Non-small-cell lung cancer (NSCLC) has become a paradigm of precision medicine, with the discovery of numerous disease subtypes defined by specific oncogenic driver mutations leading to the development of a range of molecularly targeted therapies. Over the past decade, rapid progress has also been made in the development of immune-checkpoint inhibitors (ICIs), especially antagonistic antibodies targeting the PD-L1–PD-1 axis, for the treatment of NSCLC. Although many of the major oncogenic drivers of NSCLC are associated with intrinsic resistance to ICIs, patients with certain oncogene-driven subtypes of the disease that are highly responsive to specific targeted therapies might also derive benefit from immunotherapy. However, the development of effective immunotherapy approaches for oncogene-addicted NSCLC has been challenged by a lack of predictive biomarkers for patient selection and limited knowledge of how ICIs and oncogene-directed targeted therapies should be combined. Therefore, whether ICIs alone or with chemotherapy or even in combination with molecularly targeted agents would offer comparable benefit in the context of selected oncogenic driver alterations to that observed in the general unselected NSCLC population remains an open question. In this Review, we discuss the effects of oncogenic driver mutations on the efficacy of ICIs and the immune tumour microenvironment as well as the potential vulnerabilities that could be exploited to overcome the challenges of immunotherapy for oncogene-addicted NSCLC.
In the era of immuno-oncology, emerging evidence indicates that driver oncogenes have different effects on the immune tumour microenvironment that influence the potential for clinical benefit from treatment with immune-checkpoint inhibitors (ICIs).
Patients with non-small-cell lung cancer (NSCLC) harbouring BRAF mutations or KRAS and TP53 co-mutations benefit the most from ICIs, whereas EGFR mutations or ALK or ROS1 rearrangements are commonly associated with lower tumour PD-L1 levels and mutational burdens, limited immune infiltration of the tumour microenvironment and resistance to ICIs.
Understanding factors resulting in resistance to ICIs is crucial for developing approaches for (re-)sensitizing tumours to these immunotherapies.
A meaningful understanding of NSCLC genomics and immunophenotypes might provide a stratification for the selection of patients most likely to benefit from ICI-based therapies.
Combination strategies with agents targeting oncogenic signalling-related immune-inhibitory mechanisms might increase tumour immunogenicity and sensitize oncogene-driven NSCLC to ICIs.
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Soerjomataram, I. & Bray, F. Planning for tomorrow: global cancer incidence and the role of prevention 2020–2070. Nat. Rev. Clin. Oncol. 18, 663–672 (2021).
Hirsch, F. R. et al. Lung cancer: current therapies and new targeted treatments. Lancet 389, 299–311 (2017).
Hanna, N. H. et al. Therapy for stage IV non-small-cell lung cancer with driver alterations: ASCO and OH (CCO) joint guideline update. J. Clin. Oncol. 39, 1040–1091 (2021).
Hanna, N. H. et al. Therapy for stage IV non-small-cell lung cancer without driver alterations: ASCO and OH (CCO) joint guideline update. J. Clin. Oncol. 38, 1608–1632 (2020).
Leach, D. R., Krummel, M. F. & Allison, J. P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734–1736 (1996).
Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).
Hellmann, M. D. et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N. Engl. J. Med. 381, 2020–2031 (2019).
Paz-Ares, L. et al. Durvalumab plus platinum–etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet 394, 1929–1939 (2019).
Trujillo, J. A., Sweis, R. F., Bao, R. & Luke, J. J. T cell-inflamed versus non-T cell-inflamed tumors: a conceptual framework for cancer immunotherapy drug development and combination therapy selection. Cancer Immunol. Res. 6, 990–1000 (2018).
Skoulidis, F. & Heymach, J. V. Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy. Nat. Rev. Cancer 19, 495–509 (2019).
Mok, T. S. et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361, 947–957 (2009).
Maemondo, M. et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med. 362, 2380–2388 (2010).
Ramalingam, S. S. et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N. Engl. J. Med. 382, 41–50 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04862780 (2021).
Solomon, B. J. et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N. Engl. J. Med. 371, 2167–2177 (2014).
Shaw, A. T. et al. First-line lorlatinib or crizotinib in advanced ALK -Positive lung cancer. N. Engl. J. Med. 383, 2018–2029 (2020).
Paik, P. K. et al. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring met mutations causing exon 14 skipping. Cancer Discov. 5, 842–850 (2015).
Drilon, A. et al. Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial. Lancet Oncol. 17, 1653–1660 (2016).
Drilon, A. et al. Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration. Nat. Med. 26, 47–51 (2020).
Gautschi, O. et al. Targeting RET in patients with RET-rearranged lung cancers: results from the global, multicenter RET registry. J. Clin. Oncol. 35, 1403–1410 (2017).
Mazières, J. et al. Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J. Clin. Oncol. 31, 1997–2003 (2013).
Fontana, E. & Valeri, N. Class(y) dissection of BRAF heterogeneity: beyond non-V600. Clin. Cancer Res. 25, 6896–6898 (2019).
Hong, D. S. et al. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 21, 531–540 (2020).
Doebele, R. C. et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1–2 trials. Lancet Oncol. 21, 271–282 (2020).
Shaw, A. T. et al. Crizotinib in ROS1 -rearranged non-small-cell lung cancer. N. Engl. J. Med. 371, 1963–1971 (2014).
Canon, J. et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 575, 217–223 (2019).
Fakih, M. G. et al. Sotorasib for previously treated colorectal cancers with KRASG12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial. Lancet Oncol. 23, 115–124 (2022).
