Prediction of Treatment Response to Chemoimmunotherapy: Concerted Effort Needed

Immune checkpoint inhibitors (ICIs) and their combination with platinum doublets (chemoimmunotherapy) play pivotal roles in the treatment of advanced NSCLC without targetable genomic alterations such as EGFR or ALK mutations. Despite much effort in identifying predictive factors of response to ICI, practical tools for identifying patients who are most likely to benefit clinically from chemoimmunotherapy are still lacking. The programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) is a candidate biomarker for selecting patients with advanced NSCLC for ICI monotherapy on the basis of the apparent association between higher percentages of tumor cells expressing PD-L1 in tumors and the increased benefit of ICI. Phase 3 KEYNOTE-189 and -407 studies revealed importantly better overall survival (OS) and progression-free survival (PFS) in patients with metastatic NSCLC treated with first-line chemoimmunotherapy compared with chemotherapy alone irrespective of PD-L1 TPS.1Gandhi L. Rodríguez-Abreu D. Gadgeel S. et al.Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer.N Engl J Med. 2018; 378: 2078-2092Crossref PubMed Scopus (3750) Google Scholar,2Paz-Ares L. Luft A. Vicente D. et al.Pembrolizumab plus chemotherapy for squamous non–small-cell lung cancer.N Engl J Med. 2018; 379: 2040-2051Crossref PubMed Scopus (2130) Google Scholar The association between higher PD-L1 TPS and longer OS or PFS reported in KEYNOTE-189 and -407 studies suggests that the extent of PD-L1 expression should be considered as a continuous variable to account for potential responsiveness to chemoimmunotherapy. These findings are particularly important because the use of first-line ICI monotherapy is currently limited to patients with high PD-L1 TPS whereas most patients with metastatic NSCLC have tumors with low, negative, or unknown PD-L1 expression status.3Socinski M.A. Jotte R.M. Cappuzzo F. et al.Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC.N Engl J Med. 2018; 378: 2288-2301Crossref PubMed Scopus (2252) Google Scholar Tumor mutational burden (TMB) is another potential predictive biomarker. Nevertheless, because of the variability among sequencing platforms and the cutoffs used to define the high TMB value, TMB alone is still not routinely used to make treatment decisions for patients with NSCLC.4Ricciuti B. Wang X. Alessi J.V. et al.Association of high tumor mutation burden in non–small cell lung cancers with increased immune infiltration and improved clinical outcomes of PD-L1 blockade across PD-L1 expression levels.JAMA Oncol. 2022; 8: 1160-1168Crossref PubMed Scopus (32) Google Scholar Furthermore, there is conflicting evidence for TMB as a biomarker for treatment outcomes with first-line chemoimmunotherapy.5Garassino M.C. Gadgeel S. Novello S. et al.Associations of tissue tumor mutational burden and mutational status with clinical outcomes with pembrolizumab plus chemotherapy versus chemotherapy for metastatic NSCLC.JTO Clin Res Rep. 2023; 4100431PubMed Google Scholar Genomic alterations in STK11 or KEAP1 define subgroups of KRAS-mutant lung adenocarcinoma with distinct biology, therapeutic vulnerabilities, and immune profiles. Inactivating alterations in STK11 have emerged as a driver of the non–T-cell inflamed tumor microenvironment (TME), characterized by a paucity of infiltrating CD3+, CD4+, and CD8+ T cells and low percentages of PD-L1–expressing tumor cells.6Cristescu R. Mogg R. Ayers M. et al.Pan-tumor genomic biomarkers for PD-1 checkpoint blockade–based immunotherapy.Science. 2018; 362: eaar3593Crossref PubMed Scopus (1179) Google Scholar,7Skoulidis F. Goldberg M.E. Greenawalt D.M. et al.STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma.Cancer Discov. 2018; 8: 822-835Crossref PubMed Scopus (832) Google Scholar Inactivating mutations in KEAP1 have also been associated with an altered TME. Comutation of STK11 and KEAP1 has been associated with worse clinical outcomes of ICI treatment in KRAS-mutant NSCLC. Similarly, genomic alterations in the SWI/SNF complex, particularly SMARCA4, were associated with worse ICI outcomes in KRAS-mutant NSCLC.8Alessi J.V. Ricciuti B. Spurr L.F. et al.SMARCA4 and other SWItch/Sucrose nonfermentable family genomic alterations in NSCLC: clinicopathologic characteristics and outcomes to immune checkpoint inhibition.J Thorac Oncol. 