Lenvatinib Plus Pembrolizumab and Chemotherapy Versus Chemotherapy in Advanced Metastatic Gastroesophageal Adenocarcinoma: The Phase III, Randomized LEAP-015 Study
Kohei Shitara, Sylvie Lorenzen, Jin Li, Yuxian Bai, M. Fernández, Mynor Aguilar, Hirokazu Shoji, Felipe Reyes-Cosmelli, Yamilé Peña, Luis Corrales, Lucjan Wyrwicz, Daniel Acosta Eyzaguirre, Yueyin Pan, Min‐Hee Ryu, Deirdre J. Cohen, Zev A. Wainberg, Geoffrey Ku, Josep Tabernero, Eric Van Cutsem, Shukui Qin, Do‐Youn Oh, Jianming Xu, Li Liang, Sonal Bordia, Pooja Bhagia, Sun Young Rha, on behalf of the LEAP-015 Investigators, Ezequiel Slutsky, Juan Cundom, Andrea Gabriela Soria, Marcela Carballido, Juan Manuel O’Connor, Julieta Grasseli, Matthew Burge, Daniel Paul Brungs, Muhammad Adnan Khattak, Karen Geboes, Eric Van Cutsem, Jeroen Dekervel, Lionel D. Hondt, Frédéric Lemay, Rosalyn A. Juergens, Felipe Reyes, Gonzalo Pizarro Brito, Maria Alejandra Ojeda, Hiwot Araya, Patricio Yañez, Jianwei Yang, Xi Chen, Yuxian Bai, Hongming Pan, Nong Xu, Yueyin Pan, Qinghong Guo, Baorui Liu, Feng Ye, Xin Wang, Qi Li, Yong Tang, Huiting Xu, Haichuan Su, Ying Cheng, Xianli Yin, Qun Zhao, Ning Li, Jun You, Yi Ba, Jiang We, Lin Shen, Jin Li, Wangjun Liao, Zhen Li, Lei Yang, Yamilé Peña, Iván Bustillo, Carlos Jose Narvaez, Manuel Enrique Gonzalez Fernandez, Raimundo Manneh, Ana Iris Arias, Luis Corrales, Andres Wiernik Rodriguez, T. Aparicio, Y. Touchefeu, Helene Boussion-Desloges, Laurent Mineur, Christophe Tournigand, François Ghiringhelli, Marie Pierre Galais, Eric Terrebonne, Thomas Walter, Mathieu Baconnier, Sylvie Lorenzen, Eray Goekkurt, Annika Kurreck, Arne Kandulski, Thorsten Oliver Goetze, Florian Lordick, Mynor Aguilar, Karla Alejandra Lopez, Rixci Augusto Lenin Ramirez Fallas
Abstract
PURPOSE The phase III randomized open-label LEAP-015 study (ClinicalTrials.gov identifier: NCT04662710 ) evaluated first-line lenvatinib plus pembrolizumab and chemotherapy versus chemotherapy for advanced metastatic gastroesophageal adenocarcinoma. METHODS Eligible participants 18 years and older with untreated human epidermal growth factor receptor 2–negative locally advanced unresectable or metastatic gastroesophageal adenocarcinoma were randomly assigned 1:1 to induction with oral lenvatinib 8 mg once daily plus pembrolizumab 400 mg intravenously once every 6 weeks (×2) and investigators’ choice of capecitabine and oxaliplatin once every 3 weeks (×4) or fluorouracil, leucovorin, and oxaliplatin once every 2 weeks (×6) and consolidation with lenvatinib plus pembrolizumab, or chemotherapy. Dual primary end points were progression-free survival (PFS) and overall survival (OS) in participants with PD-L1 combined positive score (CPS) ≥1 and all participants. Secondary end points included objective response rate (ORR) and duration of response. RESULTS Of 880 participants randomly assigned, 443 received lenvatinib plus pembrolizumab and 437 received chemotherapy. The median follow-ups were 32.2 months (range, 19.0-41.7) in participants with PD-L1 CPS ≥1 and 31.8 months (19.0-41.7) in all participants. At interim analysis, PFS was statistically significant with lenvatinib plus pembrolizumab versus chemotherapy in participants with PD-L1 CPS ≥1 (median, 7.3 v 6.9 months; hazard ratio [HR], 0.75 [95% CI, 0.62 to 0.9]; P = .0012) and all participants (median, 7.2 v 7.0 months; HR, 0.78 [95% CI, 0.66 to 0.92]; P = .0019). The ORR was 59.5% versus 45.4% in participants with PD-L1 CPS ≥1 and 58.0% versus 43.9% in all participants, P < .0001 for both. At final analysis, OS was not statistically significant in participants with PD-L1 CPS ≥1 (median, 12.6 v 12.9 months; HR, 0.84 [95% CI, 0.71 to 1.00]; P = .0244; P value boundary = .0204). Grade ≥3 drug-related adverse event rates were 65% versus 49%. CONCLUSION Lenvatinib plus pembrolizumab and chemotherapy versus chemotherapy provided a statistically significant improvement in PFS in advanced unresectable or metastatic gastroesophageal carcinoma at interim analysis although the clinical significance of this difference seems to be limited. No significant improvement occurred in OS in participants with PD-L1 CPS ≥1.