Skip to main content

Advertisement

SpringerLink
Log in

Efficacy and safety of pembrolizumab as first-line therapy in advanced non-small cell lung cancer with at least 50% PD-L1 positivity: a multicenter retrospective cohort study (HOPE-001)

  • PHASE III STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Objectives As first line therapy, pembrolizumab provides longer progression free survival (PFS) and overall survival (OS) than platinum doublets in programmed death ligand 1 (PD-L1)-positive non-small cell lung cancer (NSCLC) with tumor propensity scores (TPS) ≥50%. However, clinical trials do not represent real-world patients. Materials and Methods This multicenter retrospective study conducted across 11 medical centers in Japan analyzed clinical data from patients receiving first-line pembrolizumab for NSCLC between February 1, 2017 and April 30, 2018. The efficacy, safety, and suitability of pembrolizumab monotherapy were evaluated. Results The median age of the 213 enrolled patients was 71 (range: 39–91) years. Among them, 176 (82.6%) were male, 20 (9.4%) were never smokers (median Brinkman index: 900), 172 (80.8%) had an ECOG PS of 0–1, 55 (25.8%) had squamous-cell carcinoma (SQ). PD-L1 TPS were 50–74%, 75–89%, and 90–100% in 97 (45.5%), 47 (22.1%), and 69 (32.4%) patients, respectively. Adverse events (AEs) of grades ≥3 were observed in 39 (18.3%) patients. Pneumonitis was the most common severe AE, occurring in 10 patients (4.7%) including 1 with grade 4 toxicity; no severe AE-related deaths occurred. The overall response rate, median PFS, and median OS was 51.2%, 8.3 months, and 17.8 months, respectively. On multivariate analysis, ECOG PS (0–1 vs. ≥2: HR: 1.69, 95.0% CI: 1.05–2.72; p = 0.03138), CRP/Alb (<0.3 vs. ≥0.3: HR: 1.92, 95.0% CI: 1.28–2.87; p = 0.00153), steroid usage (not usage vs. usage: HR: 2.94, 95.0% CI: 1.45–5.95; p = 0.00267), and PD-L1 TPS (50–89% vs. 90–100%: HR: 0.65, 95.0% CI: 0.43–1.00; p = 0.04984) were significantly and independently correlated with PFS of pembrolizumab. Conclusion The results confirm the efficacy and safety of pembrolizumab in real-world patients. Poor PS and steroid usage at the time of commencing pembrolizumab treatment indicate poor outcomes. First-line pembrolizumab particularly benefits patients with PD-L1 TPS ≥90% or low inflammatory states (CRP/ALB<0.3).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Spiro SG, Porter JC (2002) Lung cancer--where are we today? Current advances in staging and nonsurgical treatment. Am J Respir Crit Care Med 166:1166–1196. https://doi.org/10.1164/rccm.200202-070SO

    Article  PubMed  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin 67:7–30. https://doi.org/10.3322/caac.21387

    Article  PubMed  Google Scholar 

  3. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264. https://doi.org/10.1038/nrc3239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Melosky B, Chu Q, Juergens R, Leighl N, McLeod D, Hirsh V (2016) Pointed Progress in second-line advanced non-Small-cell lung Cancer: the rapidly evolving field of checkpoint inhibition. J Clin Oncol 34:1676–1688. https://doi.org/10.1200/JCO.2015.63.8049

    Article  CAS  PubMed  Google Scholar 

  5. Francisco LM, Sage PT, Sharpe AH (2010) The PD-1 pathway in tolerance and autoimmunity. Immunol Rev 236:219–242. https://doi.org/10.1111/j.1600-065X.2010.00923.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8:793–800. https://doi.org/10.1038/nm730

    Article  CAS  PubMed  Google Scholar 

  7. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N (2002) Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A 99:12293–12297. https://doi.org/10.1073/pnas.192461099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Greenwald RJ, Freeman GJ, Sharpe AH (2005) The B7 family revisited. Annu Rev Immunol 23:515–548. https://doi.org/10.1146/annurev.immunol.23.021704.115611