Reck, M. et al. MO01.32 CodeBreaK 200: a phase 3 multicenter study of Sotorasib, a KRAS(G12C) inhibitor, versus Docetaxel in patients with previously treated advanced non-small cell lung cancer (NSCLC) harboring KRAS p.G12C mutation. J. Thorac. Oncol. 16, S29 (2021).
Riely, G. J. et al. 99O_PR KRYSTAL-1: activity and preliminary pharmacodynamic (PD) analysis of adagrasib (MRTX849) in patients (Pts) with advanced non-small cell lung cancer (NSCLC) harboring KRASG12C mutation. J. Thorac. Oncol. 16, S751–S752 (2021).
Heist, R. S., Sequist, L. V. & Engelman, J. A. Genetic changes in squamous cell lung cancer: a review. J. Thorac. Oncol. 7, 924–933 (2012).
Niu, Z., Jin, R., Zhang, Y. & Li, H. Signaling pathways and targeted therapies in lung squamous cell carcinoma: mechanisms and clinical trials. Signal Transduct. Target. Ther. 7, 353 (2022).
Yohann, L., Martin, H. S., Gopa, I. & Shubham, P. Tumor agnostic efficacy and safety of erdafitinib in patients (pts) with advanced solid tumors with prespecified fibroblast growth factor receptor alterations (FGFRalt) in RAGNAR: interim analysis (IA) results. J. Clin. Oncol. 40 (Suppl. 16), 3007 (2022).
Lewis, W. E. et al. Efficacy of targeted inhibitors in metastatic lung squamous cell carcinoma with EGFR or ALK alterations. JTO Clin. Res. Rep. 2, 100237 (2021).
Wang, C. et al. The heterogeneous immune landscape between lung adenocarcinoma and squamous carcinoma revealed by single-cell RNA sequencing. Signal Transduct. Target. Ther. 7, 289 (2022).
Horn, L. et al. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (CheckMate 017 and CheckMate 057). J. Clin. Oncol. 35, 3924–3933 (2017).
Calles, A. et al. Expression of PD-1 and its ligands, PD-L1 and PD-L2, in smokers and never smokers with KRAS-mutant lung cancer. J. Thorac. Oncol. 10, 1726–1735 (2015).
Wang, X. et al. Association between smoking history and tumor mutation burden in advanced non-small cell lung cancer. Cancer Res. 81, 2566–2573 (2021).
Sun, L. Y. et al. Smoking status combined with tumor mutational burden as a prognosis predictor for combination immune checkpoint inhibitor therapy in non-small cell lung cancer. Cancer Med. 10, 6610–6617 (2021).
Gainor, J. F. et al. Clinical activity of programmed cell death 1 (PD-1) blockade in never, light, and heavy smokers with non-small-cell lung cancer and PD-L1 expression ≥50%. Ann. Oncol. 31, 404–411 (2020).
Negrao, M. et al. Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer. J. Immunother. Cancer 9, e002891 (2021).
Passaro, A. et al. Recent advances on the role of EGFR tyrosine kinase inhibitors in the management of NSCLC with uncommon, non exon 20 insertions, EGFR mutations. J. Thorac. Oncol. 16, 764–773 (2021).
Provencio, M., Molina, M. A., Méndez, M. & Rosell, R. Screening for epidermal growth factor receptor mutations in lung cancer and tyrosine-kinase inhibitors. Eur. J. Clin. Med. Oncol. 3, 42–48 (2011).
Chakravarty, D. et al. OncoKB: a precision oncology knowledge base. JCO Precis. Oncol. https://doi.org/10.1200/po.17.00011 (2017).
Borghaei, H. et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N. Engl. J. Med. 373, 123–135 (2015).
Rittmeyer, A. 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 389, 255–265 (2017).
Herbst, R. S. et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387, 1540–1550 (2016).
Garassino, M. C. et al. Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study. Lancet Oncol. 19, 521–536 (2018).
Gainor, J. F. et al. EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis. Clin. Cancer Res. 22, 4585–4593 (2016).
Lee, C. K. et al. Checkpoint inhibitors in metastatic EGFR-mutated non-small cell lung cancer — a meta-analysis. J. Thorac. Oncol. 12, 403–407 (2017).
Mazieres, J. et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann. Oncol. 30, 1321–1328 (2019).
Hastings, K. et al. EGFR mutation subtypes and response to immune checkpoint blockade treatment in non-small-cell lung cancer. Ann. Oncol. 30, 1311–1320 (2019).
Lisberg, A. et al. A phase II study of pembrolizumab in EGFR-mutant, PD-L1+, tyrosine kinase inhibitor naïve patients with advanced NSCLC. J. Thorac. Oncol. 13, 1138–1145 (2018).
Li, B. T. et al. Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N. Engl. J. Med. 386, 241–251 (2022).
Guisier, F. et al. Efficacy and safety of anti-PD-1 immunotherapy in patients with advanced NSCLC with BRAF, HER2, or MET mutations or RET translocation: GFPC 01-2018. J. Thorac. Oncol. 15, 628–636 (2020).
Drilon, A. et al. ROS1-dependent cancers — biology, diagnostics and therapeutics. Nat. Rev. Clin. Oncol. 18, 35–55 (2021).
Jain, A., Fujioka, N. & Patel, M. Immune checkpoint inhibitors in ROS1-rearranged non-small cell lung cancer: a report of two cases. J. Thorac. Oncol. 14, e165–e167 (2019).
Drilon, A., Hu, Z. I., Lai, G. G. Y. & Tan, D. S. W. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat. Rev. Clin. Oncol. 15, 151–167 (2018).
Gainor, J. F. et al. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study. Lancet Oncol. 22, 959–969 (2021).
Drilon, A. et al. Efficacy of selpercatinib in RET fusion–positive non-small-cell lung cancer. N. Engl. J. Med. 383, 813–824 (2020).