2021; 16: 1176-1187Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar NSCLC with both KRAS and SMARCA4 mutations was found to have lower proportions of CD8+ and activated CD4+ memory T cells, suggesting having an immunosuppressive landscape, than NSCLC with KRAS-mutant alone. The impact of mutations in STK11, KEAP1, and SMARCA4 on outcomes of patients with NSCLC treated with ICI should be evaluated in large data sets because STK11, KEAP1, and SMARCA4 mutations often co-occur owing to their close colocalization in the same chromosome. Nevertheless, recent analysis with data of KEYNOTE-189 and -407 studies reveals that chemoimmunotherapy provides clinical benefit regardless of STK11, KEAP1, or KRAS mutation status.5Garassino M.C. Gadgeel S. Novello S. et al.Associations of tissue tumor mutational burden and mutational status with clinical outcomes with pembrolizumab plus chemotherapy versus chemotherapy for metastatic NSCLC.JTO Clin Res Rep. 2023; 4100431PubMed Google Scholar This result suggests that STK11, KEAP1, and KRAS mutation status have limited clinical utility as predictive biomarkers for patients with metastatic NSCLC treated with first-line chemoimmunotherapy. In addition to tumor cell-intrinsic biomarkers, multiple tumor microenvironmental factors are reported to be potentially associated with the ICI response of patients with NSCLC. Li et al.9Li F. Li C. Cai X. et al.The association between CD8+ tumor-infiltrating lymphocytes and the clinical outcome of cancer immunotherapy: a systematic review and meta-analysis.EClinicalMedicine. 2021; 41101134Abstract Full Text Full Text PDF Scopus (74) Google Scholar present that high number of CD8+ tumor-infiltrated lymphocytes is associated with better OS and PFS in patients treated with ICIs on the basis of their meta-analysis of 2559 patients with cancer from 33 studies, including NSCLC. Kumagai et al.10Kumagai S. Togashi Y. Kamada T. et al.The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies.Nat Immunol. 2020; 21: 1346-1358Crossref PubMed Scopus (274) Google Scholar reveal that a ratio between PD-1+CD8+ T cells and PD-1+ regulatory T cells in the TME can better predict the response to ICIs than previously defined response factors such as PD-L1 TPS and TMB. Furthermore, there have been multiple studies linking the gut microbiome of patients with NSCLC and their ICI response, highlighting the potential use of the gut microbiome as a predictor for ICI outcomes.11Routy B. Le Chatelier E. Derosa L. et al.Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors.Science. 2018; 359: 91-97Crossref PubMed Scopus (2817) Google Scholar, 12Jin Y. Dong H. Xia L. et al.The diversity of gut microbiome is associated with favorable responses to anti–programmed death 1 immunotherapy in Chinese patients with NSCLC.J Thorac Oncol. 2019; 14: 1378-1389Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar, 13Hakozaki T. Richard C. Elkrief A. et al.The gut microbiome associates with immune checkpoint inhibition outcomes in patients with advanced non–small cell lung CancerGut microbiome impact on ICI efficacy in patients with NSCLC.Cancer Immunol Res. 2020; 8: 1243-1250Crossref PubMed Scopus (99) Google Scholar, 14Derosa L. Routy B. Thomas A.M. et al.Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer.Nat Med. 2022; 28: 315-324Crossref PubMed Scopus (87) Google Scholar In the Journal of Thoracic Oncology, Alessi et al.15Alessi J.V. Elkrief A. Ricciuti B. et al.Clinicopathologic and genomic factors impacting efficacy of first-line chemoimmunotherapy in advanced NSCLC.J Thorac Oncol. 