In a letter recently published in The New England Journal of Medicine and reviewed in this issue of The ASCO Post, Rousseau and colleagues reported data on the spectrum of benefit from immune checkpoint blockade in hypermutated tumors.1 Indeed, the U.S. Food and Drug Administration (FDA) recently approved the PD-1–blocking antibody pembrolizumab for patients who have treatment-refractory cancers with a tumor mutational burden greater than 10 mutations per megabase (TMB-high).2 This approval in a tissue-agnostic fashion was based on retrospective evidence from a single-arm study (KEYNOTE-158) showing that TMB-high status was predictive of radiographic response to pembrolizumab in patients with 10 rare cancers.3
Thierry André, MD
Romain Cohen, MD, PhD
Focus on Advanced Colorectal Cancer
The first part of this letter focused on patients with advanced colorectal cancer, for whom the efficacy of immune checkpoint inhibitors is demonstrated only in the group with microsatellite instability and/or DNA mismatch repair deficiency (MSI/dMMR)4,5 and also for the rare subgroup harboring pathogenic mutations in the exonucleasic domain of polymerase ε (POLE) or polymerase δ1 (POLD1). These POLE and POLD1 mutations are associated with the hypermutated phenotype and mostly observed in microsatellite-stable and MMR-proficient tumors.
The authors of this letter evaluated 137 patients with advanced colorectal cancer treated by immune checkpoint inhibitors at Memorial Sloan Kettering Cancer Center (MSK). Median overall survival was longer (43.1 vs 12.1 months; hazard ratio [HR] = 0.40, 95% confidence interval [CI] = 0.24–0.65) in patients with a high TMB status than in those with a low TMB status (TMB-low, < 10 mutations per megabase).1 Median overall survival was not reached for patients with MSI/dMMR tumors or POLE and POLD1 mutations (n = 40). Excluding the 40 patients with microsatellite-stable and MMR-proficient tumors as well as POLE and POLD1 colorectal cancer, median overall survival for patients with microsatellite-stable and MMR-proficient TMB-low tumors (n = 84) was 12.1 months vs 10.6 months for those with microsatellite-stable and MMR-proficient TMB-high tumors (n = 13; HR = 1.17, 95% CI = 0.59–2.32).
In a previous analysis of 5,702 microsatellite-stable and MMR-proficient colorectal cancers tested with the FoundationOne CDx assay, 2.9% had high TMB, ranging from 11.7 to 707.2 mutations per megabase. Other series found similar rates, with less than 5% of colorectal cancers being microsatellite-stable and MMR-proficient TMB-high, depending on the panel used for TMB determination and the tumor stage.6,7 Overall, data are not in favor of immune checkpoint blockade efficacy in the microsatellite-stable and MMR-proficient colorectal cancer group, with the exception of POLE and POLD1-mutated tumors. POLE and POLD1 deleterious mutations are predominantly described in microsatellite-stable and MMR-proficient colorectal and endometrial cancers, with an estimated frequency of 0.5 and 1%.8 With next-generation sequencing being routinely performed in advanced colorectal cancer for the determination of RAS/BRAF mutational status, it seems worthwhile to include hotspot mutations of POLE and POLD1 exonucleasic domain in next-generation sequencing panels to identify patients eligible for treatment with immune checkpoint inhibitors.
A universal TMB threshold to guide treatment does not seem the optimal way to select patients who may derive survival benefit from immune checkpoint inhibitors in all cancer types.— Thierry André, MD, and Romain Cohen, MD, PhD
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Focus on Assorted Tumors
In the second part of the letter, Rousseau and colleagues extended their analysis to 1,661 patients with various tumors treated with immune checkpoint inhibitors. In patients with tumors in which mismatch repair and POLE and POLD1 were intact (ie, microsatellite-stable and MMR-proficient and POLE/POLD1 wild-type; n = 1,594), high TMB was associated with enhanced overall survival only for those with head and neck cancer (n = 144), non–small cell lung cancer (n = 347), and melanoma (n = 256), with a hazard ratio of 0.52 (95% CI = 0.31–0.64).1 No benefit was observed in patients with other cancer types, including colorectal (n = 78), esophageal or gastric (n = 116), urinary tract (n = 203), brain (n = 117), unknown primary tumor (n = 63), and other (n = 270).
Relationship Between Overall Survival and TMB After Immunotherapy
TMB measurement quantifies the number of mutations per megabase in tumor cells, and tumors with high TMB tend to have more immunogenic neoantigens. It is important to know that TMB can be determined using different methods, the gold standard evaluating the mutational load based on exome-wide sequencing of approximately 30 megabases.
Rousseau and colleagues used the MSK IMPACT TMB score, which has been shown to highly correlate with other methods of genetic sequencing assessment, including the FoundationOne CDx assay. The FoundationOne CDx assay used in KEYNOTE-158 calculates the mutational load based on a limited panel of genes (~0.8 megabases). TMB score may be influenced by tumor heterogeneity, the origin of the tumor specimen (primary tumor or metastatic tissue), and prior therapies. Discrepancies may occur between different methods of TMB score determination.