Offin, M. et al. Immunophenotype and response to immunotherapy of RET-rearranged lung cancers. JCO Precis. Oncol. https://doi.org/10.1200/po.18.00386 (2019).
Hegde, A. et al. Responsiveness to immune checkpoint inhibitors versus other systemic therapies in RET-aberrant malignancies. ESMO Open 5, e000799 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT05048797 (2022).
Kadara, H. et al. Whole-exome sequencing and immune profiling of early-stage lung adenocarcinoma with fully annotated clinical follow-up. Ann. Oncol. 28, 75–82 (2017).
US Food and Drug Administration. FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sotorasib-kras-g12c-mutated-nsclc (2021).
Skoulidis, F. et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N. Engl. J. Med. 384, 2371–2381 (2021).
Nakajima, E. C., Ren, Y. & Singh, H. Outcomes of first-line immune checkpoint inhibitors with or without chemotherapy according to KRAS mutational status and PD-L1 expression in patients with advanced NSCLC: FDA pooled analysis. J. Clin. Oncol. 40 (Suppl. 16), 9001 (2022).
Noordhof, A. L. et al. Prognostic impact of KRAS mutation status for patients with stage IV adenocarcinoma of the lung treated with first-line pembrolizumab monotherapy. Lung Cancer 155, 163–169 (2021).
Jeanson, A. et al. Efficacy of immune checkpoint inhibitors in KRAS-mutant non-small cell lung cancer (NSCLC). J. Thorac. Oncol. 14, 1095–1101 (2019).
Ferrer, I. et al. KRAS-Mutant non-small cell lung cancer: from biology to therapy. Lung Cancer 124, 53–64 (2018).
Skoulidis, F. et al. Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov. 5, 860–877 (2015).
Skoulidis, F. et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov. 8, 822–835 (2018).
Dong, Z. Y. et al. Potential predictive value of TP53 and KRAS mutation status for response to PD-1 blockade immunotherapy in lung adenocarcinoma. Clin. Cancer Res. 23, 3012–3024 (2017).
West, H. J. et al. Clinical efficacy of atezolizumab plus bevacizumab and chemotherapy in KRAS- mutated non-small cell lung cancer with STK11, KEAP1, or TP53 comutations: subgroup results from the phase III IMpower150 trial. J. Immunother. Cancer 10, e003027 (2022).
Ricciuti, B. 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. 17, 399–410 (2022).
Tabbò, F. et al. How far we have come targeting BRAF-mutant non-small cell lung cancer (NSCLC). Cancer Treat. Rev. 103, 102335 (2022).
Dagogo-Jack, I. et al. Impact of BRAF mutation class on disease characteristics and clinical outcomes in BRAF-mutant lung cancer. Clin. Cancer Res. 25, 158–165 (2019).
US Food and Drug Administration. FDA grants regular approval to dabrafenib and trametinib combination for metastatic NSCLC with BRAF V600E mutation. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-dabrafenib-and-trametinib-combination-metastatic-nsclc-braf-v600e (2017).
Murciano-Goroff, Y. R. et al. Immune biomarkers and response to checkpoint inhibition of BRAF V600 and BRAF non-V600 altered lung cancers. Br. J. Cancer 126, 889–898 (2022).
Dudnik, E. et al. BRAF mutant lung cancer: programmed death ligand 1 expression, tumor mutational burden, microsatellite instability status, and response to immune check-point inhibitors. J. Thorac. Oncol. 13, 1128–1137 (2018).
Tan, I. et al. Therapeutic outcomes in non-small cell lung cancer with BRAF mutations: a single institution, retrospective cohort study. Transl. Lung Cancer Res. 8, 258–267 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02224781 (2022)
Haas, L. et al. Acquired resistance to anti-MAPK targeted therapy confers an immune-evasive tumor microenvironment and cross-resistance to immunotherapy in melanoma. Nat. Cancer 2, 693–708 (2021).
Recondo, G., Che, J., Jänne, P. A. & Awad, M. M. Targeting MET dysregulation in cancer. Cancer Discov. 10, 922–934 (2020).
US Food and Drug Administration. FDA grants accelerated approval to tepotinib for metastatic non-small cell lung cancer. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tepotinib-metastatic-non-small-cell-lung-cancer (2021).
US Food and Drug Administration. FDA approves capmatinib for metastatic non-small cell lung cancer. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-capmatinib-metastatic-non-small-cell-lung-cancer (2022).
Sabari, J. K. et al. PD-L1 expression, tumor mutational burden, and response to immunotherapy in patients with MET exon 14 altered lung cancers. Ann. Oncol. 29, 2085–2091 (2018).
Sevenich, L. Turning ‘cold’ into ‘hot’ tumors — opportunities and challenges for radio-immunotherapy against primary and metastatic brain cancers. Front. Oncol. 9, 163 (2019).
Hegde, P. S. & Chen, D. S. Top 10 challenges in cancer immunotherapy. Immunity 52, 17–35 (2020).
Hegde, P. S., Karanikas, V. & Evers, S. The where, the when, and the how of immune monitoring for cancer immunotherapies in the era of checkpoint inhibition. Clin. Cancer Res. 22, 1865–1874 (2016).
Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014).
Liu, C. et al. The superior efficacy of anti-PD-1/PD-L1 immunotherapy in KRAS-mutant non-small cell lung cancer that correlates with an inflammatory phenotype and increased immunogenicity. Cancer Lett. 470, 95–105 (2020).
Kortlever, R. M. et al. Myc cooperates with ras by programming inflammation and immune suppression. Cell 171, 1301–1315 (2017).
