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Table of Contents
EDITORIAL
Year : 2021  |  Volume : 4  |  Issue : 2  |  Page : 363-364

Biomarkers for response to immune checkpoint inhibitors: Where do we stand?


Department of Medical Oncology, Mahamana Pandit Madan Mohan Malviya Cancer Center & Homi Bhabha Cancer Hospital, Tata Memorial Center, Varanasi, Uttar Pradesh, India

Date of Submission12-Jun-2021
Date of Decision13-Jun-2021
Date of Acceptance13-Jun-2021
Date of Web Publication30-Jun-2021

Correspondence Address:
Bal Krishna Mishra
Department of Medical Oncology, Tata Memorial Center, Mahamana Pandit Madan Mohan Malviya Cancer Center, Homi Bhabha Cancer Hospital, Varanasi, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/crst.crst_139_21

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How to cite this article:
Khaddar S, Mishra BK. Biomarkers for response to immune checkpoint inhibitors: Where do we stand?. Cancer Res Stat Treat 2021;4:363-4

How to cite this URL:
Khaddar S, Mishra BK. Biomarkers for response to immune checkpoint inhibitors: Where do we stand?. Cancer Res Stat Treat [serial online] 2021 [cited 2021 Oct 23];4:363-4. Available from: https://www.crstonline.com/text.asp?2021/4/2/363/320176



The advent of immune checkpoint inhibitors (ICIs) has tremendously changed the treatment armamentarium for many tumors. However, a validated biomarker for the selection of patients who could benefit from ICIs is still lacking. The commonly tested biomarkers, such as the programmed death-ligand 1 (PD-L1), tumor mutational burden (TMB), and microsatellite instability (MSI) have inherent limitations. A major drawback of PD-L1 as a biomarker is the variability in testing for PD-L1 expression levels for different ICIs such as Combined Positive Score (CPS), Tumor Proportional Score (TPS), and Immune Cell Score (ICS); moreover, different scoring systems are used in different tumor types for the same ICI, which makes data interpretation even more cumbersome. Pembrolizumab has been approved as the first- and second-line therapy for metastatic lung cancers, based on the PD-L1 expression levels.[1] However, the trials of nivolumab and atezolizumab have failed to show a strong correlation between the PD-L1 levels and treatment response, thus making it difficult to justify the use of the PD-L1 immunohistochemistry assay as a companion diagnostic test for these drugs.[2],[3] Although the Blueprint study demonstrated that various platforms such as Dako 22C3, 28-8, and Ventana SP263 are analytically similar, SP142 was an outlier which restricted the use of a common platform for testing for all ICIs.[4] Disparities in the trial results and the observation that a subgroup of patients with PD-L1-negative tumors also benefit from ICIs have made the experts hesitant about labeling PD-L1 as a robust clinical biomarker.

The MSI-high (MSI-H) status has been proposed as a marker of response based on the observation that a higher number of tumor-infiltrating lymphocytes are present in the tumor microenvironment and there is an increased expression of tumor-associated antigens due to a frame-shift mutation, deletion, and insertion in the microsatellite region in MSI-H tumors. Metastatic colorectal cancers are the most studied tumors with regard to ICI response based on the MSI-H status of the patients, but only 40% of the patients respond to pembrolizumab[5] and even fewer respond to nivolumab.[6] Although pembrolizumab has received tumor-agnostic approval by the United States Food and Drug Administration based on the MSI-H status,[7] there are subsets of tumors, such as pancreatic cancers and glioblastoma, which show lower response rates and survival in this scenario.

TMB is an emerging biomarker for ICIs, based on the hypothesis that an increased mutational load in the tumor correlates with a greater response rate to ICIs. Besides a few retrospective studies, a prospective study from the Memorial Sloan Kettering (MSK) Cancer Center has shown a correlation between TMB and response to ICIs.[8],[9] However, this correlation is not always linear. Tumors such as renal cell carcinoma, Merkel cell carcinoma, and mesothelioma have been shown to have higher than anticipated response rates with respect to their TMBs, suggesting that a different mechanism is at play in these tumors.[10] Another issue is the use of different assays such as MSK-Impact, FoundationOne CDx; gene coverage such as whole exome sequencing versus targeted gene panel and cutoffs used to measure TMB in different studies ranging from more than 5 to more than 200 mut/Mb which makes standardization even more complex.

