Blood tumor mutational burden (bTMB) may predict response to first-line atezolizumab in patients with non-small cell lung cancer (NSCLC), according to researchers.

The team found that high bTMB was associated with a significant improvement in overall response rate (ORR) as well as a trend toward improvement in progression-free survival (PFS) and overall survival (OS). 

These results, from the B-F1RST trial, were published in Nature Medicine


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B-F1RST (ClinicalTrials.gov identifier NCT02848651) is a single-arm, phase 2 trial designed to investigate the clinical utility of bTMB as a predictive biomarker in patients with locally advanced or metastatic NSCLC treated with atezolizumab monotherapy in the first-line setting.

The trial’s intention-to-treat population included 152 patients with immunotherapy-naive stage IIIB to IVB NSCLC who had any PD-L1 status and did not have EGFR mutations or ALK alterations. 

TMB status was evaluated in blood samples using the Foundation Medicine bTMB assay. Of the 152 patients, 78% had adequate circulating tumor DNA for valid detection of bTMB. 

At a median follow-up of 20.9 months, the ORR was 17.1%, and the median duration of response was 16.3 months. The median PFS was 4.1 months, and the median OS was 14.8 months. 

The ORR was significantly higher among patients with a high bTMB score (16 or higher) than among patients with a low bTMB score (below 16) — 35.7% and 5.5%, respectively (P <.0001).

The PFS did not differ significantly by bTMB score. The median PFS was 5.0 months for patients with a high bTMB and 3.5 months for those with a low bTMB (HR, 0.80; 90% CI, 0.54-1.18; P =.35).

Similarly, the median OS did not differ significantly between bTMB cohorts at a median follow-up of 20.9 months. The median OS was 23.9 months for patients with a high bTMB and 13.4 months for those with a low bTMB (HR, 0.66; 90% CI, 0.40-1.10; P =.18).

However, in an exploratory analysis at a median follow-up of 36.5 months, the median OS was significantly longer in patients with high bTMB than in those with low bTMB — 29.1 months and 13.4 months, respectively (HR, 0.54; 90% CI, 0.34-0.87; P =.032). 

A genomic analysis showed alterations in TP53, LRP1B, and CDKN2A were more common in the high bTMB cohort than in the low bTMB cohort, but the difference was significant only for TP53 alterations (P =.017).

On the basis of the overall findings, the researchers suggested that bTMB may eventually serve as a predictive biomarker for atezolizumab benefit in NSCLC. 

“Further study and assay optimization will be required to develop bTMB as a predictive, standalone biomarker of immunotherapy or for use in conjunction with other biomarkers,” the researchers concluded.

Disclosures: This research was supported by Genentech. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures. 

Reference

Kim ES, Velcheti V, Mekhail T, et al. Blood-based tumor mutational burden as a biomarker for atezolizumab in non-small cell lung cancer: The phase 2 B-F1RST trial. Nat Med. Published online April 14, 2022. doi:10.1038/s41591-022-01754-x