Indirect comparisons for efficacy outcomes showed that ICIs were associated with a statistically significant advantage over CT alone in terms of response rate (RR 1.37, 95% CI 0.94 - 1.99), progression-free survival (PFS; HR 0.57, 95% CI 0.48 - 0.67) and OS (HR 0.72, 95% CI 0.60 - 0.86), supporting the use of I-O regimens strategy within the TMB-high subgroup (1255 patients)....Although more prospective data are warranted, we inferred that monitoring TMB, in addition to the existing PD-L1 expression level, could represent the preferable option for the first-line management of advanced non-oncogene addicted NSCLC.

Overall survival (OS) was significantly longer for patients with TMB-H versus TMB low tumors in non-small-cell lung cancer (NSCLC; n = 1,593), head and neck (H&N) cancer (n = 222), and urothelial cancer (n = 332)….Consistent with previous studies, a predictive value of TMB ≥10 mut/Mb for ICI response was found in NSCLC and H&N, but not in esophageal/gastric cancer.

The cohort with either TMB > 18 or POLE/POLD1 mutated (n = 54, 15.4%) had significant OS improvement with ICI treatment when compared with those without the biomarker signature of POLE/POLD1 mutated or TMB > 18 (p < 0.0001) (Figure 4a).

In this cohort study of patients with advanced solid tumors treated with ICIs in diverse clinics, TMB-H cancers were significantly associated with improved clinical outcomes compared with TMB-L cancers....Our results were generally consistent with our pancancer cohort, with the 1-year survival probability of TMB-H patients being higher than that of TMB-L patients with NSCLC, bladder, melanoma, and CRC (Figure 3).

We observed that the RNA measure of TMB was significantly higher in responders to immune blockade treatment (P = 0.028) and that it was predictive of response (AUC = 0.640 with 95% CI [0.493, 0.786]). By contrast, the expression of immune-cell-restricted genes was uncorrelated with patient outcome.

Patients with advanced NSCLC without driver alterations who were treated with ICI and platinum-based chemotherapy (N=80) were identified....The OS and PFS of patients with KRAS mutations were significantly higher than those in the non-KRAS mutant group (P<0.05)....This work provides evidence that KRAS mutation in advanced NSCLC may be served as a potential predictive biomarker for immunotherapeutic efficacy.

This retrospective study analyzed a cohort of Hispanic patients (N=103) diagnosed with mNSCLC from the US and seven Latin American countries (LATAM) treated with immune checkpoint inhibitors (ICI) alone or in combination...TMB-H favored better OS.

TMB high patients exhibited higher RR (49.1% versus 25.4%; p=0.0084) and SR 6 months after start ICI (85.5% versus 70.4%; p=0.0468) than TMB low patients.

NSCLC patients treated with ICIs in the high bTMB group had better survival benefits than chemotherapy patients in terms of OS (HR = 0.63; 95% CI: 0.51-0.76, P <0.001), PFS (HR = 0.63; 95% CI: 0.52-0.76, P <0.001), and ORR (RR = 1.86; 95% CI: 1.32-2.62, P <0.001)...subgroup analysis revealed that patients with high bTMB could benefit more from ICIs than chemotherapy (HR = 0.63; 95% CI: 0.52–0.76, P <0.001), but not patients with low bTMB (HR = 1.21, 95% CI: 0.93–1.58, P = 0.154) (Figure 5). A similar situation occurred in the ORR....TMB is a feasible and reliable predictive biomarker for identifying NSCLC patients who are candidates for ICIs therapy....ICIs may be a better option than chemotherapy for NSCLC patients with high TMB.

In patients with high TMB, immunotherapy was associated with improved PFS (HR = 0.62, 95%CI: 0.53-0.72), OS (HR = 0.67, 95%CI: 0.57-0.79) and ORR (OR = 2.35, 95%CI: 1.74-3.18) when compared with chemotherapy. However, in patients with low TMB, immunotherapy seemed to predict inferior PFS (HR = 1.20, 95%CI: 1.02-1.41) and ORR (OR = 0.61, 95%CI: 0.44-0.84) and have no OS benefit (HR = 0.88, 95%CI: 0.74-1.05) as compared with chemotherapy.

