Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial
Tina Cascone, William N William Jr, Annikka Weissferdt, Cheuk H Leung, Heather Y Lin, Apar Pataer, Myrna C B Godoy, Brett W Carter, Lorenzo Federico, Alexandre Reuben, Md Abdul Wadud Khan, Hitoshi Dejima, Alejandro Francisco-Cruz, Edwin R Parra, Luisa M Solis, Junya Fujimoto, Hai T Tran, Neda Kalhor, Frank V Fossella, Frank E Mott, Anne S Tsao, George Blumenschein Jr, Xiuning Le, Jianjun Zhang, Ferdinandos Skoulidis, Jonathan M Kurie, Mehmet Altan, Charles Lu, Bonnie S Glisson, Lauren Averett Byers, Yasir Y Elamin, Reza J Mehran, David C Rice, Garrett L Walsh, Wayne L Hofstetter, Jack A Roth, Mara B Antonoff, Humam Kadara, Cara Haymaker, Chantale Bernatchez, Nadim J Ajami, Robert R Jenq, Padmanee Sharma, James P Allison, Andrew Futreal, Jennifer A Wargo, Ignacio I Wistuba, Stephen G Swisher, J Jack Lee, Don L Gibbons, Ara A Vaporciyan, John V Heymach, Boris Sepesi, Tina Cascone, William N William Jr, Annikka Weissferdt, Cheuk H Leung, Heather Y Lin, Apar Pataer, Myrna C B Godoy, Brett W Carter, Lorenzo Federico, Alexandre Reuben, Md Abdul Wadud Khan, Hitoshi Dejima, Alejandro Francisco-Cruz, Edwin R Parra, Luisa M Solis, Junya Fujimoto, Hai T Tran, Neda Kalhor, Frank V Fossella, Frank E Mott, Anne S Tsao, George Blumenschein Jr, Xiuning Le, Jianjun Zhang, Ferdinandos Skoulidis, Jonathan M Kurie, Mehmet Altan, Charles Lu, Bonnie S Glisson, Lauren Averett Byers, Yasir Y Elamin, Reza J Mehran, David C Rice, Garrett L Walsh, Wayne L Hofstetter, Jack A Roth, Mara B Antonoff, Humam Kadara, Cara Haymaker, Chantale Bernatchez, Nadim J Ajami, Robert R Jenq, Padmanee Sharma, James P Allison, Andrew Futreal, Jennifer A Wargo, Ignacio I Wistuba, Stephen G Swisher, J Jack Lee, Don L Gibbons, Ara A Vaporciyan, John V Heymach, Boris Sepesi
Abstract
Ipilimumab improves clinical outcomes when combined with nivolumab in metastatic non-small cell lung cancer (NSCLC), but its efficacy and impact on the immune microenvironment in operable NSCLC remain unclear. We report the results of the phase 2 randomized NEOSTAR trial (NCT03158129) of neoadjuvant nivolumab or nivolumab + ipilimumab followed by surgery in 44 patients with operable NSCLC, using major pathologic response (MPR) as the primary endpoint. The MPR rate for each treatment arm was tested against historical controls of neoadjuvant chemotherapy. The nivolumab + ipilimumab arm met the prespecified primary endpoint threshold of 6 MPRs in 21 patients, achieving a 38% MPR rate (8/21). We observed a 22% MPR rate (5/23) in the nivolumab arm. In 37 patients resected on trial, nivolumab and nivolumab + ipilimumab produced MPR rates of 24% (5/21) and 50% (8/16), respectively. Compared with nivolumab, nivolumab + ipilimumab resulted in higher pathologic complete response rates (10% versus 38%), less viable tumor (median 50% versus 9%), and greater frequencies of effector, tissue-resident memory and effector memory T cells. Increased abundance of gut Ruminococcus and Akkermansia spp. was associated with MPR to dual therapy. Our data indicate that neoadjuvant nivolumab + ipilimumab-based therapy enhances pathologic responses, tumor immune infiltrates and immunologic memory, and merits further investigation in operable NSCLC.
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References
- Martin J, et al. Long-term results of combined-modality therapy in resectable non-small-cell lung cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20, 1989–1995 (2002).
- Pignon JP, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26, 3552–3559 (2008).
- Group, N.M.-a.C. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet 383, 1561–1571 (2014).
- Pataer A, et al. Histopathologic response criteria predict survival of patients with resected lung cancer after neoadjuvant chemotherapy. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 7, 825–832 (2012).
- Hellmann MD, et al. Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint. Lancet Oncol 15, e42–50 (2014).
- Chaft JE, et al. Phase II trial of neoadjuvant bevacizumab plus chemotherapy and adjuvant bevacizumab in patients with resectable nonsquamous non-small-cell lung cancers. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 8, 1084–1090 (2013).
- Cascone T, et al. Induction Cisplatin Docetaxel Followed by Surgery and Erlotinib in Non-Small Cell Lung Cancer. Ann Thorac Surg 105, 418–424 (2018).
- Wei SC, et al. Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade. Cell 170, 1120–1133 e1117 (2017).
