Patients with advanced non-small cell lung cancer (NSCLC) who did not respond to immune checkpoint blockade (ICB) had unique molecular characteristics, revealing possible approaches to overcoming primary resistance. The study was recently reported at the 34th Annual Meeting & Preconference Programs of the Society for Immunotherapy of Cancer, or SITC 2019.

The patients were from the prospective, ongoing MATCH-R trial (ClinicalTrials.gov Identifier: NCT02517892), which includes patients with unresectable or metastatic cancer. The aim of the study is to identify mechanisms of resistance to targeted therapies, and patients are considered resistant to therapy if disease progression was seen on the first radiological examination or if they had a median progression-free survival of fewer than 3 months. Biopsies were obtained from all patients.

The study included 31 patients with advanced NSCLC; 10 individuals responded to ICB therapy and 21 did not. Analysis of the tumor biopsies revealed that patients who responded had a higher tumor mutational burden (TMB) and more immune infiltration in their tumors than the tumors of patients who did not respond. Nonresponder patients could be grouped as “hot” tumors (ie, the same immune infiltration as responders) or “cold” tumors (ie, less immune infiltration than responders).

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ICB resistance was linked to mutations in the IFN-γ and/or KRAS/STK11/KEAP pathways and upregulation of hypoxia response, transforming growth factor (TGF-β), and MYC pathways. For cold tumors specifically, TGF-β pathway activation was linked to ICB resistance.

“We have further refined our understanding of the primary ICB resistance mechanisms in that there are both ‘hot’ and ‘cold’ nonresponsive tumors, which suggests that different therapeutic approaches be may be required in these 2 subtypes,” the study authors wrote. That is, the TGF-β pathway could be targeted in the “cold” nonresponding tumor class.

“We are continuing to increase our baseline cohort size and will include posttreatment biopsies collected with this protocol,” the study authors wrote.

Reference

Besse B, Fraslon C, Cao H, et al. Integrated molecular characterization of primary resistance mechanisms to immune checkpoint blockade in advanced non-small cell lung carcinoma (a-NSCLC). Poster presented at: the 34th Annual Meeting & Pre-Conference Programs (SITC 2019); November 6–10, 2019; National Harbor, MD. Abstract P285.