Table 2.

Studies on TMB analysis as a negative biomarker of response to ICIs.

Drug Trial	Study Type	Pts, n	Patient Population	Purpose of Study	Tmb Method & Cutoff	Clinical Outcomes	Conclusion
KEYNOTE-010 (NCT01905657)	Exploratory retrospective analysis of a randomised controlled trial phase II/III	253 (24% from the all sample)	Previously treated or untreated advanced NSCLC PD-L1(+) with tumour proportion score (TPS)≥ 1% having evaluable Ttmb	Association between tTMB and clinical benefit with pembrolizumab monotherapy	tTMB determined by WES of tumour and matched normal DNA Cutpoint of 175 mutations per exome	tTMB ≥ 175: OS 14.1 m vs. 7.6 m (CI, 0.38–0.83); PFS 4.2 m vs. 2.4 m (CI, 0.40–0.87); ORR 23.5% vs. 9.8% with pembrolizumab and chemotherapy respectively	tTMB was associated with OS, PFS and ORR for the pembrolizumab arms but tTMB was not associated with outcomes for chemotherapy [59,60].
KEYNOTE-042 (NCT02220894)	Exploratory retrospective analysis of a randomised controlled trial phase III	793 (62% from the all sample)				tTMB ≥ 175: OS 21.9 m vs. 11.6 m (CI, 0.48–0.80); PFS 6.3 m vs. 6.5 m (CI, 0.59–0.95); ORR 34.4% vs. 30.9% with pembrolizumab and chemotherapy respectively
KEYNOTE-021 (NCT02039674)	Exploratory analysis of a randomised controlled trial phase I/II study	267 (48% of patients in cohorts C and G)	Stage IIIb/IV non-squamous NSCLC	Association of tTMB with outcomes for pembrolizumab + chemotherapy and for chemotherapy	tTMB determined by WES of tumour and matched normal DNA Cutpoint of 175 mutations per exome	In cohort G, ORR was higher with pembrolizumab + chemotherapy vs chemotherapy in the 31 patients with tTMB ≥175 mutations per exome (71.4% vs. 30%)	No significant association was determined between tTMB and efficacy of pembrolizumab + chemotherapy or chemotherapy alone. TMB does not seem to identify responders from non responders either for the combination treatment or chemotherapy alone. [60,61,62,63].
KEYNOTE-189 (NCT02578680)	Exploratory analysis of a randomised controlled trial phase III	616 (48% from the all sample)				tTMB ≥ 175: OS was improved with pembrolizumab + chemotherapy over chemotherapy (HR 0.64; CI 0.38-1.07), PFS (HR 0.32; CI 0.21-0´51)
KEYNOTE-407 (NCT02775435)	Exploratory analysis of a randomised controlled phase III study	559 (56% from the all sample)	Stage IV squamous NSCLC			tTMB ≥ 175: OS was improved with pembrolizumab + chemotherapy over chemotherapy (HR 0.74; CI 0.50-1.08), PFS (HR 0.57; CI 0.41-0.81)
CHECKMATE-026 (NCT02041533)	Exploratory analysis of randomised phase III study	312 (58% of the patients who had undergone randomization)	Stage IV or recurrent (PD-L1)–positive NSCLC	Assess the effect of the TMB on outcomes with nivolumab vs. docetaxel	TMB determined in tumor and blood samples by WES 0to100 (low burden) 100to242 (medium) ≥ 243 (high)	tTMB ≥ 243: ORR was higher in the nivolumab group than in the chemotherapy (47% vs. 28%), and PFS was longer (median, 9.7 vs. 5.8 months; HR 0.62; 95% CI, 0.38 to 1.00).	No significant difference was observed in OS between the nivolumab and chemotherapy groups regardless of TMB, according to findings published in the New England Journal of Medicine [33].
CHECKMATE-227 (NCT02477826)	Exploratory analysis of randomised phase III study	679 (58.2% from the all sample)	Stage IV or recurrent NSCLC	Evaluate TMB as a potential predictive biomarker of efficacy of nivolumab, nivolumab + ipilimumab, nivolumab + platinum-doublet chemotherapy and of platinum-doublet.	TMB determined by WES Cutpoint of 10 mutations per megabase	Similar degree of OS benefit in nivolumab + ipilimumab, regardless of TMB (≥10 vs. <10 mutations per megabase, respectively) OS benefit for nivolumab plus ipilimumab vs chemotherapy regardless of TMB or PD-L1	A similar degree of OS benefit was found for nivolumab and ipilimumab regardless of TMB according to findings published in the New England Journal of Medicine Combination of PD-L1 and TMB did not reveal a subgroup with an increased benefit for nivo + ipi vs chemotherapy [64].