    Article  CAS  PubMed  Google Scholar 

  9. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192:1027–1034. https://doi.org/10.1084/jem.192.7.1027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR (2015) Nivolumab versus docetaxel in advanced nonsquamous non-Small-cell lung Cancer. N Engl J Med 373:1627–1639. https://doi.org/10.1056/NEJMoa1507643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB (2016) 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. https://doi.org/10.1016/S0140-6736(15)01281-7

    Article  CAS  PubMed  Google Scholar 

  12. Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, Cortinovis DL, Leach J, Polikoff J, Barrios C, Kabbinavar F, Frontera OA, De Marinis F, Turna H, Lee JS, Ballinger M, Kowanetz M, He P, Chen DS, Sandler A, Gandara DR (2017) 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. https://doi.org/10.1016/S0140-6736(16)32517-X

    Article  PubMed  Google Scholar 

  13. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csöszi T, Fülöp 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 J (2016) Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 375:1823–1833. https://doi.org/10.1056/NEJMoa1606774

    Article  CAS  PubMed  Google Scholar 

  14. Reck M, Rodríguez–Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O’Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR (2019) Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. J Clin Oncol 37:537–546. https://doi.org/10.1200/JCO.18.00149

    Article  CAS  PubMed  Google Scholar 

  15. Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, Kubota K, Lubiniecki GM, Zhang J, Kush D, Lopes G (2019) 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. 393:1819–1830. https://doi.org/10.1016/S0140-6736(18)32409-7

    Article  CAS  PubMed  Google Scholar 

  16. 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. https://doi.org/10.1056/NEJMoa1801005

    Article  CAS  PubMed  Google Scholar 

  17. Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, Hermes B, Çay Şenler F, Csőszi T, Fülöp A, Rodríguez-Cid J, Wilson J, Sugawara S, Kato T, Lee KH, Cheng Y, Novello S, Halmos B, Li X, Lubiniecki GM, Piperdi B, Kowalski DM (2018) Pembrolizumab plus chemotherapy for squamous non-Small-cell lung Cancer. N Engl J Med 379:2040–2051. https://doi.org/10.1056/NEJMoa1810865

    Article  CAS  PubMed  Google Scholar 

  18. Fuks A, Weijer C, Freedman B, Shapiro S, Skrutkowska M, Riaz A (1998) A study in contrasts: eligibility criteria in a twenty-year sample of NSABP and POG clinical trials. National Surgical Adjuvant Breast and Bowel Program Pediatric Oncology Group. J Clin Epidemiol 51:69–79. https://doi.org/10.1016/S0895-4356(97)00240-0

    Article  CAS  PubMed  Google Scholar 

  19. A.M. Denicoff, W. McCaskill-Stevens, S.S. Grubbs, S.S. Bruinooge, R.L. Comis, P. Devine, D. M. Dilts, M.E. Duff, J.G. Ford, S. Joffe, L. Schapira, K.P. Weinfurt, M. Michaels, D. Raghavan, E.S. Richmond, R. Zon, T.L. Albrecht, M.A. Bookman, A. Dowlati, R.A. Enos, , M. N. Fouad, M. Good, W.J. Hicks, P.J. Loehrer, Sr, A.P. Lyss, S.N. Wolff, D.M. Wujcik, N.J. Meropol. The National Cancer Institute-American Society of Clinical Oncology Cancer trial accrual symposium: summary and recommendations. J Oncol Pract 9 (2013): 267–276. doi: https://doi.org/10.1200/JOP.2013.001119.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Baggstrom MQ, Waqar SN, Sezhiyan AK, Gilstrap E, Gao F, Morgensztern D, Govindan R (2011) Barriers to enrollment in non-small cell lung cancer therapeutic clinical trials. J Thorac Oncol 6:98–102. https://doi.org/10.1097/JTO.0b013e3181fb50d8

    Article  PubMed  Google Scholar 

  21. Kawachi H, Fujimoto D, Morimoto T, Ito M, Teraoka S, Sato Y, Nagata K, Nakagawa A, Otsuka K, Tomii K (2018) Clinical characteristics and prognosis of patients with advanced non-Small-cell lung Cancer who are ineligible for clinical trials. Clin Lung Cancer. 19:e721–e734. https://doi.org/10.1016/j.cllc.2018.05.014

