Crizotinib Restored Pembrolizumab Response in Advanced Non-Small Cell Lung Cancer

Laila C Roisman, Nir Peled, Kiran Kundu, Susmita Ghosh, Bilal Krayim, Jonah M Cooper, Walid Shalata, Yehonatan Aharon Cohen, Moshe Elkabets, Angel Porgador, Ariel Sobarzo

Research output: Contribution to journalArticlepeer-review


Background: PD-1/PD-L1 immune checkpoint inhibitors, such as pembrolizumab and nivolumab, are used as a backbone treatment in various types of cancers, including lung cancer. However, PD-1/PD-L1 inhibitors effect a small number of patients, and acquired resistance to those treatments is still unresolved. Furthermore, the identification of potential anti-PD-1/PD-L1 sensitizers for restoring treatment response and effectiveness is a challenge. Materials and Methods: In this report, we presented a patient with non-small cell lung cancer (NSCLC) who received repeated rounds of pembrolizumab and showed a prolonged effective response, although eventually, he developed resistance to this treatment course. Results: Notably, this patient developed acquired resistance to PD-1/PD-L1, which was associated with several driver gene alternations, including a de novo profound MET overexpression. In vitro studies using the patient tumor cells and CD8+ T cells revealed significant reactivation and resensitization to pembrolizumab upon combined treatment with crizotinib. Combined treatment of crizotinib and pembrolizumab in this patient resulted in a significant clinical and RECIST response. Conclusions: Treatment strategy in patients with PD-1/PD-L1 acquired resistance should routinely include comprehensive genotyping of targetable driver oncogenes such as MET overexpression, along with the determination of PD-L1 status. These driver gene mutations may provide a vital target for immune checkpoint inhibitors therapy resensitization and optimize treatment stratification.
Original languageEnglish
Pages (from-to)268-275
Number of pages8
JournalEuropean Journal of Respiratory Medicine
Issue number1
StatePublished - 16 Feb 2022


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