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Morphological, immune and genetic features in biopsy sample associated with the efficacy of pembrolizumab in patients with non-squamous non-small cell lung cancer

  • Original Article – Clinical Oncology
  • Published:
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Abstract

Introduction

The usefulness of the histopathology of biopsy samples for predicting the efficacy of immunotherapy in non-squamous, non-small cell lung cancer (NSq NSCLC) patients remains unclear.

Methods

We retrospectively investigated the associations between the histopathological features in biopsy samples and survival outcomes in advanced NSq NSCLC patients receiving pembrolizumab. NSq NSCLC was classified histopathologically as morphological adenocarcinoma or non-small cell carcinoma (NSCC: absence of definitive features of either adenocarcinoma or a squamous morphology). We investigated the association between the tumor morphological features and immune/genetic features by examining the tumor PD-L1 expression and tumor mutation burden (TMB).

Results

Among 33 advanced NSq NSCLC patients with tumor PD-L1 scores ≥ 50% receiving pembrolizumab as first-line therapy, a biopsy diagnosis of NSCC was associated with a significantly longer progression-free survival [median 16.8 vs. 2.3 months; hazard ratio (HR) 0.26; 95% CI 0.10–0.62, P = 0.01] and overall survival (median NR vs. 10.1 months; HR 0.35; 0.12–0.97, P = 0.04) as compared to that of morphological adenocarcinoma. In an analysis of 367 biopsy samples, the NSCC group showed a higher percentage of samples with PD-L1 scores ≥ 50% than the morphological adenocarcinoma group (35% vs. 10%). The NSCC group (n = 8) also showed a significantly higher TMB than the morphological adenocarcinoma group (n = 7) (median 236 vs. 25 mutations/whole exome, P = 0.01).

Conclusion

Absence of definitive morphological features in a biopsy sample could be a useful predictor of the efficacy of pembrolizumab in NSq NSCLC patients with tumor PD-L1 scores ≥ 50%, as these tumors are likely to show high tumor PD-L1 expression and high TMB.

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References

  • Aguilar EJ, Ricciuti B, Gainor JF, Kehl KL, Kravets S, Dahlberg S, Nishino M, Sholl LM, Adeni A, Subegdjo S, Khosrowjerdi S, Peterson RM, Digumarthy S, Liu C, Sauter J, Rizvi H, Arbour KC, Carter BW, Heymach JV, Altan M, Hellmann MD, Awad MM (2019) Outcomes to first-line pembrolizumab in patients with non-small-cell lung cancer and very high PD-L1 expression. Ann Oncol 30:1653–1659

    Article  CAS  Google Scholar 

  • Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, Felip E, van den Heuvel MM, Ciuleanu TE, Badin F, Ready N, Hiltermann TJN, Nair S, Juergens R, Peters S, Minenza E, Wrangle JM, Rodriguez-Abreu D, Borghaei H, Blumenschein GR Jr, Villaruz LC, Havel L, Krejci J, Corral Jaime J, Chang H, Geese WJ, Bhagavatheeswaran P, Chen AC, Socinski MA (2017) First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med 376:2415–2426

    Article  CAS  Google Scholar 

  • Dong ZY, Zhang C, Li YF, Su J, Xie Z, Liu SY, Yan LX, Chen ZH, Yang XN, Lin JT, Tu HY, Yang JJ, Zhou Q, Sun YL, Zhong WZ, Wu YL (2018) Genetic and immune profiles of solid predominant lung adenocarcinoma reveal potential immunotherapeutic strategies. J Thorac Oncol 13:85–96

    Article  CAS  Google Scholar 

  • Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SYS, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC (2018) Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med 378:2078–2092

    Article  CAS  Google Scholar 

  • Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, Linardou H, Burgers S, Salman P, Borghaei H, Ramalingam SS, Brahmer J, Reck M, O'Byrne KJ, Geese WJ, Green G, Chang H, Szustakowski J, Bhagavatheeswaran P, Healey D, Fu Y, Nathan F, Paz-Ares L (2018) Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 378:2093–2104

