Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC

Author(s): David Planchard, M.D., Ph.D., Pasi A. Jänne, M.D., Ph.D., Ying Cheng, M.D., James C.-H. Yang, M.D., Ph.D., Noriko Yanagitani, M.D., Ph.D., Sang-We Kim, M.D., Shunichi Sugawara, M.D., Ph.D., Yan Yu, M.D., Yun Fan, M.D., Sarayut L. Geater, M.D., Konstantin Laktionov, Ph.D., Chee K. Lee, M.D., Ph.D., et al., for the FLAURA2 Investigators*

Source: N Engl J Med 2023; 389:1935-1948 DOI: 10.1056/NEJMoa2306434

Dr. Anjan Patel's Thoughts

Osimertinib with chemotherapy improved the chance of being alive at two years compared to targeted therapy alone at 57 vs 41%. Further analysis of FLAURA2 and new studies will surely look to identify which patients benefit most from the combination of targeted therapy and chemotherapy. For young or healthy patients, this is an acceptable first line option. This is not yet reflected on NCCN but is likely to be added soon.

BACKGROUND

Osimertinib is a third-generation epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR-TKI) that is selective for EGFR-TKI–sensitizing and EGFR T790M resistance mutations. Evidence suggests that the addition of chemotherapy may extend the benefits of EGFR-TKI therapy.

METHODS

In this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with EGFR-mutated (exon 19 deletion or L858R mutation) advanced non–small-cell lung cancer (NSCLC) who had not previously received treatment for advanced disease to receive osimertinib (80 mg once daily) with chemotherapy (pemetrexed [500 mg per square meter of body-surface area] plus either cisplatin [75 mg per square meter] or carboplatin [pharmacologically guided dose]) or to receive osimertinib monotherapy (80 mg once daily). The primary end point was investigator-assessed progression-free survival. Response and safety were also assessed.

RESULTS

A total of 557 patients underwent randomization. Investigator-assessed progression-free survival was significantly longer in the osimertinib–chemotherapy group than in the osimertinib group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; P<0.001). At 24 months, 57% (95% CI, 50 to 63) of the patients in the osimertinib–chemotherapy group and 41% (95% CI, 35 to 47) of those in the osimertinib group were alive and progression-free. Progression-free survival as assessed according to blinded independent central review was consistent with the primary analysis (hazard ratio, 0.62; 95% CI, 0.48 to 0.80). An objective (complete or partial) response was observed in 83% of the patients in the osimertinib–chemotherapy group and in 76% of those in the osimertinib group; the median response duration was 24.0 months (95% CI, 20.9 to 27.8) and 15.3 months (95% CI, 12.7 to 19.4), respectively. The incidence of grade 3 or higher adverse events from any cause was higher with the combination than with monotherapy — a finding driven by known chemotherapy-related adverse events. The safety profile of osimertinib plus pemetrexed and a platinum-based agent was consistent with the established profiles of the individual agents.

CONCLUSIONS

First-line treatment with osimertinib–chemotherapy led to significantly longer progression-free survival than osimertinib monotherapy among patients with EGFR-mutated advanced NSCLC. (Funded by AstraZeneca; FLAURA2 ClinicalTrials.gov number, NCT04035486. opens in new tab.)

Author Affiliations

From the Department of Medical Oncology, Institut Gustave Roussy, Thoracic Group and International Center for Thoracic Cancers, Villejuif, and the Faculty of Medicine, Paris-Saclay University, Paris — both in France (D.P.); the Department of Medical Oncology, Lowe Center for Thoracic Oncology, Dana–Farber Cancer Institute, Boston (P.A.J.); the Department of Thoracic Oncology, Jilin Cancer Hospital, Changchun (Y.C.), the Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin (Y.Y.), and the Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou (Y.F.) — all in China; the Department of Oncology, National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei (J.C.-H.Y.); the Department of Thoracic Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo (N.Y.), the Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai (S.S.), and the Department of Respiratory Medicine, Saitama Medical University International Medical Center, Hidaka (K.K.) — all in Japan; the Department of Oncology, Asan Medical Center, Seoul, South Korea (S.-W.K.); the Department of Internal Medicine, Prince of Songkla University, Songkhla, Thailand (S.L.G.); the Federal State Budgetary Institution “N.N. Blokhin National Medical Research Center of Oncology” of the Ministry of Health of the Russian Federation, Moscow (K.L.); the Department of Medical Oncology, Cancer Care Centre, St. George Hospital, Kogarah, NSW, Australia (C.K.L.); the Department of Oncology, Instituto Nacional de Enfermedades Neoplásicas, Surquillo, Peru (N.V.); the Department of Medical Oncology, University Hospitals of Leicester, Leicester (S.A.), and Oncology Research and Development (D.G., Y.R.) and Oncology Biometrics (A.T.), AstraZeneca, Cambridge — both in the United Kingdom; the Department of Clinical Oncology, Rondebosch Oncology Centre, Cape Town, South Africa (J.-M.M.); the Department of Radiotherapy and Oncology, Východoslovenský Onkologický Ústav, Košice, Slovakia (I.A.); and the David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles (J.G.). Dr. Planchard can be contacted at david.planchard@gustaveroussy.fr or at the Department of Medical Oncology, Institut Gustave Roussy, Thoracic Group and International Center for Thoracic Cancers, 114 Rue Edouard Vaillant, 94805 Villejuif, France. Dr. Jänne can be contacted at pasi_janne@dfci.harvard.edu or at the Department of Medical Oncology, Lowe Center for Thoracic Oncology, Dana–Farber Cancer Institute, 450 Brookline Ave., LC4114, Boston, MA 02215.

