Osimertinib remains one of the global standard of care for first-line treatment of EGFR-mutant advanced non-small-cell-lung-cancer (NSCLC), but optimal sequencing after progression is less clear. In a new retrospective analysis across 11 European centres presented at the IASLC World Conference on Lung Cancer 2025, Dr Igor Gómez-Randulfe (The Christie NHS Foundation Trust, Manchester, UK) et al. examined outcomes with second-line carboplatin plus pemetrexed following first-line osimertinib. Among 91 patients, response rates were modest, median progression-free survival was just over five months, and overall survival was under a year – highlighting the limited durability of chemotherapy in this setting. These findings provide pragmatic real-world benchmarks and underscore the need for more effective post-osimertinib strategies and personalised treatment intensification.
Q1. What was the rationale behind investigating carboplatin plus pemetrexed in the second-line setting for EGFR-mutant NSCLC?
Following standard-of-care first-line osimertinib, clinicians frequently default to carboplatin plus pemetrexed at progression, yet the real-world effectiveness of this second-line approach is poorly characterized. With FLAURA2 now showing overall survival (OS) benefits for upfront osimertinib plus chemotherapy, the “sequence vs. upfront” question has become more pressing. We therefore examined outcomes with 2L carboplatin plus pemetrexed after first-line osimertinib across multiple European centres to provide pragmatic benchmarks for response, durability and tolerability in routine practice. Our goal was to contextualize expectations for patients who progress on osimertinib and to inform future trial design and guideline discussions about optimal sequencing, particularly when molecularly targeted options are not available at resistance.
Q2. What was the methodology and design of the analysis?
We conducted a retrospective, multicentre cohort study across 11 European centres. Eligible patients had EGFR-mutant advanced NSCLC treated with second-line carboplatin plus pemetrexed after first-line osimertinib between May 2018 and June 2023. The primary endpoint was overall response rate (ORR), secondary endpoints were progression-free survival (PFS) and OS from chemotherapy start, as well as toxicity. Responses were assessed in routine practice; survival outcomes were estimated from chemotherapy initiation. We also performed Cox regression for OS to explore prognostic factors.
Q3. Please summarize your key findings, and what conclusions can be drawn from the data?
Among 91 patients, ORR was 33.3% (72 evaluable). Median PFS was 5.3 months (95% CI 4.4–6.1) and median OS 9.2 months (95% CI 7.5–10.8). Grade 3-4 toxicities occurred in 24.4%; 23.1% required dose reductions and 14.3% stopped due to toxicity. ORR and PFS were broadly in line with prior reports, but OS was notably shorter, underscoring the limited durability of benefit with second-line carboplatin plus pemetrexed after osimertinib. Taken together, these results highlight a persistent unmet need and reinforce the rationale for more effective post-osimertinib strategies and/or treatment intensification earlier in the pathway.
Q4. What questions remain unanswered in this area, and are there any further investigations planned?
With FLAURA2, the question is no longer whether to combine but how to personalise intensification. Two priorities for me. First, dynamic intensification using serial ctDNA: if early on-treatment molecular clearance is absent (e.g., ~8–12 weeks on osimertinib), escalate by adding a defined course of chemotherapy, rather than a blanket “everyone upfront” or “only at progression” rule. (This response-adaptive approach is actively being explored). Second, biology at progression: routine, high-quality tissue/plasma profiling to map resistance (MET, C797S, fusions, HER2/HER3 signalling shifts, small-cell transformation) and triage patients to targeted agents, bispecifics or ADCs, reserving chemotherapy for scenarios where it clearly adds value.
Q5. Please summarize any highlights and exciting presentations from the WCLC 2025 conference
The final FLAURA2 analysis confirms that osimertinib plus platinum–pemetrexed improves OS versus osimertinib alone, extending median survival to nearly four years and reducing the risk of death. Adding carboplatin and pemetrexed to first-line osimertinib gave a clear, clinically meaningful OS benefit, with median survival close to four years. That sets a new benchmark in EGFR-mutant advanced NSCLC. The key debate was who actually needs upfront intensification and how to tailor it to disease burden, comorbidities, and patient preference.
In the EGFR space, the PD-L1/VEGF bispecific ivonescimab (HARMONi) looked interesting in the post-osimertinib setting, but not practice-changing yet. There is also a growing wave of ADCs, including an EGFR×HER3 bispecific with encouraging early signals. Overall, WCLC 2025 reinforced a practical message: define the subgroup, intensify where it matters, and use rational combinations to stay ahead of resistance.
About Igor Gómez-Randulfe
Igor Gómez-Randulfe, MD, is a Consultant Medical Oncologist at The Christie NHS Foundation Trust (Manchester, UK), specialised in thoracic and acute oncology. His practice centres on lung cancer, with interests in targeted therapy and immuno-oncology. He collaborates across multidisciplinary teams, contributes to clinical research and service improvement, and presents at national and international meetings to translate innovation into better patient outcomes.
Disclosure: Igor Gómez-Randulfe has received grant/research support from Janssen and is a member of the Advisory Board for Janssen and AstraZeneca.
Cite: WCLC 2025 highlights: Real-world outcomes in EGFR-mutant NSCLC. touchONCOLOGY. September 18th, 2025
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