Mugarza, E. et al. Therapeutic KRASG12C inhibition drives effective interferon-mediated antitumor immunity in immunogenic lung cancers. Sci. Adv. 8, eabm8780 (2022).
Hu, J. et al. High expression of RAD51 promotes DNA damage repair and survival in KRAS-mutant lung cancer cells. BMB Rep. 52, 151–156 (2019).
Grabocka, E. et al. Wild-type H- and N-Ras promote mutant K-Ras-driven tumorigenesis by modulating the DNA damage response. Cancer Cell 25, 243–256 (2014).
van Grieken, N. C. T. et al. KRAS and BRAF mutations are rare and related to DNA mismatch repair deficiency in gastric cancer from the East and the West: results from a large international multicentre study. Br. J. Cancer 108, 1495–1501 (2013).
Zhao, W. et al. Mutations of BRAF and KRAS in gastric cancer and their association with microsatellite instability. Int. J. Cancer 108, 167–169 (2004).
Brennetot, C. et al. Frequent Ki-ras mutations in gastric tumors of the MSI phenotype. Gastroenterology 125, 1282 (2003).
Miao, D. et al. Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors. Nat. Genet. 50, 1271–1281 (2018).
Coelho, M. A. et al. Oncogenic RAS signaling promotes tumor immunoresistance by stabilizing PD-L1 mRNA. Immunity 47, 1083–1099.e6 (2017).
Lee, J. W. et al. The combination of MEK inhibitor with immunomodulatory antibodies targeting programmed death 1 and programmed death ligand 1 results in prolonged survival in Kras/p53-driven lung cancer. J. Thorac. Oncol. 14, 1046–1060 (2019).
Hashimoto, S. et al. ARF6 and AMAP1 are major targets of KRAS and TP53 mutations to promote invasion, PD-L1 dynamics, and immune evasion of pancreatic cancer. Proc. Natl Acad. Sci. USA 116, 17450–17459 (2019).
Skoulidis, F. et al. Association of inactivation of STK11/ LKB1 with a suppressive immune microenvironment in lung adenocarcinoma (LUAC). J. Clin. Oncol. 33 (Suppl. 15), 11002 (2015).
Cristescu, R. et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 362, eaar3593 (2018).
Deng, J. et al. ULK1 inhibition overcomes compromised antigen presentation and restores antitumor immunity in LKB1-mutant lung cancer. Nat. Cancer 2, 503–514 (2021).
Kitajima, S. et al. Suppression of STING associated with lkb1 loss in KRAS-driven lung cancer. Cancer Discov. 9, 34–45 (2019).
Koyama, S. et al. STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment. Cancer Res. 76, 999–1008 (2016).
Anastasia-Maria, Z. et al. KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance. Preprint at bioRxiv https://doi.org/10.1101/2021.09.24.461709 (2021).
Dong, Z. Y. et al. EGFR mutation correlates with uninflamed phenotype and weak immunogenicity, causing impaired response to PD-1 blockade in non-small cell lung cancer. Oncoimmunology 6, e1356145 (2017).
Sugiyama, E. et al. Blockade of EGFR improves responsiveness to PD-1 blockade in EGFR-mutated non-small cell lung cancer. Sci. Immunol. 5, eaav3937 (2020).
Reuben, A. et al. Comprehensive T cell repertoire characterization of non-small cell lung cancer. Nat. Commun. 11, 603 (2020).
Wu, D. et al. Identification of clonal neoantigens derived from driver mutations in an EGFR-mutated lung cancer patient benefitting from anti-PD-1. Front. Immunol. 11, 1366 (2020).
Chen, N. et al. Upregulation of PD-L1 by EGFR activation mediates the immune escape in EGFR-driven NSCLC: implication for optional immune targeted therapy for NSCLC patients with EGFR mutation. J. Thorac. Oncol. 10, 910–023 (2015).
Azuma, K. et al. Association of PD-L1 overexpression with activating EGFR mutations in surgically resected nonsmall-cell lung cancer. Ann. Oncol. 25, 1935–1940 (2014).
Rech, A. J. & Vonderheide, R. H. Dynamic interplay of oncogenes and T cells induces PD-L1 in the tumor microenvironment. Cancer Discov. 3, 1330–1332 (2013).
Spigel, D. R. et al. Total mutation burden (TMB) in lung cancer (LC) and relationship with response to PD-1/PD-L1 targeted therapies. J. Clin. Oncol. 34 (Suppl. 15), 9017 (2016).
Fang, Y. et al. Comprehensive analyses reveal TKI-induced remodeling of the tumor immune microenvironment in EGFR/ALK-positive non-small-cell lung cancer. Oncoimmunology 10, 1951019 (2021).
Zhang, Y. et al. MET amplification attenuates lung tumor response to immunotherapy by inhibiting STING. Cancer Discov. 11, 2726–2737 (2021).
Le, X. Heterogeneity in MET-aberrant NSCLC. J. Thorac. Oncol. 16, 504–506 (2021).
Kumar, M. S. et al. The GATA2 transcriptional network is requisite for RAS oncogene-driven non-small cell lung cancer. Cell 149, 642–655 (2012).
Arendt, K. A. M. et al. An in vivo inflammatory loop potentiates KRAS blockade. Biomedicines 10, 592 (2022).
Brooks, G. D. et al. IL6 trans-signaling promotes KRAS-driven lung carcinogenesis. Cancer Res. 76, 866–876 (2016).
Sunaga, N. et al. Oncogenic KRAS-induced interleukin-8 overexpression promotes cell growth and migration and contributes to aggressive phenotypes of non-small cell lung cancer. Int. J. Cancer 130, 1733–1744 (2012).
