Alectinib in Resected ALK-Positive Non–Small-Cell Lung Cancer

Author(s): Yi-Long Wu, M.D. https://orcid.org/0000-0002-3611-0258, Rafal Dziadziuszko, M.D., Ph.D., Jin Seok Ahn, M.D., Ph.D., Fabrice Barlesi, M.D., Ph.D., Makoto Nishio, M.D., Ph.D., Dae Ho Lee, M.D., Ph.D., Jong-Seok Lee, M.D., Ph.D., Wenzhao Zhong, M.D., Ph.D., Hidehito Horinouchi, M.D., Ph.D., Weimin Mao, M.D., Ph.D., Maximilian Hochmair, M.D., Filippo de Marinis, M.D., M. Rita Migliorino, M.D., Igor Bondarenko, M.D., Ph.D., Shun Lu, M.D., Qun Wang, M.D., Tania Ochi Lohmann, Ph.D., Tingting Xu, M.D., Andres Cardona, M.Sc., Thorsten Ruf, M.D., Johannes Noe, Ph.D., and Benjamin J. Solomon, M.B., B.S., Ph.D., for the ALINA Investigators*

Source: N Engl J Med 2024;390:1265-1276 DOI: 10.1056/NEJMoa2310532

Dr. Maen Hussein's Thoughts

This is another target for adjuvant therapy. The results are impressive. Notice that there was no chemotherapy in the study arm. Patients started on alectinib after surgery. Chemotherapy is losing ground to more tolerable treatments, more to follow, most likely, in the future.

BACKGROUND

Platinum-based chemotherapy is the recommended adjuvant treatment for patients with resectable, ALK-positive non–small-cell lung cancer (NSCLC). Data on the efficacy and safety of adjuvant alectinib as compared with chemotherapy in patients with resected ALK-positive NSCLC are lacking.

METHODS

We conducted a global, phase 3, open-label, randomized trial in which patients with completely resected, ALK-positive NSCLC of stage IB (tumors ≥4 cm), II, or IIIA (as classified according to the seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer and Union for International Cancer Control) were randomly assigned in a 1:1 ratio to receive oral alectinib (600 mg twice daily) for 24 months or intravenous platinum-based chemotherapy in four 21-day cycles. The primary end point was disease-free survival, tested hierarchically among patients with stage II or IIIA disease and then in the intention-to-treat population. Other end points included central nervous system (CNS) disease–free survival, overall survival, and safety.

RESULTS

In total, 257 patients were randomly assigned to receive alectinib (130 patients) or chemotherapy (127 patients). The percentage of patients alive and disease-free at 2 years was 93.8% in the alectinib group and 63.0% in the chemotherapy group among patients with stage II or IIIA disease (hazard ratio for disease recurrence or death, 0.24; 95% confidence interval [CI], 0.13 to 0.45; P<0.001) and 93.6% and 63.7%, respectively, in the intention-to-treat population (hazard ratio, 0.24; 95% CI, 0.13 to 0.43; P<0.001). Alectinib was associated with a clinically meaningful benefit with respect to CNS disease–free survival as compared with chemotherapy (hazard ratio for CNS disease recurrence or death, 0.22; 95% CI, 0.08 to 0.58). Data for overall survival were immature. No unexpected safety findings were observed.

Among patients with resected ALK-positive NSCLC of stage IB, II, or IIIA, adjuvant alectinib significantly improved disease-free survival as compared with platinum-based chemotherapy. (Funded by F. Hoffmann–La Roche; ALINA ClinicalTrials.gov number, NCT03456076.)

Author Affiliations

From the Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou (Y.-L.W., W.Z.), the Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou (W.M.), and the Department of Medical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine (S.L.), the Department of Thoracic Surgery, Zhongshan Hospital, Fudan University (Q.W.), and the Department of Clinical Science, Roche (China) Holding (T.X.), Shanghai — all in China; the Department of Oncology and Radiotherapy and the Early Phase Clinical Trials Center, Medical University of Gdansk, Gdansk, Poland (R.D.); the Department of Hematology and Oncology, Samsung Medical Center (J.S.A.), and Asan Medical Center (D.H.L.), Seoul, and Seoul National University Bundang Hospital, Seongnam (J.-S.L.) — all in South Korea; the Department of Medical Oncology, International Center for Thoracic Cancers, Gustave Roussy, Villejuif, and Paris-Saclay University, Faculty of Medicine, Le Kremlin-Bicêtre — both in France (F.B.); the Cancer Institute Hospital, Japanese Foundation for Cancer Research (M.N.), and the Department of Thoracic Oncology, National Cancer Center Hospital (H.H.) — both in Tokyo; the Department of Respiratory and Critical Care Medicine, Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Klinik Floridsdorf, Vienna (M.H.); the Thoracic Oncology Division, European Institute of Oncology, IRCCS, Milan (F.M.); the Pneumo-Oncology Unit, San Camillo Forlanini Hospital, Rome (M.R.M.); the Oncology and Medical Radiology Department, Dnipropetrovsk State Medical Academy, Dnipro, Ukraine (I.B.); PD Oncology (T.O.L.), Data and Statistical Sciences (A.C.), PD Safety Risk Management (T.R.), and Translational Medicine (J.N.), F. Hoffmann–La Roche, Basel, Switzerland; and the Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (B.J.S.).

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.