Other examples of biomarkers being explored in immunotherapy include serum proteins, tumor-specific receptor expression patterns, factors related to the tumor microenvironment, and inflammatory biomarkers such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, and a combination of platelet count and NLR (COP-NLR).[11],[12],[13],[14] The roles of the gut microbiome, sex, and age have been explored as biomarkers in patients with melanoma.[15],[16],[17] A meta-analysis of studies conducted in patients with melanoma and non-small cell lung cancer showed that male patients had better progression-free survival (PFS) and overall survival (OS) than female patients treated with ICIs.

Kapoor et al. in their retrospective audit published in this issue of the journal have attempted to assess if the responses to ICIs are different in the two sexes.[18] Out of 155 patients included in the study, 76.8% were men. The authors have reported that the median PFS was 2.8 months (95% confidence interval [CI], 1.4–4.2) for the male patients, and 1.9 months for the female patients (hazard ratio [HR] 1.06, 95% CI, 0.69–1.66, P = 0.764). In addition, the median OS was statistically similar for the male and female patients (5.9 and 4.2 months), respectively (HR 1.27, 95% CI, 0.77–2.12, P = 0.342). The key drawback is the inclusion of a heterogeneous patient population which might have precluded statistical power to detect differences, if any, between the two sexes. The study did not include all solid tumors rather the authors included only patients treated in one particular unit of the Medical Oncology Department of the Tata Memorial Hospital (Mumbai, India). This might have introduced some level of bias in the results, making the results not generalizable for all solid tumors. Despite these limitations, the authors need to be applauded for their effort and for bringing out real-world data. The results are consoling for a physician to prescribe ICIs to both sexes; however, it needs to be highlighted that balanced inclusion of both the sexes in future randomized studies should be the norm.

In conclusion, it appears that a single biomarker may not be adequate to identify the responders to ICIs. Therefore, a tool that takes into account the status of various biomarkers might be helpful in predicting the possible response to ICIs.



 
  References Top

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US Food and Drug Administration. Pembrolizumab (KEYTRUDA) checkpoint inhibitor. FDA. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/pembrolizumab-keytruda-checkpoint-inhibitor (2016). [Last accessed on Accessed on 2021 Jun 12].  Back to cited text no. 1
    
2.
Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373:123-35.  Back to cited text no. 2
    
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Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): A Phase 3, open-label, multicentre randomised controlled trial. Lancet 2017;389:255-65.  Back to cited text no. 3
    
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Hirsch FR, McElhinny A, Stanforth D, Ranger-Moore J, Jansson M, Kulangara K, et al. PD-L1 immunohistochemistry assays for lung cancer: Results from Phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project. J Thorac Oncol 2017;12:208-22.  Back to cited text no. 4
    
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Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): An open-label, multicentre, Phase 2 study. Lancet Oncol 2017;18:1182-91.  Back to cited text no. 6
    
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Samstein RM, Lee CH, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet 2019;51:202-6.  Back to cited text no. 9
    
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Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med 2017;377:2500-1.  Back to cited text no. 10
    
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Yuan J, Zhou J, Dong Z, Tandon S, Kuk D, Panageas KS, et al. Pretreatment serum VEGF is associated with clinical response and overall survival in advanced melanoma patients treated with ipilimumab. Cancer Immunol Res 2014;2:127-32.  Back to cited text no. 11
    
12.
Yuan J, Adamow M, Ginsberg BA, Rasalan TS, Ritter E, Gallardo HF, et al. Integrated NY-ESO-1 antibody and CD8+T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab. Proc Natl Acad Sci U S A 2011;108:16723-8.  Back to cited text no. 12
    
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Rangarajan B, Abhinav RK. Beyond the tumor and tumor milieu-Factors affecting responses to immunotherapy. Cancer Res Stat Treat 2019;2:224-5.  Back to cited text no. 14
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Wu Y, Ju Q, Jia K, Yu J, Shi H, Wu H, et al. Correlation between sex and efficacy of immune checkpoint inhibitors (PD-1 and CTLA-4 inhibitors). Int J Cancer 2018;143:45-51.  Back to cited text no. 15
    
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Nishijima TF, Muss HB, Shachar SS, Moschos SJ. Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: A systematic review and meta-analysis. Cancer Treat Rev 2016;45:30-7.  Back to cited text no. 16
    
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Chaput N, Lepage P, Coutzac C, Soularue E, Le Roux K, Monot C, et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol 2017;28:1368-79.  Back to cited text no. 17
    
18.
Kapoor A, Noronha V, Patil VM, Joshi A, Menon N, Mahajan A, et al. Impact of sex of the patient on efficacy and safety of cancer immunotherapy: A retrospective audit. Cancer Res Stat Treat 2021;4:238-43.  Back to cited text no. 18
  [Full text]  




 

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