Patients with advanced-stage endometrial cancer (EC) saw superior outcomes after treatment with the combination of lenvatinib plus pembrolizumab versus chemotherapy, according to results from the Study 309–KEYNOTE-775 trial.

In >800 patients with mismatch repair-proficient (pMMR; n=697) or mismatch repair-deficient (dMMR; n=130) disease, median progression-free survival (PFS) and median overall survival (OS) were longer with lenvatinib-pembrolizumab than with physician’s-choice chemotherapy, reported Vikky Makker, MD, of Memorial Sloan Kettering Cancer Center in New York City, and co-authors.

Specifically, they found the following results:

  • PFS for the pMMR population: 6.6 versus 3.8 months, hazard ratio (HR) for progression or death 0.60 (95% CI 0.50 to 0.72, P<0.001)
  • PFS for the overall population: 7.2 versus 3.8 months, HR 0.56 (95% CI 0.47 to 0.66, P<0.001)
  • OS for the pMMR population: 17.4 versus 12.0 months, HR for death 0.68 (95% CI 0.56 to 0.84, P<0.001)
  • OS for overall population: 18.3 versus 11.4 months, HR 0.62 (95% CI 0.51 to 0.75, P<0.001)

While one of the limitations was a relatively short follow-up period, at a median of 12.2 months in the two-agent group and 10.7 months in the chemo group, “these results address a need for effective therapy in these patient populations,” Makker and co-authors wrote in the The New England Journal of Medicine.

The phase III trial tested lenvatinib, a multikinase inhibitor of VEGFR1, VEGFR2, and VEGFR3 kinases, and the programmed cell death 1 (PD-1) inhibitor pembrolizumab in patients with advanced, metastatic, or recurrent EC that progressed after a prior platinum-based regimen.

Results were initially presented at the 2021 Society of Gynecologic Oncology virtual meeting, and Makker noted in a March 2021 press release that patients with EC “face low survival rates when diagnosed at an advanced stage or at recurrence, especially once the disease progresses after prior platinum-based therapy and is not amenable to curative surgery or radiation.”

Study 309/KEYNOTE-775 is the confirmatory trial for Study 111/KEYNOTE-146, which led to the FDA’s 2019 accelerated approval of the lenvatinib-pembrolizumab combination for the treatment of patients with advanced EC that is not microsatellite instability-high (MSI-H) or dMMR, who have disease progression following prior systemic therapy, and who are not candidates for curative surgery or radiation. The FDA reupped its approval in July 2021.

The accelerated approval was the first granted via Project Orbis, an FDA Oncology Center of Excellence initiative that provides a framework for concurrent submission and review of oncology drugs among its international partners, such as Health Canada and the Australian Therapeutic Goods Administration.

In a presentation at the 2021 European Society for Medical Oncology virtual meeting, Study 309/KEYNOTE-775 co-investigator Nicoletta Colombo, MD, of the European Institute of Oncology in Milan, and co-authors discussed a subgroup analysis of efficacy outcomes in patients grouped by tumor histology and prior therapy.

They reported that the combination offered meaningful efficacy improvements in those with previously treated advanced EC across all histologies—including difficult-to-treat histologies, such as pMMR—and regardless of prior therapies (adjuvant or neoadjuvant) and platinum-free interval from most recent platinum therapy. The authors also noted that patients with one prior line of platinum had greater benefit than those with more than one line.

The latter finding “suggested that it would be better to use this combination as soon as possible, and not wait [for] after too many lines of treatment because the efficacy could be decreasing,” Colombo explained in a VJOncology interview. “So this is actually our take-home message from this subgroup analysis,” she said, although she cautioned that the study was a post-hoc analysis so the results “should be interpreted with caution.”

Makker’s group enrolled 827 women (median age about 64; >59% White; >80% with pMMR disease; <about 22% with high-grade EC) who were treated with one of the following regimens:

  • Once-daily oral lenvatinib at 20 mg plus IV pembrolizumab at 200 mg every 3 weeks
  • IV doxorubicin at 60 mg/m2 body-surface area every 3 weeks or IV paclitaxel at 80 mg/m2 weekly with a cycle of 3 weeks on and 1 week off

They noted that at least three-fourths of the patients in both groups had been treated previously with one platinum-based therapy. Around 20% of those in the two-agent group received two previous platinum-based therapies, as did about 24% of those in the chemo group, while about 9% and 10% got previous palliative hormonal therapy, and 46% and about 48% received previous external-beam radiotherapy.

