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Expert Point of View: Alex A. Adjei, MD, PhD


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Alex A. Adjei, MD, PhD

Alex A. Adjei, MD, PhD

Alex A. Adjei, MD, PhD, of Mayo Clinic, Rochester, Minnesota, who was not involved in KEYNOTE-189 or KEYNOTE-021, provided some perspective on the exploratory analyses of tumor mutational burden from these and other studies.

“Four studies at this meeting presented data on tumor mutational burden as a predictive marker of the effect of programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors. The first two were subset analyses of the MYSTIC trial1 and the CheckMate 8172 trial of ipilimumab plus nivolumab for patients with performance status 2. Both of these studies utilized next-generation sequencing to establish tumor mutational burden. High tumor mutational burden was defined as 20 mutations per megabase in MYSTIC and 10 mutations per megabase in CheckMate 817. In both of these studies, high tumor mutational burden was predictive of a superior outcome,” Dr. Adjei explained.

Turning to the studies reported by Drs. Garassino and Langer,3,4 Dr. Adjei pointed out that whole-exome sequencing was used to assess tumor mutational burden, and 175 mutations per exome was defined as the cutoff point for high tumor mutational burden.

“In these two studies of chemotherapy with or without pembrolizumab, high tumor mutational burden was not predictive of benefit. These four studies illustrate the current problem with tumor mutational burden as a biomarker. There are multiple assays to identify mutations, and there are different cutoffs for defining what a ‘high’ tumor mutational burden is. Until assays and definitions are harmonized, simply saying ‘high’ tumor mutational burden predicts for response will be meaningless,” Dr. Adjei stated. 

DISCLOSURE: Dr. Adjei reported no conflicts of interest.

REFERENCES

1. Rizvi N, Cho BC, Reinmuth N, et al: Mutations associated with sensitivity or resistance to immunotherapy in MNSCLC: Analysis from the MYSTIC trial. 2019 World Conference on Lung Cancer. Abstract OA04.07. Presented September 8, 2019.

2. Barlesi, F, Audigier-Valette C, Felip E, et al: CheckMate 817: First-line nivolumab + ipilimumab in patients with ECOG PS 2 and other special populations with advanced NSCLC. 2019 World Conference on Lung Cancer. Abstract OA04.02. Presented September 8, 2019.

3. Garassino M, Rodriguez-Abrreu D, Gadgeel S, et al: Evaluation of TMB in KEYNOTE-189: Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for nonsquamous NSCLC. 2019 World Conference on Lung Cancer. Abstract OA04.06. Presented September 8, 2019.

4. Langer C, Gadgeel SM, Borghaei H, et al: KEYNOTE-021: TMB and outcomes for carboplatin and pemetrexed with or without pembrolizumab for non-squamous NSCLC. 2019 World Conference on Lung Cancer. Abstract OA04.05. Presented September 8, 2019.


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