2023; 18: 731-743Abstract Full Text Full Text PDF Scopus (1) Google Scholar conducted a study to investigate predictive factors associated with the efficacy of first-line chemoimmunotherapy for advanced NSCLC. Although there have been increasing number of studies aiming to identify predictors of the treatment response to first-line chemoimmunotherapy, this study adds valuable information. With a large cohort of 1285 patients from four academic medical centers, the authors find that a better performance status, a low derived neutrophil-to-lymphocyte ratio, and high PD-L1 TPS are associated with greater benefit from first-line chemoimmunotherapy. In addition, cancers with STK11, KEAP1, or SMARCA4 mutations in the KRAS-mutant NSCLC and those with KEAP1 and/or SMARCA4 in the KRAS wild-type NSCLC have less favorable outcomes to chemoimmunotherapy. Patients whose NSCLC have a very high TMB level (≥90th percentile) are independently associated with better clinical outcomes than patients whose cancers have lower TMB values. This study suggests that clinical trials in the future should subdivide patients by considering various factors such as PD-L1 TPS, TMB, and concurrent mutations to define subgroups suitable for chemoimmunotherapy. The results from Alessi et al.15Alessi J.V. Elkrief A. Ricciuti B. et al.Clinicopathologic and genomic factors impacting efficacy of first-line chemoimmunotherapy in advanced NSCLC.J Thorac Oncol. 2023; 18: 731-743Abstract Full Text Full Text PDF Scopus (1) Google Scholar suggest that more granular PD-L1 TPS should be routinely reported in clinical trials of chemoimmunotherapy. The need for granular cutoff TPS has been suggested in previous studies. In the KEYNOTE-042 study, ICI monotherapy significantly prolongs OS compared with platinum doublets in patients with a PD-L1 TPS of greater than or equal to 50%, greater than or equal to 20%, and greater than or equal to 1% in their NSCLC.16Mok T.S. Wu Y.L. Kudaba I. et al.Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.Lancet. 2019; 393: 1819-1830Abstract Full Text Full Text PDF PubMed Scopus (1788) Google Scholar Nevertheless, in a prespecified analysis of patients with NSCLC and a PD-L1 TPS of 1% to 49%, there is no significant difference in OS. Another study reveals that among patients with PD-L1 TPS greater than or equal to 50% in their NSCLC treated with first-line ICI, clinical outcomes are improved with increasing PD-L1 TPS greater than or equal to 75% and particularly greater than or equal to 90%.17Aguilar E. Ricciuti B. Gainor J. et al.Outcomes to first-line pembrolizumab in patients with non-small-cell lung cancer and very high PD-L1 expression.Ann Oncol. 2019; 30: 1653-1659Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar In this way, by dividing patients into two groups based on a single cutoff of PD-L1 level, patients who do not benefit from ICI can be misclassified into the same group as patients who have better treatment responses to ICI. In previous studies, TMB did not have a significant impact on OS on the basis of a cutoff of 175 mutations per exome or 10 mutations per megabase.4Ricciuti B. Wang X. Alessi J.V. et al.Association of high tumor mutation burden in non–small cell lung cancers with increased immune infiltration and improved clinical outcomes of PD-L1 blockade across PD-L1 expression levels.JAMA Oncol. 2022; 8: 1160-1168Crossref PubMed Scopus (32) Google Scholar,18Hellmann M.D. Paz-Ares L. Bernabe Caro R. et al.Nivolumab plus ipilimumab in advanced non–small-cell lung cancer.N Engl J Med. 2019; 381: 2020-2031Crossref PubMed Scopus (1401) Google Scholar Nevertheless, Alessi et al. reveal that there is a significant difference in the overall response rate to chemoimmunotherapy, median OS, and median PFS between patients with very high (≥90 percentile) and those with lower (<90 percentile) TMBs. It indicates that a higher TMB threshold closer to the 90th percentile may be necessary to precisely distinguish patients most likely to benefit from chemoimmunotherapy. We suggest that it would be better to indicate the cutoff value of TMB as a numerical value rather than a percentile for clinical applications in the future. The question of whether STK11 or KEAP1 mutations are only predictive factors for ICI in KRAS-mutant NSCLC remains unresolved. A previous study revealed that KRAS-mutant lung adenocarcinomas with STK11 or KEAP1 mutations were associated with worse outcomes than those with STK11 and KEAP1 wild-type when treated with platinum doublets.19Ricciuti B. Arbour K.C. Lin J.J. et al.Diminished efficacy of programmed death-(ligand) 1 inhibition in STK11-and KEAP1-mutant lung adenocarcinoma is affected by KRAS mutation status.J Thorac Oncol. 