The median duration of treatment was 231 days for the two-agent group and 104.5 days for the chemo group. In the two-agent group, the median dose intensity of lenvatinib was 13.8 mg/d while the median number of pembrolizumab cycles was 10. Also, the median time to the first dose reduction of lenvatinib was 1.9 months, and almost 46% of the patients in the two-agent group had two or more dose reductions of lenvatinib.

PFS and OS were the primary endpoints of the global trial, which was conducted in multiple countries including Australia, Canada, Israel, New Zealand, and the U.S.

Makker’s group reported that among patients with a response, the median duration of response (DoR) in the pMMR population was 9.2 months in the two-agent group compared with 5.7 months in the chemo group, and the median DoR in the overall population was 14.4 months compared with 5.7 months, respectively (95% CI 0.0 to 24.2).

As for patients with dMMR, the trial was not designed or powered to compare the regimens in these patients, but “clinically meaningful” results were still seen, such as a median DoR of 4.1 months, these researchers reported.

“Overall, more patients in the lenvatinib-pembrolizumab group than in the chemotherapy group had tumor shrinkage,” they noted.

For adverse events (AEs), >99% of all patients had on-treatment AEs, with the most common being hypertension (64.0% in the two-agent group) and anemia (48.7% in the chemo group), and grade ≥3 AEs occurred in 88.9% and 72.7%, respectively. Makker’s group also reported that more patients in the two-agent group experienced dose reductions or interruptions versus those in the chemo group. Hyperthyroidism was the most common AE of interest with pembrolizumab.

Finally, the authors found no substantial between-group differences for quality-of-life scores at 12 weeks post-randomization. In the intention-to-treat population, 28.0% of the patients in the two-agent group required subsequent systemic anti-cancer medications, such as PD-1 pathway-targeting monotherapy or combination regimens, as did 48.1% of those in the chemo arm.

Makker and co-authors noted that “[a]lthough the protocol specified criteria were met for the efficacy analyses, safety and efficacy monitoring is ongoing.”

But these results are good news for gynecologic cancer specialists because EC is the second most prevalent gynecologic cancer in women worldwide, and its incidence has been on the upswing. The ECHO trial, a multicenter, retrospective chart review in U.S. women diagnosed with advanced EC, showed that >86% discontinued second-line therapy, mainly because of disease progression.

“There continues to be a significant unmet need in this group of women. Novel therapies are needed that delay progression and/or improve overall survival and further research is indicated to explore this,” stated Vimalanand Prabhu, PhD, of Merck, Sharp & Dohme in Kennilworth, New Jersey, in a presentation at the 2021 American Society of Clinical Oncology virtual meeting.

Still, pembrolizumab is proving to be a powerhouse in EC as the “most used regimen in the immunotherapy group was pembrolizumab monotherapy, in nine out of 10 patients,” Prabhu told VJOncology at the 2021 European Society of Gynaecological Oncology congress. “Overall real-world evidence suggests that pembrolizumab monotherapy has become the standard of care.”

The recent KEYNOTE-158 trial results showed that pembrolizumab monotherapy turned in robust and clinically meaningful antitumor activity in patients with previously treated, advanced MSI-H/dMMR tumors.

As in the subgroup analysis by Colombo’s group, the “higher ORR [overall response rate] among patients who had received <2 lines of prior therapy (53% v 44%) may provide support for earlier use of pembrolizumab in this setting,” noted David M. O’Malley, MD, of the Ohio State University Wexner Medical Center and James Comprehensive Cancer Center in Columbus, and co-authors in the Journal of Clinical Oncology.

The currently active phase III ENGOT-en9/LEAP-001 trial (estimated study completion in 2023) will compare the efficacy and safety of first-line pembrolizumab-lenvatinib versus paclitaxel-carboplatin in patients with newly diagnosed stage III/IV or recurrent EC with measurable or radiographically apparent disease.


Study 309/KEYNOTE-775 was funded by Eisai and Merck Sharp and Dohme/Merck. Some co-authors are employees of Eisai or Merck.

Makkar reported support from, and/or relationships with AstraZeneca, Bristol Myers Squibb, Clovis Oncology, Eisai, Eli Lilly, Faeth, Genentech, GlaxoSmithKline, Karyopharm, Merck, Moreo, Takeda Oncology, and Zymeworks. Co-authors reported support from, and/or relationships with, multiple entities including Eisai and Merck.



Shalmali Pal, Contributing Writer, BreakingMED™

Kaiser Health News

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