Simultaneous Durvalumab and Platinum-Based Chemoradiotherapy in Unresectable Stage III Non–Small Cell Lung Cancer: The Phase III PACIFIC-2 Study

PACIFIC-2 was a phase III trial testing durva given concurrently with cCRT (and continued as consolidation) versus placebo + cCRT in unresectable stage III NSCLC, and it did not meet its primary endpoint. The overall response rate (ORR) was essentially identical (60.7% vs 60.6%), and pneumonitis rates were similar (any grade 28.8% vs 28.7%; grade ≥3: 4.6% vs 5.6%), but adverse events (AEs) leading to discontinuation and fatal AEs were higher with durva (25.6% vs 12.0%; 13.7% vs 10.2%), especially early on. Starting IO up front with cCRT didn’t improve outcomes and added early toxicity—consolidation durva after cCRT is still the way to go.

Sevabertinib in Advanced HER2-Mutant Non–Small-Cell Lung Cancer

Sevabertinib shows strong efficacy in HER2-mutant NSCLC, with an overall response rate (ORR) of 64% and median progression-free survival (PFS) of 8.3 months in previously treated, HER2-TKI–naive patients, and an overall response rate (ORR) of 71% with a duration of response (DOR) of 11.0 months in first-line therapy. Activity is highest in TKD mutations, especially Y772_A775dupYVMA, and intracranial responses are seen. Safety is manageable: diarrhea is common but mostly low grade, with grade ≥3 in 5–23% and rare discontinuations. Notably, interstitial lung disease (ILD) was not observed. These data position sevabertinib as a viable oral TKI alongside ADCs for HER2-mutant NSCLC, particularly for TKD/YVMA disease.

Overall Survival with Amivantamab–Lazertinib in EGFR-Mutated Advanced NSCLC

The combination therapy demonstrated improved overall survival (a 25% reduction in mortality) but was associated with increased toxicity, including skin rash and venous thromboembolic events (VTEs). Single-agent osimertinib may lose its role as monotherapy for EGFR-mutated NSCLC, as the FLAURA2 trial showed that combining osimertinib with chemotherapy yielded better outcomes than osimertinib alone.

Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non–Small Cell Lung Cancer

The phase III NeoADAURA trial evaluated neoadjuvant osimertinib (OSI) with or without platinum-based chemotherapy (CT) versus CT alone in resectable, EGFR-mutated stage II-IIIB non-small cell lung cancer (NSCLC). Both OSI+CT and OSI monotherapy significantly improved major pathologic response (MPR: 26% and 25% vs 2%), and 12-month event-free survival (EFS) rates were higher with OSI-containing regimens (OSI+CT 93%, OSI 95%, CT 83%). Nodal downstaging was also more frequent with OSI arms (53% vs 21%). Neoadjuvant OSI—with or without CT—looks like a real step forward for our EGFR-mutant NSCLC patients, especially given the robust pathologic responses and high rates of surgical completion.

Phase III Study of Mediastinal Lymph Node Dissection for Ground Glass Opacity–Dominant Lung Adenocarcinoma

This large, well-done study compared systematic mediastinal lymph node dissection (LND) versus no LND in patients with GGO-dominant invasive lung adenocarcinoma (CTR ≤0.5, ≤3 cm, cT1N0M0). Interim analysis of 302 patients showed no lymph node metastases in either arm, with both groups achieving 3-year disease-free survival (DFS) and overall survival (OS) of 100% at the time of analysis. The no LND arm had significantly shorter surgery duration (74 vs 109 min), less blood loss (44 vs 82 mL), shorter hospital stays (3.9 vs 4.5 days), and fewer grade ≥2 complications (3.3% vs 9.3%). Based on these findings, the trial was terminated early for nonmaleficence, and the authors recommend omitting systematic mediastinal LND in this population. In short, for carefully selected GGO-dominant lung adenocarcinoma, skipping mediastinal LND appears safe and spares patients’ unnecessary morbidity—this could be a real practice-changer for our early-stage, node-negative cases.