    Article  CAS  Google Scholar 

  • Ikematsu Y, Yoneshima Y, Ijichi K, Tanaka K, Harada T, Oda Y, Nakanishi Y, Okamoto I (2017) Marked response to pembrolizumab in a patient with pulmonary pleomorphic carcinoma highly positive for PD-L1. Lung Cancer 112:230–231

    Article  Google Scholar 

  • Kim S, Kim MY, Koh J, Go H, Lee DS, Jeon YK, Chung DH (2015) Programmed death-1 ligand 1 and 2 are highly expressed in pleomorphic carcinomas of the lung: comparison of sarcomatous and carcinomatous areas. Euro J Cancer (Oxford, England: 1990) 51:2698–2707

  • Lang D, Huemer F, Rinnerthaler G, Horner A, Wass R, Brehm E, Akbari K, Granitz M, Hutarew G, Kaiser B, Greil R, Lamprecht B (2019) Therapy line and associated predictors of response to PD-1/PD-L1-inhibitor monotherapy in advanced non-small-cell lung cancer: a retrospective bi-centric cohort study. Targeted Oncol 14:707–717

    Article  Google Scholar 

  • Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372:2509–2520

    Article  CAS  Google Scholar 

  • Matsuzawa R, Kirita K, Kuwata T, Umemura S, Matsumoto S, Fujii S, Yoh K, Kojima M, Niho S, Ohmatsu H, Ochiai A, Tsuboi M, Goto K, Ishii G (2016) Factors influencing the concordance of histological subtype diagnosis from biopsy and resected specimens of lung adenocarcinoma. Lung Cancer 94:1–6

    Article  Google Scholar 

  • Miyazawa T, Marushima H, Saji H, Kojima K, Hoshikawa M, Takagi M, Nakamura H (2019) PD-L1 expression in non-small-cell lung cancer including various adenocarcinoma subtypes. Ann Thoracic Cardiovasc Surg 25:1–9

    Article  Google Scholar 

  • Ott PA, Bang YJ, Piha-Paul SA, Razak ARA, Bennouna J, Soria JC, Rugo HS, Cohen RB, O'Neil BH, Mehnert JM, Lopez J, Doi T, van Brummelen EMJ, Cristescu R, Yang P, Emancipator K, Stein K, Ayers M, Joe AK, Lunceford JK (2019) T-Cell-Inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028. J Clin Oncol 37:318–327.

  • Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gumus M, Mazieres J, Hermes B, Cay Senler F, Csoszi T, Fulop A, Rodriguez-Cid J, Wilson J, Sugawara S, Kato T, Lee KH, Cheng Y, Novello S, Halmos B, Li X, Lubiniecki GM, Piperdi B, Kowalski DM, Investigators K (2018) Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med 379:2040–2051

    Article  CAS  Google Scholar 

  • Pelosi G, Haspinger ER, Bimbatti M, Leone G, Paolini B, Fabbri A, Tamborini E, Perrone F, Testi A, Garassino M, Maisonneuve P, de Braud F, Pilotti S, Pastorino U (2014) Does immunohistochemistry affect response to therapy and survival of inoperable non-small cell lung carcinoma patients? A survey of 145 stage III-IV consecutive cases. Int J Surg Pathol 22:136–148

    Article  Google Scholar 

  • Ready N, Hellmann MD, Awad MM, Otterson GA, Gutierrez M, Gainor JF, Borghaei H, Jolivet J, Horn L, Mates M, Brahmer J, Rabinowitz I, Reddy PS, Chesney J, Orcutt J, Spigel DR, Reck M, O'Byrne KJ, Paz-Ares L, Hu W, Zerba K, Li X, Lestini B, Geese WJ, Szustakowski JD, Green G, Chang H, Ramalingam SS (2019) First-line nivolumab plus ipilimumab in advanced non-small-cell lung cancer (CheckMate 568): outcomes by programmed death ligand 1 and tumor mutational burden as biomarkers. J Clin Oncol 37:992–1000

