatin and paclitaxel, for patients with either mismatch repair (MMR)-deficient or MMR-proficient disease, based on results of the KEYNOTE-868/NRG-GY018 trial.

And on Friday, the agency approved the PD-L1 inhibitor (Imfinzi) in combination with the same chemotherapy regimen for women with MMR-deficient disease only based on results of the DUO-E trial.

Both phase III trials met their primary endpoints, demonstrating improvement in progression-free survival (PFS) with the addition of immunotherapy.

Last summer, dostarlimab (Jemperli) become the first checkpoint inhibitor to be approved for primary advanced or recurrent endometrial cancer, with the indication limited to MMR-deficient or microsatellite instability-high tumors.

Pembrolizumab Approval

The randomized KEYNOTE-868/NRG-GY018 trial had two separate cohorts, including 222 patients with MMR-deficient tumors and 588 with MMR-proficient tumors. All were randomized to standard chemotherapy plus either pembrolizumab or placebo. Patients received carboplatin-paclitaxel plus concurrent pembrolizumab (200 mg) or placebo every 3 weeks for six cycles, followed by a single-agent treatment with either the checkpoint inhibitor (400 mg) or placebo every 6 weeks for up to 14 cycles.

In the MMR-deficient cohort, median PFS was not reached in the pembrolizumab arm, as compared with 6.5 months for the group assigned to placebo (HR 0.30, 95% CI 0.19-0.48, P<0.0001). In the MMR-proficient cohort, median PFS reached 11.1 months with the addition of pembrolizumab versus 8.5 months with chemotherapy alone (HR 0.60, 95% CI 0.46-0.78, P<0.0001).

Overall survival (OS) data were immature at the time of the analysis, but recently reported results favoring the immunotherapy arms in both cohorts:

• MMR-proficient: HR 0.79 (95% CI 0.53-1.17)
• MMR-deficient: HR 0.55 (95% CI 0.25-1.19)

"The addition of pembrolizumab to chemotherapy represents a new frontline therapeutic option for patients with primary advanced or recurrent endometrial carcinoma, demonstrating a statistically significant and clinically meaningful progression-free survival benefit compared to chemotherapy alone, regardless of mismatch repair status," said investigator Ramez Eskander, MD, of Moores Cancer Center at University of California San Diego Health, in a from drugmaker Merck.

Adverse events (AEs) in the trial increased with the addition of pembrolizumab (grade ≥3 in 55-63% vs 45-47% with placebo). Toxicities were in line with the known safety profiles of pembrolizumab, carboplatin, and paclitaxel, the FDA stated, with the exception of a higher incidence of rash.

Durvalumab Approval

DUO-E was a three-arm trial testing two investigational combinations added to standard carboplatin-paclitaxel chemotherapy.

Regardless of MMR status, the addition of durvalumab to carboplatin-paclitaxel, followed by durvalumab maintenance, improved PFS versus chemotherapy plus placebo, but exploratory analysis suggested the MMR-deficient group drove most of the benefit.

In the 95 patients with MMR-deficient tumors, median PFS was not reached in the durvalumab arm versus 7 months in the placebo arm (HR 0.42, 95% CI 0.22-0.80). OS data were immature.

"With the incidence and mortality of endometrial cancer expected to continue to increase significantly in the coming decades, it is more important than ever that we bring new treatment options to patients at the earliest possible moment in their care," DUO-E investigator Shannon Westin, MD, of the University of Texas MD Anderson Cancer Center in Houston, said in a from drugmaker AstraZeneca. "This approval underlines clear evidence that durvalumab plus chemotherapy followed by durvalumab monotherapy delivers important clinical benefits for patients with mismatch repair-deficient endometrial cancer."

Common AEs with durvalumab included "peripheral neuropathy, musculoskeletal pain, nausea, alopecia, fatigue, abdominal pain, constipation, rash, diarrhea, vomiting, and cough," the FDA said. Serious AEs occurred in 30%, most commonly rash or constipation (4.5% for each). Overall, AEs leading to discontinuation of durvalumab occurred in 11% of patients.

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