Although measurement of expression of the programmed death-ligand 1 (PD-L1) protein on cancer cells is a far from perfect test, it has an established role in helping to predict which patients with advanced non-small cell lung cancer (NSCLC) are more or less likely to benefit significantly from PD-1 or PD-L1 checkpoint inhibitors. Despite this utility, PD-L1 measurement is neither necessary nor sufficient to predict response to immunotherapy.
Tumor mutational burden (TMB), a measurement of the overall number of genomic alterations seen in a cancer, has been suggested as a potentially helpful marker in this capacity as well, in part on the basis of a provocative and influential retrospective analysis of the results from the CheckMate 026 trial of nivolumab versus any of several platinum-based doublet chemotherapy options as first-line therapy for modestly selected patients with advanced NSCLC (≥ 1% PD-L1 expression using the 28-8 antibody assay).
Although the CheckMate 026 results were negative for any improvement in efficacy for nivolumab relative to platinum doublet chemotherapy, when outcomes were divided into TMB by tertiles (high, intermediate, or low), the data demonstrated that outcomes were significantly better for nivolumab in the tertile with high TMB, whereas there was no difference in the intermediate- or low-TMB tertiles.
These hypothesis-generating results have been widely recognized as insufficient to change practice for many reasons. With nivolumab not indicated for first-line treatment of advanced NSCLC today, a retrospective analysis of a trial that was otherwise completely negative—and, I would speculate, probably one of multiple retrospective analyses explored to identify positive results—requires far more corroborating evidence. Moreover, there is no standard, validated commercially available test for TMB; instead, the definition of high, intermediate, or low TMB was self-referential, defined relative to the patient population in that study rather than to any independent metric.
Despite the limitations, these initial promising results have now been corroborated by an analysis of another trial that is arguably more clinically relevant. The National Comprehensive Cancer Network guidelines in small cell lung cancer (SCLC) currently include a recommendation to consider treatment with nivolumab alone or with ipilimumab, on the basis of the early but encouraging results of the phase 1/2 CheckMate 012 trial. This study initially enrolled only nonrandomized cohorts of patients with relapsed SCLC who received either nivolumab monotherapy (n = 98) or the nivolumab/ipilimumab combination (n = 61), then initiated a phase in which patients were randomly assigned in a 3:2 ratio to receive monotherapy (n = 147) or the combination therapy (n = 95).
Despite the fact that PD-L1 expression levels are typically quite low in SCLC, with less than 20% of SCLC tumors even demonstrating PD-L1 expression > 1%, 2-year survival in the combined nonrandomized and randomized cohorts was 14% for nivolumab alone and 26% with the nivolumab/ipilimumab combination. Unlike PD-L1, TMB levels are typically very high in SCLC. So if a subset of patients with SCLC does very well with immunotherapy, but PD-L1 is poorly associated with the benefit seen in SCLC, does TMB serve as a helpful predictor?
The retrospective analysis recently presented by Antonia and colleagues at the World Conference on Lung Cancer makes a compelling argument that TMB can serve as a valuable predictive biomarker of benefit in this setting. TMB data were available for 133 of 245 (54%) of the nivolumab recipients and 78 of 156 (50%) of the combination therapy recipients, and progression-free survival (PFS) and overall survival (OS) among patients for whom TMB data were available mirrored that of the broader "intention to treat" population.
When patients were divided into low, intermediate, and high TMB tertiles in the same way as was done in the CheckMate 026 analysis, striking differences in objective response rates (ORRs) were observed (Table). Although the ORR was higher in all tertiles receiving the immunotherapy combination compared with nivolumab monotherapy, the ORRs for both nivolumab monotherapy and nivolumab/ipilimumab were more than twofold higher in patients in the high TMB tertile compared with those in the low or intermediate tertiles.
The Table also illustrates that PFS and OS showed the same trends, with the high-TMB tertile demonstrating a remarkable median OS of 22.0 months and a 1-year OS of 62.4%. Considering that the median survival of patients receiving standard second-line topotecan is only 25 weeks, with 1-year survival of only 14%, these results in the high-TMB arm are extraordinary.
Table. Efficacy in CheckMate 032, by Tumor Mutational Burden
|Subgroup||Patients (n)||ORR (%)||1-Year PFS (mo)||1-Year OS (mo)|
|Low TMB, nivolumab alone||42||5||0a||22|
|Low TMB, nivolumab/ipilimumab||27||22||6||23|
|Intermediate TMB, nivolumab alone||44||7||3||26|
|Intermediate TMB, nivolumab/ipilimumab||25||16||8||20|
|High TMB, nivolumab alone||47||21||21||35|
|High TMB, nivolumab/ipilimumab||26||46||30||62|
| TMB = tumor mutational burden; ORR = objective response rate; OS = overall survival; PFS = progression-free survival
aNot calculable or censored.
That said, TMB measurement is still not standardized, and there is no commercially available tool for clinical use. But as somewhat of a historical skeptic about TMB as well as immunotherapy combinations in relapsed SCLC, I must acknowledge that I am far more optimistic about both in light of these data.
Although it would be helpful to be able to reliably identify a subset of patients with SCLC whom we know will definitely not benefit from immunotherapy, it is certainly valuable to identify others who are highly likely to do remarkably well with immunotherapy, potentially as strong candidates to receive immunotherapy in the first-line setting for SCLC. The fact that TMB measurement as assessed by plasma samples in trials with atezolizumab in previously treated advanced NSCLC has also been correlated with efficacy makes me increasingly optimistic that TMB will prove to be an integral biomarker alongside, if not replacing, PD-L1 in the coming years.
Medscape Oncology © 2017 WebMD, LLC
Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
Cite this: Tumor Mutational Burden as a Predictive Biomarker in Immunotherapy for Lung Cancer: Analysis of CheckMate-032 - Medscape - Nov 28, 2017.