    Article  CAS  Google Scholar 

  • Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR, Investigators K (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375:1823–1833

    Article  CAS  Google Scholar 

  • Rekhtman N, Ang DC, Riely GJ, Ladanyi M, Moreira AL (2013) KRAS mutations are associated with solid growth pattern and tumor-infiltrating leukocytes in lung adenocarcinoma. Mod Pathol 26:1307–1319

    Article  CAS  Google Scholar 

  • Rizvi H, Sanchez-Vega F, La K, Chatila W, Jonsson P, Halpenny D, Plodkowski A, Long N, Sauter JL, Rekhtman N, Hollmann T, Schalper KA, Gainor JF, Shen R, Ni A, Arbour KC, Merghoub T, Wolchok J, Snyder A, Chaft JE, Kris MG, Rudin CM, Socci ND, Berger MF, Taylor BS, Zehir A, Solit DB, Arcila ME, Ladanyi M, Riely GJ, Schultz N, Hellmann MD (2018) Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing. J Clin Oncol 36:633–641

    Article  CAS  Google Scholar 

  • Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, Miller ML, Rekhtman N, Moreira AL, Ibrahim F, Bruggeman C, Gasmi B, Zappasodi R, Maeda Y, Sander C, Garon EB, Merghoub T, Wolchok JD, Schumacher TN, Chan TA (2015) Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science (New York, NY) 348:124–128

    Article  CAS  Google Scholar 

  • Roszik J, Haydu LE, Hess KR, Oba J, Joon AY, Siroy AE, Karpinets TV, Stingo FC, Baladandayuthapani V, Tetzlaff MT, Wargo JA, Chen K, Forget MA, Haymaker CL, Chen JQ, Meric-Bernstam F, Eterovic AK, Shaw KR, Mills GB, Gershenwald JE, Radvanyi LG, Hwu P, Futreal PA, Gibbons DL, Lazar AJ, Bernatchez C, Davies MA, Woodman SE (2016) Novel algorithmic approach predicts tumor mutation load and correlates with immunotherapy clinical outcomes using a defined gene mutation set. BMC Med 14:168

    Article  Google Scholar 

  • Shiran I, Heller E, Jessel S, Kamer I, Daniel-Meshulam I, Navon R, Urban D, Onn A, Bar J (2017) Non-small-cell lung cancer patients with adenocarcinoma morphology have a better outcome compared with patients diagnosed with non-small-cell lung cancer favor adenocarcinoma. Clin Lung Cancer 18:316–323.e311

    Article  Google Scholar 

  • Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA 68:7–30.

  • Takada K, Okamoto T, Shoji F, Shimokawa M, Akamine T, Takamori S, Katsura M, Suzuki Y, Fujishita T, Toyokawa G, Morodomi Y, Okano S, Oda Y, Maehara Y (2016) Clinical significance of PD-L1 protein expression in surgically resected primary lung adenocarcinoma. J Thorac Oncol 11:1879–1890

    Article  Google Scholar 

  • Travis WD, Brambilla E, Burke AP, Marx A, (Eds.) AGN (2015) WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart, fourth ed edn. Internatilnal Agency for Reserch on Cancer, Lyon

  • Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, Beer DG, Powell CA, Riely GJ, Van Schil PE, Garg K, Austin JH, Asamura H, Rusch VW, Hirsch FR, Scagliotti G, Mitsudomi T, Huber RM, Ishikawa Y, Jett J, Sanchez-Cespedes M, Sculier JP, Takahashi T, Tsuboi M, Vansteenkiste J, Wistuba I, Yang PC, Aberle D, Brambilla C, Flieder D, Franklin W, Gazdar A, Gould M, Hasleton P, Henderson D, Johnson B, Johnson D, Kerr K, Kuriyama K, Lee JS, Miller VA, Petersen I, Roggli V, Rosell R, Saijo N, Thunnissen E, Tsao M, Yankelewitz D (2011) International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 6:244–285