    Article  PubMed  Google Scholar 

  22. Vardy J, Dadasovich R, Beale P, Boyer M, Clarke SJ (2009) Eligibility of patients with advanced non-small cell lung cancer for phase III chemotherapy trials. BMC Cancer 9:130. https://doi.org/10.1186/1471-2407-9-130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zukin M, Barrios CH, Pereira JR, De R, Ribeiro A, Beato CA, do Nascimento YN, Murad A, Franke FA, Precivale M, Araujo LH, Baldotto CS, Vieira FM, Small IA, Ferreira CG, Lilenbaum RC (2013) Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung cancer and eastern cooperative oncology group performance status of 2. J Clin Oncol 31:2849–2853. https://doi.org/10.1200/JCO.2012.48.1911.

    Article  CAS  PubMed  Google Scholar 

  24. Langer C, Li S, Schiller J, Tester W, Rapoport BL, Johnson DH (2007) Randomized phase II trial of paclitaxel plus carboplatin or gemcitabine plus cisplatin in eastern cooperative oncology group performance status 2 non-small-cell lung cancer patients: ECOG 1599. J Clin Oncol 25:418–423. https://doi.org/10.1200/JCO.2005.04.9452

    Article  CAS  PubMed  Google Scholar 

  25. Fujimoto D, Yoshioka H, Kataoka Y, Morimoto T, Kim YH, Tomii K, Ishida T, Hirabayashi M, Hara S, Ishitoko M, Fukuda Y, Hwang MH, Sakai N, Fukui M, Nakaji H, Morita M, Mio T, Yasuda T, Sugita T, Hirai T (2018) Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: a multicenter retrospective cohort study. Lung Cancer 119:14–20. https://doi.org/10.1016/j.lungcan.2018.02.017

    Article  PubMed  Google Scholar 

  26. Inoue T, Tamiya M, Tamiya A, Nakahama K, Taniguchi Y, Shiroyama T, Isa SI, Nishino K, Kumagai T, Kunimasa K, Kimura M, Suzuki H, Hirashima T, Atagi S, Imamura F (2018) Analysis of early death in Japanese patients with advanced non-small-cell lung Cancer treated with Nivolumab. Clin Lung Cancer 19:e171–e176. https://doi.org/10.1016/j.cllc.2017.09.002

    Article  CAS  PubMed  Google Scholar 

  27. Wei XL, Wang FH, Zhang DS, Qiu MZ, Ren C, Jin Y, Zhou YX, Wang DS, He MM, Bai L, Wang F, Luo HY, Li YH, Xu RH (2015) A novel inflammation-based prognostic score in esophageal squamous cell carcinoma: the C-reactive protein/albumin ratio. BMC Cancer 15:350. https://doi.org/10.1186/s12885-015-1379-6

    Article  PubMed  PubMed Central  Google Scholar 

  28. Kinoshita A, Onoda H, Imai N, Iwaku A, Oishi M, Tanaka K, Fushiya N, Koike K, Nishino H, Matsushima M (2015) The C-reactive protein/albumin ratio, a novel inflammation-based prognostic score, predicts outcomes in patients with hepatocellular carcinoma. Ann Surg Oncol 22:803–810. https://doi.org/10.1245/s10434-014-4048-0

    Article  PubMed  Google Scholar 

  29. Zhang F, Ying L, Jin J, Chen K, Zhang N, Wu J, Zhang Y, Su D (2017) The C-reactive protein/albumin ratio predicts long-term outcomes of patients with operable non-small cell lung cancer. Oncotarget. 8:8835–8842. https://doi.org/10.18632/oncotarget.13053

    Article  PubMed  Google Scholar 

  30. Arbour KC, Mezquita L, Long N, Rizvi H, Auclin E, Ni A, Martínez-Bernal G, Ferrara R, Lai WV, Hendriks LEL, Sabari JK, Caramella C, Plodkowski AJ, Halpenny D, Chaft JE, Planchard D, Riely GJ, Besse B, Hellmann MD (2018) Impact of baseline steroids on efficacy of programmed cell Death-1 and programmed death-ligand 1 blockade in patients with non-Small-cell lung Cancer. J Clin Oncol 36:2872–2878. https://doi.org/10.1200/JCO.2018.79.0006

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank all the patients who participated in this study.