2022; 17: 399-410Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar Furthermore, real-world data suggested that STK11 and KEAP1 mutations were prognostic factors and not uniquely associated with inadequate response to ICI.20Papillon-Cavanagh S. Doshi P. Dobrin R. Szustakowski J. Walsh A.M. STK11 and KEAP1 mutations as prognostic biomarkers in an observational real-world lung adenocarcinoma cohort.ESMO Open. 2020; 5e000706Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar These results indicate that STK11 and KEAP1 mutations are prognostic rather than predictive factors. KEAP1 is a mediator for the ubiquitylation and proteasomal degradation of NRF2, a crucial transcription factor involved in cellular antioxidant, metabolic, cytoprotective, and anti-inflammatory pathways.21Skoulidis F. Heymach J.V. Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy.Nat Rev Cancer. 2019; 19: 495-509Crossref PubMed Scopus (398) Google Scholar Potentiation of cellular antioxidant, anabolic, and detoxification pathway activities support the aggressive phenotype of NSCLC with KEAP1 mutations, which is consistent with the role of KEAP1 mutations as an independent negative prognostic indicator. In addition, SMARCA4 mutations, combined with STK11 and/or KEAP1 mutations, have an additive impact on worse clinical outcome.8Alessi J.V. Ricciuti B. Spurr L.F. et al.SMARCA4 and other SWItch/Sucrose nonfermentable family genomic alterations in NSCLC: clinicopathologic characteristics and outcomes to immune checkpoint inhibition.J Thorac Oncol. 2021; 16: 1176-1187Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Current National Comprehensive Cancer Network guidelines simply consider ICI monotherapy or chemoimmunotherapy if PD-L1 TPS is greater than or equal to 50% and chemoimmunotherapy if less than 50%. Now, it is necessary to subdivide the groups by considering various biomarkers and to identify an optimal treatment for the efficacies and adverse effects of each group. Future studies should consider stratification measures to ensure that randomized groups are evenly balanced by various PD-L1 TPS levels. Otherwise, differences in treatment outcomes could be confounded by disparities in the distribution of PD-L1 TPS. The utility of ICI in patients having NSCLC with driver oncogenic alternations that progress after targeted therapy remains controversial; most clinical trials using ICI have excluded these patients, making it very hard to know how best to manage these patients. Moreover, an uninflamed TME is often reported in the context of oncogenic addiction. Thus, additional biomarkers of response and resistance to ICI are needed to optimize treatment selection for patients with NSCLC. Mutational status of STK11, KEAP1, and SMARCA4 and granular cutoff level of PD-L1 TPS and TMB can be useful biomarkers for determining the optimal treatment sequence between KRAS G12C inhibitors and ICI in patients with KRAS G12C-mutant NSCLC.22Skoulidis F. Li B.T. Dy G.K. et al.Sotorasib for lung cancers with KRAS p. G12C mutation.N Engl J Med. 2021; 384: 2371-2381Crossref PubMed Scopus (464) Google Scholar In addition, evaluation of STK11/LKB1, KEAP1, and SMARCA4/BRG1 expression by immunohistochemistry could enhance the predictive utility of a biomarker panel including STK11, KEAP1, and SMARCA4 mutation. Moving forward, multiple tumor intrinsic and extrinsic biomarkers based on more comprehensive clinicopathologic features and multiomics profiles will need to be considered together to fully realize precision immunotherapy for patients with NSCLC. Jun Hyeok Lim: Conceptualization; Investigation; Roles/Writing—original draft; Writing—review and editing. Semin Lee: Conceptualization; Investigation; Roles/Writing—original draft; Writing—review and editing. Jeong-Seon Ryu: Conceptualization; Investigation; Project administration; Roles/Writing—original draft; Writing—review and editing. This work was supported by a grant (NRF-2022R1C1C1008291) from the National Research Foundation of Korea (NRF). Clinicopathologic and Genomic Factors Impacting Efficacy of First-Line Chemoimmunotherapy in Advanced NSCLCJournal of Thoracic OncologyVol. 18Issue 6PreviewAlthough programmed cell death protein 1 and programmed death-ligand 1 (PD-L1) blockade in combination with platinum-doublet chemotherapy has become a mainstay of first-line treatment for advanced NSCLC, factors associated with efficacy of chemoimmunotherapy (CIT) are not well characterized. Full-Text PDF