Wislez, M. et al. High expression of ligands for chemokine receptor CXCR2 in alveolar epithelial neoplasia induced by oncogenic Kras. Cancer Res. 66, 4198–4207 (2006).
Ji, H. et al. K-ras activation generates an inflammatory response in lung tumors. Oncogene 25, 2105–2112 (2006).
Simoncello, F. et al. CXCL5-mediated accumulation of mature neutrophils in lung cancer tissues impairs the differentiation program of anticancer CD8 T cells and limits the efficacy of checkpoint inhibitors. Oncoimmunology 11, 2059876 (2022).
Zdanov, S. et al. Mutant KRAS conversion of conventional T cells into regulatory T cells. Cancer Immunol. Res. 4, 354–365 (2016).
Busch, S. E. et al. Lung cancer subtypes generate unique immune responses. J. Immunol. 197, 4493–4503 (2016).
Katopodi, T. et al. Kras-driven intratumoral heterogeneity triggers infiltration of M2 polarized macrophages via the circHIPK3/PTK2 immunosuppressive circuit. Sci. Rep. 11, 15455 (2021).
Chang, S. H. et al. T helper 17 cells play a critical pathogenic role in lung cancer. Proc. Natl Acad. Sci. USA 111, 5664–5669 (2014).
Yang, L. et al. Single-cell transcriptome analysis revealed a suppressive tumor immune microenvironment in EGFR mutant lung adenocarcinoma. J. Immunother. Cancer 10, e003534 (2022).
Tu, E. et al. Anti-PD-L1 and anti-CD73 combination therapy promotes T cell response to EGFR-mutated NSCLC. JCI Insight 7, e142843 (2022).
McGranahan, N. et al. Allele-specific HLA loss and immune escape in lung cancer evolution. Cell 171, 1259–1271.e11 (2017).
Thommen, D. S. & Schumacher, T. N. T cell dysfunction in cancer. Cancer Cell 33, 547–562 (2018).
Li, H. et al. AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells. Cell Rep. Med. 3, 100554 (2022).
Siddiqui, I. et al. Intratumoral Tcf1+PD-1+CD8+ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity 50, 195–211.e10 (2019).
Mayoux, M. et al. Dendritic cells dictate responses to PD-L1 blockade cancer immunotherapy. Sci. Transl Med. 12, eaav7431 (2020).
Dammeijer, F. et al. The PD-1/PD-L1-checkpoint restrains T cell immunity in tumor-draining lymph nodes. Cancer Cell 38, 685–700.e8 (2020).
Horton, B. L. et al. Lack of CD8+ T cell effector differentiation during priming mediates checkpoint blockade resistance in non-small cell lung cancer. Sci. Immunol. 6, eabi8800 (2021).
Kroemer, G., Galassi, C., Zitvogel, L. & Galluzzi, L. Immunogenic cell stress and death. Nat. Immunol. 23, 487–500 (2022).
Melero, I. et al. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat. Rev. Cancer 15, 457–472 (2015).
Jia, Y. et al. EGFR-targeted therapy alters the tumor microenvironment in EGFR-driven lung tumors: implications for combination therapies. Int. J. Cancer 145, 1432–1444 (2019).
Zhang, N. et al. The EGFR pathway is involved in the regulation of PDL1 expression via the IL-6/JAK/STAT3 signaling pathway in EGFR-mutated non-small cell lung cancer. Int. J. Oncol. 49, 1360–1368 (2016).
Lin, K., Cheng, J., Yang, T., Li, Y. & Zhu, B. EGFR-TKI down-regulates PD-L1 in EGFR mutant NSCLC through inhibiting NF-κB. Biochem. Biophys. Res. Commun. 463, 95–101 (2015).
Dominguez, C., Tsang, K. Y. & Palena, C. Short-term EGFR blockade enhances immune-mediated cytotoxicity of EGFR mutant lung cancer cells: rationale for combination therapies. Cell Death Dis. 7, e2380 (2016).
Kumai, T. et al. EGFR inhibitors augment antitumour helper T-cell responses of HER family-specific immunotherapy. Br. J. Cancer 109, 2155–2166 (2013).
Kim, H. et al. EGFR inhibitors enhanced the susceptibility to NK cell-mediated lysis of lung cancer cells. J. Immunother. 34, 372–381 (2011).
Liu, Z. et al. Hypofractionated EGFR tyrosine kinase inhibitor limits tumor relapse through triggering innate and adaptive immunity. Sci. Immunol. 4, eaav6473 (2019).
Pollack, B. P., Sapkota, B. & Cartee, T. V. Epidermal growth factor receptor inhibition augments the expression of MHC class I and II genes. Clin. Cancer Res. 17, 4400–4413 (2011).
Nigro, A. et al. Enhanced expression of CD47 is associated with off-target resistance to tyrosine kinase inhibitor gefitinib in NSCLC. Front. Immunol. 10, 3135 (2020).
Pozzi, C. et al. The EGFR-specific antibody cetuximab combined with chemotherapy triggers immunogenic cell death. Nat. Med. 22, 624–631 (2016).
Garrido, G. et al. Induction of immunogenic apoptosis by blockade of epidermal growth factor receptor activation with a specific antibody. J. Immunol. 187, 4954–4966 (2011).
Isomoto, K. et al. Impact of EGFR-TKI treatment on the tumor immune microenvironment in EGFR mutation-positive non-small cell lung cancer. Clin. Cancer Res. 26, 2037–2046 (2020).
Frederick, D. T. et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin. Cancer Res. 19, 1225–1231 (2013).
Kang, S. H. et al. Inhibition of MEK with trametinib enhances the efficacy of anti-PD-L1 inhibitor by regulating anti-tumor immunity in head and neck squamous cell carcinoma. Oncoimmunology 8, e1515057 (2019).
