Lenvatinib Combo Holds Ground Against HER2 ADCs in Endometrial Cancer

Susana M. Campos, MD, MPH, clinical director of the Division of Gynecologic Oncology and director of Educational Initiatives at Dana-Farber Cancer Institute, and assistant professor of medicine at Harvard Medical School, compared the efficacy of lenvatinib (Lenvima) plus pembrolizumab (Keytruda), studied in the phase 3 Study 309/KEYNOTE-775 trial (NCT03517449), against newer HER2-directed options such as fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), evaluated in the smaller, biomarker-selected phase 2 DESTINY-PanTumor02 trial (NCT04482309). As more targeted agents enter the recurrent gynecologic cancer space, clinicians are weighing how established combinations stack up against newer, biomarker-selected options.^1,2

In a Satellite Sessions post-program conversation, Campos explained why she does not see lenvatinib plus pembrolizumab losing ground to these targeted agents, emphasizing that the combination is not biomarker directed and can therefore be used more broadly across patients with recurrent endometrial cancer, regardless of HER2 status. She also pointed out an important design difference between the 2 trials that affects how the data should be interpreted in clinical practice.

Transcript:

CancerNetwork: When comparing the objective response rates of lenvatinib plus pembrolizumab against newer options like T-DXd in patients with HER2-positive disease, does the lenvatinib/pembrolizumab combination still hold an efficacy advantage?

Campos: I don’t think it’s losing ground. It’s just another combination. There are a couple of things important to mention: KEYNOTE-775 accrued 827 patients. This is a very well-designed, randomized phase 3 trial looking at pembrolizumab and lenvatinib vs standard of care. It’s a contender in most patients with recurrent [endometrial] cancer, for patients with [mismatch repair proficient] pMMR, I should say. The DESTINY-PanTumor02 trial was an excellent trial, but it only had about 40 patients per cohort, and we must remember that. I don’t think [lenvatinib/pembrolizumab is] losing ground; it’s just another option available to patients. What’s also important is that lenvatinib and pembrolizumab is not biomarker directed. The DESTINY-PanTumor02 trial was biomarker directed, and not all patients exhibit that marker in their tumor. Sometimes, patients are left out if they don’t have that biomarker, whereas lenvatinib and pembrolizumab can be utilized, assuming no other comorbidities, in many different patients.

References

1. Makker V, Colombo N, Casado A, et al. Lenvatinib plus pembrolizumab in previously treated advanced endometrial cancer: 5-year outcomes from the randomized, phase 3 Study 309/KEYNOTE-775. J Immunother Cancer. 2026;14(2):e013713. doi:10.1136/jitc-2025-013713

2. Lee JY, Oaknin A, Manso L, et al. Trastuzumab deruxtecan in HER2-expressing gynecologic cancers from DESTINY-PanTumor02: antitumor activity, safety, and exploratory biomarker analyses. J Gynecol Oncol. 2026;37(3):e65. doi:10.3802/jgo.2026.37.e65