    Article  Google Scholar 

  • Ujiie H, Kadota K, Chaft JE, Buitrago D, Sima CS, Lee MC, Huang J, Travis WD, Rizk NP, Rudin CM, Jones DR, Adusumilli PS (2015) Solid predominant histologic subtype in resected stage I lung adenocarcinoma is an independent predictor of early, extrathoracic, multisite recurrence and of poor postrecurrence survival. J Clin Oncol 33:2877–2884

    Article  Google Scholar 

  • Warth A, Muley T, Meister M, Stenzinger A, Thomas M, Schirmacher P, Schnabel PA, Budczies J, Hoffmann H, Weichert W (2012) The novel histologic international association for the study of lung cancer/American thoracic society/European respiratory society classification system of lung adenocarcinoma is a stage-independent predictor of survival. J Clin Oncol 30:1438–1446

    Article  Google Scholar 

  • Willis C, Fiander M, Tran D, Korytowsky B, Thomas JM, Calderon F, Zyczynski TM, Brixner D, Stenehjem DD (2019) Tumor mutational burden in lung cancer: a systematic literature review. Oncotarget 10:6604–6622

    Article  Google Scholar 

Download references

Acknowledgements

The testing of whole-exome sequencing was performed as part of the Lung Cancer Genomic Screening Project for Individualized Medicine Immuno-Oncology Biomarker Study (LC-SCRUM-IBIS), which was supported by AstraZeneca (A20166-083), Bristol-Myers Squibb (A2017-171), Chugai (A2016-106), Ono (A2016-168).

Funding

This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-0882, Japan

    Tetsuya Sakai, Hibiki Udagawa, Shingo Matsumoto, Kiyotaka Yoh, Kaname Nosaki, Takaya Ikeda, Yoshitaka Zenke, Keisuke Kirita, Seiji Niho & Koichi Goto

  2. Course of Advanced Clinical Research of Cancer, Juntendo University Graduate School of Medicine, Tokyo, Japan

    Tetsuya Sakai, Tetsuo Akimoto & Genichiro Ishii

  3. Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Japan

    Tetsuya Sakai & Genichiro Ishii

  4. Department of Radiation Oncology and Particle Therapy, National Cancer Center Hospital East, Kashiwa, Japan

    Tetsuo Akimoto

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  1. Tetsuya Sakai
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  2. Hibiki Udagawa
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  3. Shingo Matsumoto
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  4. Kiyotaka Yoh
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Contributions

TS prepared the manuscript, HU designed the concepts and revised the manuscript. All the authors read and approved the final manuscript.

Corresponding author

Correspondence to Hibiki Udagawa.

