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Efficacy and Safety of Continuing Next-Generation ALK TKIs With Chemotherapy for Advanced ALK-Positive NSCLC: A

Sarah Waliany1, Shambo Guha Roy2, Federica Pecci3

  • 11Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, MA.

Journal of the National Comprehensive Cancer Network : JNCCN
|February 11, 2026
PubMed
Abstract

Insights

Continuing next-generation ALK tyrosine kinase inhibitors (TKIs) with platinum/pemetrexed chemotherapy improved progression-free survival and overall survival in advanced ALK-positive non-small cell lung cancer patients. This combination therapy also reduced intracranial progression without new safety concerns.

Area of Science:

  • Oncology
  • Pharmacology

Background:

  • Next-generation ALK tyrosine kinase inhibitors (TKIs) are first-line treatments for ALK-positive advanced/metastatic non-small cell lung cancer (NSCLC).
  • Platinum/pemetrexed (PT/Pem) chemotherapy is a standard next-line therapy, but data on continuing TKIs with PT/Pem post-progression are limited.

Purpose of the Study:

  • To evaluate the efficacy and safety of continuing next-generation ALK TKIs with PT/Pem chemotherapy compared to PT/Pem alone after TKI progression in ALK+ metastatic NSCLC.

Main Methods:

  • Retrospective, multicentered study of 156 patients with ALK+ metastatic NSCLC.
  • Patients received either PT/Pem alone or PT/Pem combined with alectinib or lorlatinib (PT/Pem/TKI) after prior next-generation ALK TKI therapy.
  • Endpoints included progression-free survival (PFS), overall survival (OS), intracranial progression, and treatment-related adverse events (trAEs).

Main Results:

  • Combining PT/Pem/TKI showed numerically longer median PFS (6.0 vs 3.5 months) compared to PT/Pem alone.
  • In patients treated with first-line TKIs, PT/Pem/TKI significantly improved median PFS (6.6 vs 3.5 months) and median OS (16.4 vs 11.4 months) versus PT/Pem alone.
  • PT/Pem/TKI significantly lowered the 12-month cumulative incidence of intracranial progression (18.7% vs 34.0%) compared to PT/Pem alone, with no unanticipated safety signals.

Conclusions:

  • Continuation of next-generation ALK TKIs with PT/Pem chemotherapy improves PFS and OS in ALK+ NSCLC patients progressing on TKI monotherapy.
  • This combination strategy demonstrates reduced intracranial progression without significant new toxicities.
  • The findings highlight the need for novel therapies for TKI-refractory ALK+ NSCLC, despite the benefits of combined treatment.

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