Author information

Authors and Affiliations

  1. Department of Thoracic Oncology, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka City, Osaka, 541-8567, Japan

    Motohiro Tamiya & Toru Kumagai

  2. Department of Internal Medicine, National Hospital Organization Kinki-Chuo Chest Medical Center, 1180, Nagasone-cho, Kita-ku, Sakai City, Osaka, 591-8555, Japan

    Akihiro Tamiya & Yoshihiko Taniguchi

  3. Department of Respiratory Medicine, Kobe City Medical Center General Hospital, 2-1-1 Minatojimaminamimachi, Chuo-ku, Kobe City, Hyogo, 650-0047, Japan

    Kazutaka Hosoya & Daichi Fujimoto

  4. Department of Respiratory Medicine, Kurashiki Central Hospital, 1-1-1, Miwa, Kurashiki City, Okayama, 710-8602, Japan

    Toshihide Yokoyama & Yasushi Fukuda

  5. Department of Respiratory Medicine, Hyogo Prefectural Amagasaki General Medical Center, 2-17-77, Higashi-Naniwa-Cho, Amagasaki City, Hyogo, 660-8550, Japan

    Katsuya Hirano & Hirotaka Matsumoto

  6. Department of Respiratory Medicine, National Hospital Organization Himeji Medical Center, 68, Honmachi, Himeji City, Hyogo, 670-8520, Japan

    Ryota Kominami

  7. Department of Thoracic Malignancy, Osaka Habikino Medical Center, 3-7-1, Habikino, Habikino City, Osaka, 583-8588, Japan

    Hidekazu Suzuki & Tomonori Hirashima

  8. Department of Respiratory Medicine, Osaka General Medical Center, 3-1-56, Bandai-Higashi, Sumiyoshi-ku, Osaka City, Osaka, 558-8558, Japan

    Junji Uchida

  9. Department of Respiratory Medicine, Kobe City Medical Center West Hospital, 2-4, Ichiban-cho, Nagata-ku, Kobe City, Hyogo, 653-0013, Japan

    Mitsunori Morita

  10. Department of Thoracic Oncology, National Hospital Organization Osaka Toneyama Medical Center, 5-1-1, Toneyama, Toyonaka City, Osaka, 560-0045, Japan

    Masaki Kanazu & Nobuhiko Sawa

  11. Department of Respiratory Medicine, Itami City Hospital, 1-100, Koyaike, Itami City, Hyogo, 664-8540, Japan

    Yoshinori Kinoshita & Satoshi Hara

Authors
  1. Motohiro Tamiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Akihiro Tamiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kazutaka Hosoya
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoshihiko Taniguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Toshihide Yokoyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yasushi Fukuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Katsuya Hirano
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hirotaka Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ryota Kominami
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hidekazu Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tomonori Hirashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Junji Uchida
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Mitsunori Morita
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Masaki Kanazu
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Nobuhiko Sawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Yoshinori Kinoshita
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Satoshi Hara
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Toru Kumagai
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Daichi Fujimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Motohiro Tamiya.

Ethics declarations

Disclosure of potential conflicts of interest

Drs. M. Tamiya, A. Tamiya, Fujimoto, Hirano, and Kumagai have received lecture fees from Taiho Pharmaceutical Co., Ltd. (Tokyo, Japan) and Merck Sharp & Dohme, Corp. (Tokyo, Japan). Drs. Yokoyama and Hirashima have received lecture fees from Taiho Pharmaceutical Co., Ltd. (Tokyo, Japan). Drs. Taniguchi, Ishida and Kanazu have received lecture fees from Merck Sharp & Dohme, Corp. (Tokyo, Japan). The remaining authors have no conflicts of interest to declare.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

For this type of study, formal consent is not required.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tamiya, M., Tamiya, A., Hosoya, K. et al. Efficacy and safety of pembrolizumab as first-line therapy in advanced non-small cell lung cancer with at least 50% PD-L1 positivity: a multicenter retrospective cohort study (HOPE-001). Invest New Drugs 37, 1266–1273 (2019). https://doi.org/10.1007/s10637-019-00843-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-019-00843-y

Keywords

Search

Navigation