- Hellmann MD, et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol 18, 31–41 (2017).
- Hellmann MD, et al. Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. The New England journal of medicine 381, 2020–2031 (2019).
- Sepesi B, et al. Nodal Immune Flare (NIF) Following Neoadjuvant Anti-PD-1 and Anti-CTLA-4 Therapy in Non-Small Cell Lung Cancer. Journal of Thoracic Oncology 14, S745–S745 (2019).
- Weissferdt A, et al. Agreement on Major Pathological Response in NSCLC Patients Receiving Neoadjuvant Chemotherapy. Clin Lung Cancer (2020).
- Cascone T, et al. A Phase I/II Study of Neoadjuvant Cisplatin, Docetaxel and Nintedanib for Resectable Non-Small Cell Lung Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research (2020).
- Forde PM, et al. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. The New England journal of medicine 378, 1976–1986 (2018).
- Kwiatkowski DJ, et al. Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): Interim analysis and biomarker data from a multicenter study (LCMC3). Journal of Clinical Oncology 37, 8503–8503 (2019).
- Gao S, et al. Neoadjuvant PD-1 inhibitor (Sintilimab) in NSCLC. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 15, 816–826 (2020).
- Amaria RN, et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nature medicine 24, 1649–1654 (2018).
- Djenidi F, et al. CD8+CD103+ tumor-infiltrating lymphocytes are tumor-specific tissue-resident memory T cells and a prognostic factor for survival in lung cancer patients. J Immunol 194, 3475–3486 (2015).
- Duhen T, et al. Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors. Nature communications 9, 2724 (2018).
- Wei SC, et al. Combination anti-CTLA-4 plus anti-PD-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies. Proceedings of the National Academy of Sciences of the United States of America 116, 22699–22709 (2019).
- Shu CA, et al. Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol (2020).
- Reuben A, et al. Comprehensive T cell repertoire characterization of non-small cell lung cancer. Nature communications 11, 603 (2020).
- Wu TD, et al. Peripheral T cell expansion predicts tumour infiltration and clinical response. Nature 579, 274–278 (2020).
- Blank CU, et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nature medicine 24, 1655–1661 (2018).
- William WN Jr., et al. Computed tomography RECIST assessment of histopathologic response and prediction of survival in patients with resectable non-small-cell lung cancer after neoadjuvant chemotherapy. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 8, 222–228 (2013).
- Gopalakrishnan V, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97–103 (2018).
- Routy B, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018).
- Ramalingam SS, et al. Nivolumab + ipilimumab versus platinum-doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer: Three-year update from CheckMate 227 Part 1. Journal of Clinical Oncology 38, 9500–9500 (2020).
- Provencio M, et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol 21, 1413–1422 (2020).
- Reck M, et al. Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA. Journal of Clinical Oncology 38, 9501–9501 (2020).
- Simon R Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10, 1–10 (1989).
- Thall PF, Simon RM & Estey EH New statistical strategy for monitoring safety and efficacy in single-arm clinical trials. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 14, 296–303 (1996).
- Eisenhauer EA, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45, 228–247 (2009).
- Woolson R a.C WR. Statistical Methods for the Analysis of Biomedical Data, (New York, 2002).
- Kaplan EL & Meier P Nonparametric-Estimation from Incomplete Observations. J Am Stat Assoc 53, 457–481 (1958).
- Mantel N Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50, 163–170 (1966).
- Bentebibel SE, et al. A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rbetagamma-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors. Cancer discovery 9, 711–721 (2019).
- Parra ER, et al. Validation of multiplex immunofluorescence panels using multispectral microscopy for immune-profiling of formalin-fixed and paraffin-embedded human tumor tissues. Sci Rep 7, 13380 (2017).
- Parra ER, Francisco-Cruz A & Wistuba II. State-of-the-Art of Profiling Immune Contexture in the Era of Multiplexed Staining and Digital Analysis to Study Paraffin Tumor Tissues. Cancers (Basel) 11(2019).
- Parra ER, et al. Procedural Requirements and Recommendations for Multiplex Immunofluorescence Tyramide Signal Amplification Assays to Support Translational Oncology Studies. Cancers (Basel) 12(2020).
- Parra ER, Villalobos P, Mino B & Rodriguez-Canales J Comparison of Different Antibody Clones for Immunohistochemistry Detection of Programmed Cell Death Ligand 1 (PD-L1) on Non-Small Cell Lung Carcinoma. Appl Immunohistochem Mol Morphol 26, 83–93 (2018).
- Tsao MS, et al. PD-L1 Immunohistochemistry Comparability Study in Real-Life Clinical Samples: Results of Blueprint Phase 2 Project. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 13, 1302–1311 (2018).
- Reuben A, et al. TCR Repertoire Intratumor Heterogeneity in Localized Lung Adenocarcinomas: an Association with Predicted Neoantigen Heterogeneity and Postsurgical Recurrence. Cancer discovery (2017).
- Edgar RC UNOISE2: improved error-correction for Illumina 16S and ITS amplicon sequencing. bioRxiv, 081257 (2016).
- Quast C, et al. The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res 41, D590–596 (2013).
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