Efficacy of Platinum/Pemetrexed Combination Chemotherapy in ALK-Positive NSCLC Refractory to Second-Generation ALK Inhibitors

J Thorac Oncol. 2020 Feb;15(2):258-265. doi: 10.1016/j.jtho.2019.10.014. Epub 2019 Oct 26.


Introduction: The current standard initial therapy for advanced ALK receptor tyrosine kinase (ALK)-positive NSCLC is a second-generation ALK tyrosine kinase inhibitor (TKI) such as alectinib. The optimal next-line therapy after failure of a second-generation ALK TKI remains to be established; however, standard options include the third-generation ALK TKI lorlatinib or platinum/pemetrexed-based chemotherapy. The efficacy of platinum/pemetrexed-based chemotherapy has not been evaluated in cases that are refractory to second-generation TKIs.

Methods: This was a retrospective study performed at three institutions. Patients were eligible if they had advanced ALK-positive NSCLC refractory to one or more second-generation ALK TKI(s) and had received platinum/pemetrexed-based chemotherapy.

Results: Among 58 patients eligible for this study, 37 had scans evaluable for response with measurable disease at baseline. The confirmed objective response rate to platinum/pemetrexed-based chemotherapy was 29.7% (11 of 37 patients; 95% confidence interval [CI]: 15.9% - 47.0%), with median duration of response of 6.4 months (95% CI: 1.6 months - not reached). The median progression-free survival for the entire cohort was 4.3 months (95% CI: 2.9 - 5.8 months). Progression-free survival was longer in patients who received platinum/pemetrexed in combination with an ALK TKI compared to those who received platinum/pemetrexed alone (6.8 months vs. 3.2 months, respectively; hazard ratio = 0.33; p = 0.025).

Conclusions: Platinum/pemetrexed-based chemotherapy shows modest efficacy in ALK-positive NSCLC after failure of second-generation ALK TKIs. The activity may be higher if administered with an ALK TKI, suggesting a potential role for continued ALK inhibition.

Keywords: ALK; Chemotherapy; Efficacy; NSCLC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Therapy, Combination
  • Family Characteristics
  • Humans
  • Lung Neoplasms* / drug therapy
  • Pemetrexed / therapeutic use
  • Platinum* / therapeutic use
  • Protein Kinase Inhibitors / therapeutic use
  • Receptor Protein-Tyrosine Kinases / genetics
  • Retrospective Studies


  • Protein Kinase Inhibitors
  • Pemetrexed
  • Platinum
  • Receptor Protein-Tyrosine Kinases