High TMB predicted significantly favorable PFS (HR = 0.54, 95%CI: 0.46-0.63, P<0.001) and OS (HR = 0.70, 95%CI: 0.57-0.87, P = 0.001), and higher ORR (OR = 3.14, 95%CI: 2.28-4.34, P<0.001) compared with low TMB. In patients with high TMB, immunotherapy was associated with improved PFS (HR = 0.62, 95%CI: 0.53-0.72), OS (HR = 0.67, 95%CI: 0.57-0.79) and ORR (OR = 2.35, 95%CI: 1.74-3.18) when compared with chemotherapy....This meta-analysis demonstrates more clinical benefits concerning treatment response and survival outcomes in high-TMB NSCLC patients who are treated with immunotherapy.

...we sought to evaluate the ability of TMB-H to predict the PFS of ICB-treated patients in high TMB (category I) cancer types...we found that TMB-H was remarkably associated with improved PFS after ICB treatment in melanoma and NSCLC...

A multi-site cohort study evaluated patients diagnosed with stage IV NSCLC....TMB >10 showed a significant association towards longer overall survival (OS) (HR: 0.43, 95% CI: 0.21-0.88, p = 0.02) and progression-free survival (PFS) (HR: 0.43, 95% CI: 0.21-0.85, p = 0.02) in patients treated with first-line immunotherapy and tested by Foundation Medicine or Caris at treatment initiation....TMB levels greater than or equal to 10 mut/Mb, when tested by Foundation Medicine or Caris at treatment initiation, were significantly associated with improved OS and PFS among patients treated with first-line immunotherapy-containing regimens.

Patients with a higher TMB had a better OS as compared with patients with a lower TMB (HR = 0.61, P < 0.001). Similarly, a higher TMB was also a good predictor of PFS in patients treated with PD1/PDL1 antibodies (HR = 0.55, P < 0.001)....NSCLC patients receiving PD1/PDL1 antibodies, patients with higher TMB could have a better survival outcome.

Comparison of high and low TMB: pooled HRs for OS, 0.57 (95% CI 0.32 to 0.99; P = 0.046); PFS, 0.48 (95% CI 0.33 to 0.69; P < 0.001); ORR, 3.15 (95% CI 2.29 to 4.33; P < 0.001)….These findings imply that NSCLC patients with high TMB possess significant clinical benefits from ICIs compared to those with low TMB.

Median progression-free (PFS) and overall survival (OS) were significantly longer in NSCLCs with TMB ≥19 mut/Mb vs <19 mut/Mb, in both cohorts (Table)...A very high TMB is associated with better outcomes to ICI and a distinct immunophenotype in NSCLC.

Here we report that high TMB, but not PD-L1, is associated with improved OS and PFS in patients treated with ICI…

All patients had at least one dose of ICI with a median time of treatment of 4 months [IQR= 2-9]...Median PFS was 4 months in patients with TMBlow compared to 8 months in patients with TMBhigh (p=0.121). Median OS was 12 months in patients with TMBlow compared to 17 months in patients with TMBhigh (p=0.187)….We observed a strong trend toward longer PFS and OS with TMBhigh compared to TMBlow in a uniquely diverse cohort of advanced NSCLC.

A total of 17 studies including 3,938 patients met eligibility criteria: the majority of patients had non-small cell lung carcinoma (n=1,481)…Comparing high (n=631) to low TMB (n=1,525), the pooled HR for 1-YR OS was -0.81 [95% CI: -1.63 to 0.02; P < 0.01] in patients with high TMB....TMB may be a tumor-agnostic biomarker of response to ICIs and survival.

NSCLC patients with high TMB by TSO500, show higher RR to immunotherapy. HLA diversity score alone could not predict response, however combined high TMB and HLA diversity score show higher RR and DCR. Combined TMB, HLA diversity and PD-L1 can identify NSCLC patients likely to respond to or unlikely to benefit from IO. Hence TMB and HLA diversity score should be considered part of comprehensive genomic profiling.

In addition to potential modulation of immune checkpoint molecules, preliminary analysis of 14,698 NSCLC cases indicate that tumors with RICTOR amplification more often have higher levels of tumor mutation burden (TMB) than other lung cancers: the mean TMB was 14.9 mut/Mb in RICTOR-amplified vs 9.2 mut/Mb in non-amplified cases. TMB is a surrogate for increased number of expressed tumor neoantigens and is an important biomarker for response to immune checkpoint inhibitors.