As noted, the FDA approval of pembrolizumab for patients who have treatment-refractory cancers was based on a retrospective analysis of the single-arm KEYNOTE-158 trial in patients with 10 different cancer types—but not colorectal, breast, or prostate cancer.3 Data from the letter by Rousseau and colleagues and other studies have further deciphered the association between overall survival and TMB after treatment with immune checkpoint inhibitors.1,9,10 In a study by McGrail and colleagues, a correlation was observed among CD8 T-cell levels, neoantigen load, and TMB in some cancer types (lung cancer, melanoma, and bladder cancer) but not in breast cancer, prostate cancer, or glioma.10
Translational research to identify and validate biomarkers predictive of sensitivity or resistance to immune checkpoint inhibition should be a priority.— Thierry André, MD, and Romain Cohen, MD, PhD
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A universal TMB threshold to guide treatment does not seem the optimal way to select patients who may derive survival benefit from immune checkpoint inhibitors in all cancer types. Data provided by Rousseau and colleagues do not support the treatment of TMB-high colorectal cancer except if the tumor exhibits the MSI/dMMR phenotype or mutations in the exonucleasic domain of POLE or POLD1. Decision-making for treatment with immune checkpoint inhibitors should not be based on TMB (at least not with one unique TMB threshold) in all cancer types, with the exception of non–small cell lung cancer, melanoma, and head and neck cancers.
TMB may play a role as a predictive biomarker for the efficacy of immunotherapy, but with several limitations.1,11 High TMB fails to predict immune checkpoint blockade efficacy in terms of overall survival across all cancer types. In addition, high TMB seems to be predictive in cancers related to environmental carcinogens (chronic exposure to ultraviolet light for melanoma and tobacco for lung, head and neck, and probably bladder cancers). For other cancers, other predictive factors such as the MSI/dMMR phenotype, pathogenic mutations in POLE and POLD1, or intratumor CD8 T-cell levels seem more relevant. Translational research to identify and validate biomarkers predictive of sensitivity or resistance to immune checkpoint inhibition should be a priority.
Dr. André and Dr. Cohen work at Sorbonne Université, Department of Medical Oncology, Saint-Antoine Hospital, Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Paris.
DISCLOSURE: Dr. André has received honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, MSD Oncology, Pierre Fabre, Roche/Genentech, Sanofi, Servier, and Vantana; has served as a consultant or advisor to Amgen, Astellas Pharma, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Clovis Oncology, Gamamabs Pharma SA, Gritstone, HalioDX, MSD Oncology, Kaleido Biosciences, Pierre Fabre, and Servier; and has been reimbursed for travel, accommodations, or other expenses by Amgen, Bristol Myers Squibb, MSD Oncology, Roche, Roche/Genentech, and Ventana. Dr Cohen has received honoraria from MSD Oncology and Servier.
1. Rousseau B, Foote MB, Maron SB, et al: The spectrum of benefit from checkpoint blockade in hypermutated tumors. N Engl J Med 384:1168-1170, 2021.
2. U.S. Food and Drug Administration: FDA approves pembrolizumab for adults and children with TMB-H solid tumors. June 17, 2020. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adults-and-children-tmb-h-solid-tumors. Accessed May 10, 2021.
3. Marabelle A, Fakih M, Lopez J, et al: Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: Prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol 21:1353-1365, 2020.
4. Cohen R, Colle R, Pudlarz T, et al: Immune checkpoint inhibition in metastatic colorectal cancer harboring microsatellite instability or mismatch repair deficiency. Cancers (Basel) 13:1149, 2021.
5. André T, Shiu KK, Kim TW, et al: Pembrolizumab in microsatellite instability-high advanced colorectal cancer. N Engl J Med 383:2207-2218, 2020.
6. Fabrizio DA, George Jr TJ, Dunne RF, et al: Beyond microsatellite testing: Assessment of tumor mutational burden identifies subsets of colorectal cancer who may respond to immune checkpoint inhibition. J Gastrointest Oncol 9:610-617, 2018.
7. Vanderwalde A, Spetzler D, Xiao N, et al: Microsatellite instability status determined by next-generation sequencing and compared with PD-L1 and tumor mutational burden in 11,348 patients. Cancer Med 7:746-756, 2018.
8. Bourdais R, Rousseau B, Pujals A, et al: Polymerase proofreading domain mutations: New opportunities for immunotherapy in hypermutated colorectal cancer beyond MMR deficiency. Crit Rev Oncol Hematol 113:242-248, 2017.
9. Samstein RM, Lee CH, Shoushtari AN, et al: Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet 51:202-206, 2019.
10. McGrail DJ, Pilié PG, Rashid NU, et al: High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types. Ann Oncol 32:661-672, 2021.
11. Strickler JH, Hanks BA, Khasraw M: Tumor mutational burden as a predictor of immunotherapy response: Is more always better? Clin Cancer Res 27:1236-1241, 2021.
In a letter to the editor in The New England Journal of Medicine, Benoit Rousseau, MD, PhD, and Michael B. Foote, MD, of Memorial Sloan Kettering Cancer Center (MSK), and colleagues presented evidence that a high tumor mutational burden (TMB) threshold of 10 alone may not be sufficient to predict...