Lenvatinib Plus Pembrolizumab Bolsters PFS2 Outcomes in Advanced Endometrial Cancer

Vicky Makker, MD

The combination of lenvatinib (Lenvima) and pembrolizumab (Keytruda) demonstrated clinically meaningful improvements in progression-free survival (PFS) on next line of therapy (PFS2) among all-comer patients with advanced endometrial cancer and those with DNA mismatch repair proficient (pMMR) disease, according to an exploratory analysis of the phase 3 KEYNOTE-775 trial (NCT03517449), presented at the 2022 ASCO Annual Meeting.¹

Patients who received lenvatinib/pembrolizumab in the all-comer population had a median PFS2 of 16.0 months (95% CI, 13.0-19.5) vs 9.5 months (95% CI, 8.6-10.7) for those who received physician’s choice therapy (HR, 0.56; 95% CI, 0.46-0.67; P < .0001). Among those pMMR disease the median PFS2 with the investigative combination was 14.4 months (95% CI, 12.1-17.3) vs 9.8 months (95% CI, 8.7-11.1) with chemotherapy (HR, 0.62; 95% CI, 0.50-0.75; P < .0001).

At 6 months, the PFS2 rate in the all-comer cohort favored the lenvatinib/pembrolizumab arm (n = 411) vs the physician’s choice arm (n = 416), 81.7% (95% CI, 77.6%-85.1%) vs 72.5% (95% CI, 67.9%-76.6%), respectively. In the pMMR group, the PFS2 rates were 82.0% (95% CI, 77.5%-85.7%) with the combination (n = 346) vs 74.8% (95% CI, 69.8%-79.1%) with chemotherapy (n = 351).

Subgroup analysis of the pMMR group showed that 31.5% of patients in the lenvatinib/pembrolizumab arm (n = 346) and 50.1% of patients in the physician’s choice arm (n = 351) received subsequent anticancer therapies. In the all-comer group, 28.0% of patients in the lenvatinib/pembrolizumab arm (n = 411) and 48.1% of patients in the physician’s choice arm (n = 416) received subsequent anticancer therapies.

Among all patients (n = 827), 38.1% received subsequent therapy, including 2.3% who received 1 line of subsequent anticancer therapy, 28.7% received 2 lines of therapy, and 17.3% received 3 lines of therapy.

In the pMMR subgroup, doxorubicin was the most common subsequent anticancer therapy administered (15.9%) in the lenvatinib/pembrolizumab arm. In the physician’s choice arm, paclitaxel was the most common anticancer treatment administered (14.2%); however, 9.1% went on to receive lenvatinib/pembrolizumab. The all-comer group had similar findings, with doxorubicin (14.1%) most commonly administered in the lenvatinib/pembrolizumab arm and paclitaxel (13.7%) most commonly administered in the physician’s choice arm; 7.7% of patients in this arm received subsequent lenvatinib/pembrolizumab.

For patients in the pMMR group, median time to next line of therapy was 7.1 months in the lenvatinib/pembrolizumab arm vs 4.7 months in the physician’s choice arm. Median duration of next-line therapy was shorter in the lenvatinib/pembrolizumab arm vs the physician’s choice arm, 2.3 months vs 2.7 months.

Investigators reported similar findings in the all-comer group with median time to next line of therapy of 7.2 months for the lenvatinib/pembrolizumab arm vs 4.7 months for the physician’s choice arm. Median duration of next line of therapy was 2.3 months for the lenvatinib/pembrolizumab arm vs 2.7 months for the physician’s choice arm.

KEYNOTE-775 enrolled patients with advanced endometrial cancer following systemic platinum-based treatment to receive lenvatinib/pembrolizumab or chemotherapy.² This prespecified exploratory analysis analyzed PFS2, defined as the time from randomization to disease progression on the next line of treatment or death, per RECIST 1.1, in both the pMMR and all-comer groups. Subgroup analyses of PFS2 further evaluated baseline characteristics, median time to randomization to next line of therapy, and median duration of next line of therapy.

Eligible patients had advanced, metastatic, or recurrent disease, had received treatment of 1 platinum-based chemotherapy, and had an ECOG performance status of 0 to 1. MMR status was stratified by pMMR vs mismatch repair deficient (dMMR).

A total of 827 patients (697 in the pMMR group and 130 in the dMMR group) were randomized 1:1 to receive oral lenvatinib (20 mg daily) and pembrolizumab (200 mg once every 3 weeks; n = 411) vs doxorubicin (60 mg/m² once every 3 weeks) or paclitaxel (80 mg/m² once weekly; n = 416) on a 3 weeks on/1 week off schedule.

Primary end points were PFS and OS and secondary end points were ORR, pharmacokinetics, and safety. Exploratory end points included duration of response and PFS2.

At data cutoff, 567 patients had discontinued treatment, with 282 patients in the investigational treatment arm and 285 patients in the control arm discontinuing. Similar baseline characteristics were reported across the pMMR and all-comer groups, including median age, race, performance status, and number of prior lines of therapy.

The primary analysis of the trial demonstrated a median PFS in all comers of 7.2 months vs 3.8 months (P < .001) and the median OS was 18.3 months vs 11.4 months (P < .001). Overall response rate also favored lenvatinib/pembrolizumab at 31.9% vs 14.7%.

The investigators concluded that these findings support the clinical utility of lenvatinib and pembrolizumab in this patient population.

References

1. Makker V, Colombo N, Santin A, et al. Efficacy of next line of therapy after treatment with lenvatinib (LEN) in combination with pembrolizumab (pembro) versus treatment of physician’s choice (TPC) in patients (pts) with advanced endometrial cancer (aEC): exploratory analysis of Study 309/KEYNOTE-775. J Clin Oncol. 2022; 40(suppl 16):5587. doi:10.1200/JCO.2022.40.16_suppl.5587
2. Makker V, Colombo N, Casado Herráez A, et al; Study 309–KEYNOTE-775 Investigators. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med. 2022;386(5):437-448. doi:10.1056/NEJMoa2108330