For the first-line treatment of metastatic esophageal squamous cell carcinoma, the addition of lenvatinib to pembrolizumab and chemotherapy failed to improve overall survival over pembrolizumab plus chemotherapy in the phase III LEAP-014 trial, as reported at the European Society for Medical Oncology (ESMO) Congress 2025.1
Median overall survival was 17.6 months with the lenvatinib regimen and 15.5 months with pembrolizumab plus chemotherapy (hazard ratio [HR] = 0.92; P > .01852). The 12-month overall survival rates were 65% and 61%, respectively, according to Jong-Mu Sun, MD, PhD, of Samsung Medical Center in Seoul, Republic of South Korea.
Jong-Mu Sun, MD, PhD
“Anti–PD-1/PD-L1 therapies in combination with chemotherapy have provided significant survival benefits in first-line metastatic esophageal squamous cell carcinoma, but overall survival remains suboptimal,” Dr. Sun said, citing around 13 to 17 months. Based on its observed clinical activity in renal cell carcinoma, endometrial cancer, and gastric/gastroesophageal cancer, lenvatinib, which targets VEGFR, was combined with pembrolizumab and chemotherapy in esophageal squamous cell carcinoma in the current LEAP-014 trial.
LEAP-014 Details
Dr. Sun presented the results from Part 2 of the second interim analysis of the phase III open-label LEAP-014 trial. The study randomized 850 patients, 66% of whom were from East Asia and 93% of whom had a PD-L1 combined positive score (CPS) of at least 1. The lenvatinib arm received induction with lenvatinib, pembrolizumab, and chemotherapy followed by consolidation with lenvatinib and pembrolizumab, and was treated until disease progression. The control arm received pembrolizumab plus chemotherapy for a maximum number of cycles per local standards.
Other Findings
No statistically significant improvements were observed in other key endpoints as well, with the following outcomes for the lenvatinib vs control arm:
- In the PD-L1 CPS ≥ 10 population, median overall survival was 18.0 vs 15.8 months (HR = 0.89, 95% confidence interval [CI] = 0.71–1.11);
- Median progression-free survival was 7.2 vs 6.9 months (HR = 0.89, 95% CI = 0.75–1.04);
- Median progression-free survival in the PD-L1 CPS ≥ 10 population was 8.1 vs 6.9 months (HR = 0.85, 95% CI = 0.69–1.04);
- Objective response rates were 62.2% vs 54.8% (95% CI = 0.7–13.8).
The above endpoints were not tested for statistical significance, as the overall survival hypothesis was not positive. The safety profiles were found to be generally consistent with the known safety profiles of lenvatinib in combination with pembrolizumab and chemotherapy.
DISCLOSURE: Dr. Sun reported personal financial relationships with AstraZeneca, Takeda, and Yuhan Corporation.
REFERENCE
1. Sun J-M, Kim S-B, Ogata T, et al: Lenvatinib plus pembrolizumab and chemotherapy vs pembrolizumab and chemotherapy in untreated metastatic esophageal squamous cell carcinoma: The randomized phase 3 LEAP-014 study. ESMO Congress 2025. Abstract LBA79. Presented October 17, 2025.
EXPERT POINT OF VIEW
As the study’s invited discussant, Sarah Derks, MD, PhD, a medical oncologist at Amsterdam University Medical Center, proposed several possible reasons for the negative outcomes observed in LEAP-014. She noted that KEYNOTE-590 had established checkpoint inhibition plus chemotherapy as the standard of care in advanced esophageal squamous cell carcinoma after showing a 27% survival benefit with pembrolizumab (hazard ratio [HR] = 0.73; P < .0001).1 The addition of a VEGFR inhibitor to the regimen made sense, she said.
Sarah Derks, MD, PhD
“The idea was to improve upon this result with lenvatinib, but unfortunately, this was not the case. It might be that for esophageal squamous cell carcinoma, angiogenesis is not a strong mechanism of resistance to checkpoint inhibitors. You have distinct microenvironments. Some are inflamed, some are full of immune cells but more immune-suppressive, and the effect of angiogenesis might be very limited,” she said.
“Or maybe the role of immune suppression is so complex that only taking away the driver, the VEGF, the vasculature, is just not enough. We know that the downstream effects of, for instance, VEGF amplification, can be very strong. It may be that there are a lot of macrophages or other cell populations that need additional therapy, and just taking away the angiogenesis signal might not be sufficient,” Dr. Derks suggested.
She advocated for “digging further into this biology” and conducting translational studies that will elucidate the pathways and the drivers involved in the cancers that seem resistant to these treatments.
DISCLOSURE: Dr. Derks has received honoraria from Bristol Myers Squibb and Benecke.
REFERENCE
1. Sun J-M, Shen L, Shah MA, et al: Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): A randomised, placebo-controlled, phase 3 study. Lancet 398:759-771, 2021.