Liu, L. et al. The BRAF and MEK inhibitors dabrafenib and trametinib: effects on immune function and in combination with immunomodulatory antibodies targeting PD-1, PD-L1, and CTLA-4. Clin. Cancer Res. 21, 1639–1651 (2015).
Dushyanthen, S. et al. Agonist immunotherapy restores T cell function following MEK inhibition improving efficacy in breast cancer. Nat. Commun. 8, 606 (2017).
Peiffer, L. et al. BRAF and MEK inhibition in melanoma patients enables reprogramming of tumor infiltrating lymphocytes. Cancer Immunol. Immunother. 70, 1635–1647 (2021).
Boni, A. et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res. 70, 5213–5219 (2010).
Verma, V. et al. MEK inhibition reprograms CD8+ T lymphocytes into memory stem cells with potent antitumor effects. Nat. Immunol. 22, 53–66 (2021).
Prasad, M. et al. MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer. J. Immunother. Cancer 10, e003917 (2022).
Baumann, D. et al. P38 MAPK signaling in M1 macrophages results in selective elimination of M2 macrophages by MEK inhibition. J. Immunother. Cancer 9, e002319 (2021).
Ebert, P. J. R. et al. MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity 44, 609–621 (2016).
Ribas, A. et al. Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma. Nat. Med. 25, 936–940 (2019).
Ascierto, P. A. et al. Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma. Nat. Med. 25, 941–946 (2019).
Gutzmer, R. et al. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 395, 1835–1844 (2020).
Morimoto, K. et al. A real-world analysis of immune checkpoint inhibitor-based therapy after osimertinib treatment in patients with EGFR-mutant NSCLC. JTO Clin. Res. Rep. 3, 100388 (2022).
Haratani, K. et al. Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment. Ann. Oncol. 28, 1532–1539 (2017).
Grant, M. J., Herbst, R. S. & Goldberg, S. B. Selecting the optimal immunotherapy regimen in driver-negative metastatic NSCLC. Nat. Rev. Clin. Oncol. 18, 625–644 (2021).
Kroemer, G., Galluzzi, L., Kepp, O. & Zitvogel, L. Immunogenic cell death in cancer therapy. Annu. Rev. Immunol. 31, 51–72 (2013).
Flieswasser, T. et al. Clinically relevant chemotherapeutics have the ability to induce immunogenic cell death in non-small cell lung cancer. Cells 9, 1474 (2020).
Fukumura, D., Kloepper, J., Amoozgar, Z., Duda, D. G. & Jain, R. K. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat. Rev. Clin. Oncol. 15, 325–340 (2018).
Martino, E. et al. Immune-modulating effects of bevacizumab in metastatic non-small-cell lung cancer patients. Cell Death Discov. 2, 16025 (2016).
Peterson, T. E. et al. Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages. Proc. Natl Acad. Sci. USA 113, 4470–4475 (2016).
Terme, M. et al. VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res. 73, 539–549 (2013).
Ozao-Choy, J. et al. The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res. 69, 2514–2522 (2009).
Osada, T. et al. The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients. Cancer Immunol. Immunother. 57, 1115–1125 (2008).
Zhang, Y. et al. VEGFR2 activity on myeloid cells mediates immune suppression in the tumor microenvironment. JCI Insight 6, e150735 (2021).
Paz-Ares, L. G., Ciuleanu, T. E., Cobo-Dols, M. & Reck, M. First-line (1L) nivolumab (NIVO)+ipilimumab (IPI)+2 cycles of chemotherapy (chemo) versus chemo alone (4 cycles) in patients (pts) with metastatic non-small cell lung cancer (NSCLC): 3-year update from CheckMate 9LA. J. Clin. Oncol. 40, LBA9026 (2022).
Peters, S., Cho, B. C., Luft, A. & Johnson, M. L. Association between KRAS/STK11/KEAP1 mutations and outcomes in POSEIDON: durvalumab ± tremelimumab + chemotherapy in mNSCLC. J. Thorac. Oncol. 17, S39-S41(2022).
Reck, M. et al. Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial. Lancet Respir. Med. 7, 387–401 (2019).
Socinski, M. A. et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N. Engl. J. Med. 378, 2288–2301 (2018).
Nogami, N. et al. IMpower150 final exploratory analyses for atezolizumab plus bevacizumab and chemotherapy in key NSCLC patient subgroups with EGFR mutations or metastases in the liver or brain. J. Thorac. Oncol. 17, 309–323 (2022).
Lu, S. et al. Sintilimab plus bevacizumab biosimilar IBI305 and chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): first interim results from a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 23, 1167–1179 (2022).
Lu, S. et al. VP9-2021: ORIENT-31: phase III study of sintilimab with or without IBI305 plus chemotherapy in patients with EGFR mutated nonsquamous NSCLC who progressed after EGFR-TKI therapy. Ann. Oncol. 33, 112–113 (2021).
Naumov, G. N. et al. Combined vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumor growth in xenograft models of EGFR inhibitor resistance. Clin. Cancer Res. 15, 3484–3494 (2009).
Le, X. et al. Dual EGFR-VEGF pathway inhibition: a promising strategy for patients with EGFR-mutant NSCLC. J. Thorac. Oncol. 16, 205–215 (2021).
Galon, J. & Bruni, D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat. Rev. Drug Discov. 18, 197–218 (2019).
Harding, J. J. et al. Blocking TIM-3 in treatment-refractory advanced solid tumors: a phase Ia/b study of LY3321367 with or without an anti-PD-L1 antibody. Clin. Cancer Res. 27, 2168–2178 (2021).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03708328?term=NCT03708328&draw=2&rank=1 (2018).
