Investigational New Drugs - Phase 2 - Open-Label Single-Arm Study Evaluating Pembrolizumab, Lenvatinib, Carboplatin and Pemetrexed in Metastatic NSCLC

Sep 28, 2026

Uploaded by Connor

A phase 2 open-label single-arm study assessed the efficacy and safety of pembrolizumab combined with lenvatinib, carboplatin, and pemetrexed in metastatic non-small cell lung cancer (NSCLC) harboring sensitizing EGFR, ALK, or ROS1 alterations after progression on standard tyrosine kinase inhibitors (TKIs). Nineteen patients (intention-to-treat) were treated following screening of 24 participants. Median follow-up was 10.7 months. Objective response rate (ORR) was 31.6% with RECIST 1.1, median progression-free survival (PFS) was 11.9 months, and median overall survival (OS) was not reached. Treatment-related adverse events were mostly grade 1–2, with common toxicities including hypothyroidism, nausea, neutropenia, thrombocytopenia, and anorexia.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages10

Reading Time25 min

AccessFree to download

Summary

Study population and design

Endpoints and outcomes

Safety and tolerability

Introduction

Current treatment challenges after TKI resistance

Rationale for combining immunotherapy, anti-VEGF signaling, and chemotherapy

Methods

Study design and Simon’s two-stage approach

Investigational New Drugs (2025) 43:1191–1200 [https://doi.org/10.1007/s10637-025-01589-6](https://doi.org/10.1007/s10637-025-01589-6) A phase 2, open‑label, single‑arm study evaluating the combination of pembrolizumab, lenvatinib, carboplatin and pemetrexed in patients with metastatic non‑small cell lung cancer harbouring targetable genomic alterations who progressed on standard tyrosine kinase inhibitors HoiWai Chan1 · Chris Chun Long Tse1 · Yu‑Chung Li2 · Roland Leung1 · Gin Wai Kwok1 · Jeffrey Sum Lung Wong1 · Karen Hoi‑Lam Li1 · Josephine Wing Yan Tsang1 · ChoWing Li1 · Jenny Wai Yan Lo1 · Vikki Tang1 · Rina Hui3 · Thomas Yau3 · James Chung Man Ho1 · Joanne Wing Yan Chiu1 Received: 25 August 2025 / Accepted: 3 October 2025 / Published online: 10 November 2025 © The Author(s) 2025 Summary Patients with metastatic non-small cell lung cancer (NSCLC) harbouring targetable genomic alterations who progressed on standard tyrosine kinase inhibitors (TKIs) have limited treatment options, with platinum-based chemotherapy offering modest efficacy. We evaluated the efficacy and safety of a novel combination of pembrolizumab, lenvatinib, carboplatin and pemetrexed in this population. This phase 2, open-label, single-arm study enrolled patients with metastatic NSCLC with sensitizing epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) or c-ROS oncogene 1 (ROS1) alteration who progressed on standard TKIs. Patients received a combination of pembrolizumab, lenvatinib, carboplatin and pemetrexed. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included progression free survival (PFS), overall survival (OS) and safety. Of the 24 patients screened, 19 were enrolled and included in the intention-to-treat population. Median follow-up time was 10.7 months (95% CI 4.4–11.9). ORR was 31.6%(6/19, 95% CI 12.6%–56.6%; all partial responses) . Median PFS was 11.9 months (95% CI 4.3–not reached) . Median OS was not reached. Most of the treatment-related adverse events (TRAEs) were grade 1–2, which occurred in 63%(12/19) of the patients. The most common TRAEs were hypothyroidism (31.6%), nausea (26.3%), neutropenia (26.3%), thrombocytopenia (26.3%) and anorexia (21.1%). The combination of pembrolizumab, lenvatinib, carboplatin and pemetrexed showed modest efficacy and manageable toxicity in metastatic NSCLC patients with targetable genomic alterations who progressed on standard TKIs. NCT04989322 . Keywords Lung cancer · Non-small-cell lung carcinoma (NSCLC) · Epidermal growth factor receptor (EGFR) · Tyrosine kinase inhibitor (TKI) · Pembrolizumab · Lenvatinib * Joanne Wing Yan Chiu[drjwychiu@outlook.com](drjwychiu@outlook.com) 1 Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pokfulam, Hong Kong 2 Hong Kong United Oncology Centre, Kowloon, Hong Kong 3 Centre of Cancer Medicine, School of Clinical Medicine, University of Hong Kong, Pokfulam, Hong Kong Introduction Lung cancer is the leading cause of cancer death in adults, with an estimated 1.8 million deaths worldwide in 2022 [1] . Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers [2] . Patients with metastatic NSCLC harbouring genomic alteration of particular tyrosine kinases, notably epidermal growth factor receptor (EGFR), andrearrangements of the anaplastic lymphoma kinase (ALK) gene and c-ROS oncogene 1 (ROS1) gene, are treated with tyrosine kinase inhibitors (TKIs) . As a first-line treatment, the response rates of TKIs are in the range of 60%–80%, and median progression-free survival (PFS) is 10–17 months [3–7]. However, acquired resistance inevitably develops, and platinum-based chemotherapy is a conventional next-line therapy, with a median PFS of only 4–5 months [8] . Immunotherapy alone is ineffective in NSCLC with mutation of EGFR or rearrangement of ALK and ROS1 [9, 10], but the IMpower150 trial demonstrated that combining the anti-PD-L1 atezolizumab with

FAQs

Who were the patients enrolled in this phase 2 study?

Patients with metastatic NSCLC harboring sensitizing EGFR, ALK, or ROS1 alterations who progressed on standard tyrosine kinase inhibitors were enrolled.

What were the primary and secondary endpoints?

The primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.

What did the study report about efficacy and overall survival?

ORR was 31.6% and median PFS was 11.9 months. Median OS was not reached at the reported follow-up.

Sep 28, 2026

Uploaded by Connor