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Conflicts of interest

T. Sakai reports personal fees from AstraZeneca, outside the submitted work, H. Udagawa reports grants and personal fees from MSD, during the conduct of the study; grants and personal fees from Abbvie, grants and personal fees from Daiichisankyo; grants and personal fees from AMGEN, personal fees from Boehringer Ingelheim, grants and personal fees from AstraZeneca, personal fees from Chugai, personal fees from ONO, personal fees from Springer Japan, personal fees from Amco, personal fees from Taiho, outside the submitted work, K. Nosaki reports personal fees from MSD K.K., during the conduct of the study; personal fees from Nippon Kayaku Co., Ltd., personal fees from AstraZeneca K.K., personal fees from Bristol-Myers Squibb, personal fees from Chugai Pharmaceutical Co., Ltd., personal fees from Eli Lilly Japan K.K., personal fees from Pfizer Japan Inc., personal fees from Taiho Pharmaceutical Co., Ltd., outside the submitted work, Y. Zenke reports grants and personal fees from MSD, during the conduct of the study; grants from Merck, personal fees from Boheringer-Ingelhaeim, personal fees from Astrazeneca, personal fees from chugai, personal fees from Ono Pharmaceutical, personal fees from Bristol-Myers Squibb, personal fees from Lilly, personal fees from TAIHO Pharmacutical, outside the submitted work, K. Kirita reports grants and personal fees from MSD, during the conduct of the study; grants and personal fees from Pfizer, personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Novartis, personal fees from Olympus, personal fees from Boston Scientific, personal fees from Amuco, personal fees from Kyowa Hakko Kirin, personal fees from Meiji Seika Kaisha, grants and personal fees from Chugai Pharma, outside the submitted work, S. Matsumoto reports grants from MSD, during the conduct of the study; grants from Novartis, grants from Chugai Pharma, grants from Merck, outside the submitted work, K. Yoh reports grants from MSD, during the conduct of the study; grants and personal fees from Chugai Pharma, grants and personal fees from AstraZeneca, grants and personal fees from Lilly, personal fees from Boehringer Ingelheim, grants and personal fees from Ono Pharmaceutical, grants and personal fees from Novartis, grants from Bayer, grants from Pfizer, grants and personal fees from MSD, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Taiho Pharmaceutical, personal fees from Kyowa Kirin, grants and personal fees from Daiichi Sankyo, grants from Takeda, outside the submitted work, S. Niho reports grants and personal fees from MSD, during the conduct of the study; grants and personal fees from AstraZeneca, grants and personal fees from Pfizer, grants and personal fees from Eli Lilly, grants and personal fees from Chugai, personal fees from Boehringer Ingelheim, personal fees from Taiho, personal fees from Bristol Myers Squibb, personal fees from Novartis, personal fees from Shionogi, personal fees from Ono, grants from Merck Biopharma, outside the submitted work, K. Goto reports grants and personal fees from MSD K.K., during the conduct of the study; grants and personal fees from AstraZeneca K.K, grants and personal fees from Pfizer Japan Inc., grants from Merck Biopharma Co., Ltd., grants and personal fees from Eli Lilly Japan K.K., grants from Xcoo, Inc., grants and personal fees from Thermo Fisher Scientific K.K., grants and personal fees from Ono Pharmaceutical Co., Ltd., grants and personal fees from Novartis Pharma K.K., grants and personal fees from TAIHO PHARMACEUTICAL CO., LTD., grants and personal fees from CHUGAI PHARMACEUTICAL CO., LTD., grants and personal fees from Nippon Boehringer lngelheim Co., Ltd., grants and personal fees from Takeda Pharmaceutical Company Limited, personal fees from Otsuka Pharmaceutical Co., Ltd., grants from Astellas Pharma Inc., grants from Guardant Health Inc., grants and personal fees from Janssen Pharmaceutical K.K., grants and personal fees from Kyowa Kirin Co., Ltd., grants and personal fees from DAIICHI SANKYO Co., Ltd., grants from Eisai Co., Ltd, grants from Sumitomo Dainippon Pharma Co., Ltd., grants from RIKEN GENESIS CO., LTD., grants from Ignyta,Inc., grants from Loxo Oncology, Inc., grants from Sysmex Corporation, grants from MEDICAL & BIOLOGICAL LABORATORIES CO., LTD., grants from Amgen Inc, outside the submitted work, G. Ishii reports grants from Miraca holdings, grants from Ono, grants from Daiichisankyo, outside the submitted work. The remaining authors declare no conflict of interest.

Ethics approval

This study was conducted with the approval of the Institutional Review Board of the National Cancer Center. The approval number for this study was 2019-098 and 2018-134. All the methods were performed in accordance with the approved guidelines.

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All the specimens and data were collected after obtaining written comprehensive informed consent from the patients.

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Sakai, T., Udagawa, H., Matsumoto, S. et al. Morphological, immune and genetic features in biopsy sample associated with the efficacy of pembrolizumab in patients with non-squamous non-small cell lung cancer. J Cancer Res Clin Oncol 147, 1227–1237 (2021). https://doi.org/10.1007/s00432-020-03413-5

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