Schöffski, P. et al. Phase I/II study of the LAG-3 inhibitor ieramilimab (LAG525) ± anti-PD-1 spartalizumab (PDR001) in patients with advanced malignancies. J. Immunother. Cancer 10, e003776 (2022).
Li, J. et al. Abstract 4248: HFB200603, a novel anti-BTLA monoclonal antibody that provides therapeutic potential for immune escape and synergizes with anti-PD-1 treatment. Cancer Res. 82, 4248–4248 (2022).
Niu, J. et al. First-in-human phase 1 study of the anti-TIGIT antibody vibostolimab as monotherapy or with pembrolizumab for advanced solid tumors, including non-small-cell lung cancer☆. Ann. Oncol. 33, 169–180 (2022).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03761017 (2022)
Zhao, Y. et al. A phase II study of AK112 (PD-1/VEGF bispecific) in combination with chemotherapy in patients with advanced non-small cell lung cancer. J. Clin. Oncol. 40, 9019–9019 (2022).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03708328 (2022).
Kraehenbuehl, L., Weng, C. H., Eghbali, S., Wolchok, J. D. & Merghoub, T. Enhancing immunotherapy in cancer by targeting emerging immunomodulatory pathways. Nat. Rev. Clin. Oncol. 19, 37–50 (2022).
Suntharalingam, G. et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N. Engl. J. Med. 355, 1018–1028 (2006).
Segal, N. H. et al. Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. Clin. Cancer Res. 23, 1929–1936 (2017).
Labrijn, A. F., Janmaat, M. L., Reichert, J. M. & Parren, P. W. H. I. Bispecific antibodies: a mechanistic review of the pipeline. Nat. Rev. Drug Discov. 18, 585–608 (2019).
Hamid, O. et al. First-in-human study of an OX40 (ivuxolimab) and 4-1BB (utomilumab) agonistic antibody combination in patients with advanced solid tumors. J. Immunother. Cancer 10, e005471 (2022).
Davis, E. J. et al. First-in-human phase I/II, open-label study of the anti-OX40 agonist INCAGN01949 in patients with advanced solid tumors. J. Immunother. Cancer 10, e004235 (2022).
Sanborn, R. E. et al. Safety, tolerability and efficacy of agonist anti-CD27 antibody (varlilumab) administered in combination with anti-PD-1 (nivolumab) in advanced solid tumors. J. Immunother. Cancer 10, e005147 (2022).
Kvarnhammar, A. M. et al. The CTLA-4 x OX40 bispecific antibody ATOR-1015 induces anti-tumor effects through tumor-directed immune activation. J. Immunother. Cancer 7, 103 (2019).
Esfandiari, A., Cassidy, S. & Webster, R. M. Bispecific antibodies in oncology. Nat. Rev. Drug Discov. 21, 411–412 (2022).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04995523 (2023).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03809624 (2022)
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03894618 (2022).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04215978 (2022).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04215978 (2022).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04903873 (2022)
Sen, T. et al. Targeting DNA damage response promotes antitumor immunity through STING-mediated T-cell activation in small cell lung cancer. Cancer Discov. 9, 646–661 (2019).
Jiao, S. et al. PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression. Clin. Cancer Res. 23, 3711–3720 (2017).
Chabanon, R. M. et al. PARP inhibition enhances tumor cell–intrinsic immunity in ERCC1-deficient non-small cell lung cancer. J. Clin. Invest. 129, 1211–1228 (2019).
Wang, Z. et al. Niraparib activates interferon signaling and potentiates anti-PD-1 antibody efficacy in tumor models. Sci. Rep. 9, 1853 (2019).
Ding, L. et al. PARP inhibition elicits STING-dependent antitumor immunity in Brca1-deficient ovarian cancer. Cell Rep. 25, 2972–2980 (2018).
Shen, J. et al. PARPI triggers the STING-dependent immune response and enhances the therapeutic efficacy of immune checkpoint blockade independent of BRCAness. Cancer Res. 79, 311–319 (2019).
Felip, E. et al. A phase II study of bemcentinib (BGB324), a first-in-class highly selective AXL inhibitor, with pembrolizumab in pts with advanced NSCLC: OS for stage I and preliminary stage II efficacy. J. Clin. Oncol. 37, 9098 (2019).
Le, X. et al. Characterization of the immune landscape of EGFR-mutant NSCLC identifies CD73/adenosine pathway as a potential therapeutic target. J. Thorac. Oncol. 16, 583–600 (2021).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT05234307 (2022)
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03274479 (2022)
AstraZeneca. Imfinzi combined with novel immunotherapies improved clinical outcomes for patients with unresectable, stage III non-small cell lung cancer. AstraZeneca https://www.astrazeneca.com/media-centre/press-releases/2021/imfinzi-combined-with-novel-immunotherapies-improved-clinical-outcomes-for-patients-with-unresectable-stage-iii-non-small-cell-lung-cancer.html (2021).
Fong, L. et al. Safety and clinical activity of adenosine A2a receptor (A2aR) antagonist, CPI-444, in anti-PD1/PDL1 treatment-refractory renal cell (RCC) and non-small cell lung cancer (NSCLC) patients. J. Clin. Oncol. 35, 3004–3004 (2017).
Chiappori, A. et al. Phase I/II study of the A2AR antagonist NIR178 (PBF-509), an oral immunotherapy, in patients (pts) with advanced NSCLC. J. Clin. Oncol. 36, 9089 (2018).
Bendell, J. C. et al. Safety and efficacy of the anti-CD73 monoclonal antibody (mAb) oleclumab ± durvalumab in patients (pts) with advanced colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), or EGFR-mutant non-small cell lung cancer (EGFRm NSCLC). J. Clin. Oncol. 39, 9047–9047 (2021).
Ye, Y. et al. Profiling of immune features to predict immunotherapy efficacy. Innovation 3, 100194 (2022).
Gay, C. M. et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell 39, 346–360 (2021).
Rudin, C. et al. MA15.02 long-term safety and clinical activity results from a phase Ib study of erlotinib plus atezolizumab in advanced NSCLC. J. Thorac. Oncol. 13, S407 (2018).
Gettinger, S. et al. Nivolumab plus erlotinib in patients with EGFR-mutant advanced NSCLC. J. Thorac. Oncol. 13, 1363–1372 (2018).
Yang, J. C. H. et al. Pembrolizumab in combination with erlotinib or gefitinib as first-line therapy for advanced NSCLC with sensitizing EGFR mutation. J. Thorac. Oncol. 14, 553–559 (2019).
Creelan, B. C. et al. A phase 1 study of gefitinib combined with durvalumab in EGFR TKI-naive patients with EGFR mutation-positive locally advanced/metastatic non-small-cell lung cancer. Br. J. Cancer 124, 383–390 (2021).
Ahn, M. J. et al. Osimertinib plus durvalumab in patients with EGFR-mutated, advanced NSCLC: a phase 1b, open-label, multicenter trial. J. Thorac. Oncol. 17, 718–723 (2022).
Spigel, D. R. et al. Phase 1/2 Study of the safety and tolerability of nivolumab plus crizotinib for the first-line treatment of anaplastic lymphoma kinase translocation — positive advanced non-small cell lung cancer (CheckMate 370). J. Thorac. Oncol. 13, 682–688 (2018).
Felip, E. et al. Ceritinib plus nivolumab in patients with advanced ALK-rearranged non-small cell lung cancer: results of an open-label, multicenter, phase 1B study. J. Thorac. Oncol. 5, 392–403 (2019).
Shaw, A. T. et al. Avelumab (anti-PD-L1) in combination with crizotinib or lorlatinib in patients with previously treated advanced NSCLC: phase 1b results from JAVELIN Lung 101. J. Clin. Oncol. 36, 9008 (2018).
Kim, D.-W. et al. Brief report: safety and antitumor activity of alectinib plus atezolizumab from a phase 1b study in advanced ALK-positive NSCLC. JTO Clin. Res. Rep. 3, 100367 (2022).
Li, B. T. et al. CodeBreaK 100/101: first report of safety/efficacy of sotorasib in combination with pembrolizumab or atezolizumab in advanced KRAS p.G12C NSCLC [abstract OA03.06]. J. Thorac. Oncol. 17, S10–S11 (2022).
Rizvi, N. A. et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).
Hellmann, M. D. et al. Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer. Cancer Cell 33, 843–852.e4 (2018).
McGrail, D. J. et al. High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types. Ann. Oncol. 32, 661–672 (2021).
Chowell, D. et al. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science 359, 582–587 (2018).
Gubin, M. M. et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515, 577–581 (2014).
Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).
Coulie, P. G., van den Eynde, B. J., van der Bruggen, P. & Boon, T. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat. Rev. Cancer 14, 135–146 (2014).
Chan, T. A. et al. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann. Oncol. 30, 44–56 (2019).
The work of I.O. is supported by The Spanish Association Against Cancer (AECC) Investigator fellowship award 2020. The L.P.-A. laboratory is supported by grants from Fundación CRIS Contra El Cáncer (2021/0091), Instituto de Salud Carlos III (PI20/00870 and AC20/00070), AECC (2018/0145/A) and Asociación Española de Alpinistas con Cáncer (2021/0157).
I.O. declares no competing interests. A.C.U. has received honoraria for participation at meetings from AstraZeneca Spain. J.Z. has received honoraria for participation at meetings from AstraZeneca Spain, Bristol Myers Squibb/Celgene, Guardant Health, NanoString Technologies, Pfizer and Roche/Genentech; speakers’ bureau fees from AstraZeneca, Bristol Myers Squibb/Celgene, Guardant Health, MSD Oncology, NanoString Technologies, Pfizer, and Roche; research funding (via his institution) from AstraZeneca and Roche/Genentech; travel and accommodation expenses from Bristol Myers Squibb/Celgene; and declares consultancy or advisory roles with AstraZeneca, Bristol Myers Squibb/Celgene, Guardant Health, Novartis and Pfizer. L.P.-A. has leadership interest (board member) in ALTUM Sequencing and Genomica; has received honoraria for participation at meetings from Amgen Sanofi, AstraZeneca Spain, Bayer, Blueprint Medicines, Bristol Myers Squibb/Celgene, Daiichi Sankyo, Ipsen, Lilly, Merck Serono, Mirati Therapeutics, Novartis, Pfizer, PharmaMar, Roche/Genentech, Servier and Takeda; speakers’ bureau fees from AstraZeneca, Bristol Myers Squibb, Merck Serono, MSD Oncology, Pfizer and Roche/Genentech; research funding (via his institution) from AstraZeneca, Bristol Myers Squibb, Kura Oncology, MSD, Pfizer and PharmaMar; and travel and accommodation expenses from AstraZeneca, Bristol Myers Squibb/Celgene, MSD, Pfizer Roche/Genentech and Takeda. L.P-A. also declares other relationships with Amgen, Ipsen, Merck, Novartis, Pfizer, Roche, Sanofi and Servier (as sponsors of clinical trials).
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Otano, I., Ucero, A.C., Zugazagoitia, J. et al. At the crossroads of immunotherapy for oncogene-addicted subsets of NSCLC. Nat Rev Clin Oncol (2023). https://doi.org/10.1038/s41571-022-00718-x