Cancer cachexia as a determinant of efficacy of first‑line pembrolizumab in patients with advanced non‑small cell lung cancer

Fujii,Hironori; Araki,Ayumu; Iihara,Hirotoshi; Kaito,Daizo; Hirose,Chiemi; Kinomura,Motohiko; Yamazaki,Mizuki; Endo,Junki; Inui,Toshiya; Yanase,Komei; Sasaki,Yuka; Gomyo,Takenobu; Sakai,Chizuru; Kawae,Daisuke; Kitamura,Yu; Fukui,Masachika; Kobayashi,Ryo; Ohno,Yasushi; Suzuki,Akio

doi:10.3892/mco.2022.2524

Cancer cachexia as a determinant of efficacy of first‑line pembrolizumab in patients with advanced non‑small cell lung cancer

Authors:
- Hironori Fujii
- Ayumu Araki
- Hirotoshi Iihara
- Daizo Kaito
- Chiemi Hirose
- Motohiko Kinomura
- Mizuki Yamazaki
- Junki Endo
- Toshiya Inui
- Komei Yanase
- Yuka Sasaki
- Takenobu Gomyo
- Chizuru Sakai
- Daisuke Kawae
- Yu Kitamura
- Masachika Fukui
- Ryo Kobayashi
- Yasushi Ohno
- Akio Suzuki
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Affiliations: Department of Pharmacy, Gifu University Hospital, Gifu University Graduate School of Medicine, Gifu 501‑1194, Japan, Department of Cardiology and Respirology Medicine, Gifu University Graduate School of Medicine, Gifu 501‑1194, Japan
Published online on: February 24, 2022 https://doi.org/10.3892/mco.2022.2524
Article Number: 91
Copyright: © Fujii et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Pembrolizumab, either as a type of monotherapy or in combination with cytotoxic anticancer agents, is effective in the treatment of advanced non‑small cell lung cancer (NSCLC). However, the development of cancer cachexia may adversely affect anticancer drug therapy. The present study investigated the effect of cancer cachexia on clinical outcomes in patients with advanced NSCLC who received first‑line pembrolizumab. The data of patients with advanced NSCLC receiving first‑line monotherapy or combination therapy with pembrolizumab were retrospectively analyzed. The primary endpoint was time to treatment failure (TTF), and the secondary endpoints were overall survival (OS) and incidence of adverse events (AEs). Clinical outcome was compared between patients with and without cancer cachexia. A total of 53 patients were analyzed. Among all patients, median TTF and OS were significantly shorter in patients with cancer cachexia than in those without [TTF: 5.8 vs. 10 months; hazard ratio (HR): 2.13; 95% confidence interval (CI): 1.07‑4.24; P=0.016; OS: 12.1 months vs. not reached; HR: 5.85; 95% CI: 2.0‑17.1; P=0.001]. In addition, TTF in the pembrolizumab monotherapy group was significantly shorter in patients with cancer cachexia than in those without, but no significant difference was detected in patients receiving pembrolizumab combination therapy. The incidence of AEs did not significantly differ between patients with and without cancer cachexia, except with regard to hypothyroidism. In conclusion, although cancer cachexia is prognostic of a poor outcome in patients with advanced NSCLC who receive first‑line pembrolizumab, cancer cachexia might not affect therapeutic efficacy in combination therapy with pembrolizumab and cytotoxic anticancer agents.

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1	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021.PubMed/NCBI View Article : Google Scholar
2	Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, et al: Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomised phase 3 trial. Lancet Oncol. 11:121–128. 2010.PubMed/NCBI View Article : Google Scholar
3	Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, et al: Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 12:735–742. 2011.PubMed/NCBI View Article : Google Scholar
4	Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, et al: Phase Ⅲ study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 31:3327–3334. 2013.PubMed/NCBI View Article : Google Scholar
5	Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, et al: First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 371:2167–2177. 2014.PubMed/NCBI View Article : Google Scholar
6	Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, Riely GJ, Varella-Garcia M, Shapiro GI, Costa DB, et al: Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 371:1963–1971. 2014.PubMed/NCBI View Article : Google Scholar
7	Planchard D, Smit EF, Groen HJM, Mazieres J, Besse B, Helland Å, Giannone V, D'Amelio AM Jr, Zhang P, Mookerjee B and Johnson BE: Dabrafenib plus trametinib in patients with previously treated BRAF (V600E)-mutant metastatic non-small cell lung cancer: An open-label, multicentre phase 2 trial. Lancet Oncol. 18:1307–1316. 2017.PubMed/NCBI View Article : Google Scholar
8	Paik PK, Felip E, Veillon R, Sakai H, Cortot AB, Garassino MC, Mazieres J, Viteri S, Senellart H, Van Meerbeeck J, et al: Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations. N Engl J Med. 383:931–943. 2020.PubMed/NCBI View Article : Google Scholar
9	Wolf J, Seto T, Han JY, Reguart N, Garon EB, Groen HJM, Tan DSW, Hida T, de Jonge M, Orlov SV, et al: Capmatinib (INC280) in METΔex14-mutated advanced non-small cell lung cancer (NSCLC): Efficacy data from the phase Ⅱ GEOMETRY mono-1 study. J Clin Oncol. 37 (Suppl 15)(9004)2019.PubMed/NCBI View Article : Google Scholar
10	Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, et al: Pembrolizumab versus Chemotherapy for PD-L1-Positive non-small-cell lung cancer. N Engl J Med. 375:1823–1833. 2016.PubMed/NCBI View Article : Google Scholar
11	Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, et al: Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 378:2078–2092. 2018.PubMed/NCBI View Article : Google Scholar
12	Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, Hermes B, Çay Şenler F, Csőszi T, Fülöp A, et al: Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 379:2040–2051. 2018.PubMed/NCBI View Article : Google Scholar
13	National Comprehensive Cancer Network (NCCN): Clinical Practice Guidelines in Oncology (NCCN Guidelines^®). Non-Small Cell Lung Cancer. Version 5.2021. NCCN, Plymouth Meeting, PA, 2021. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.
14	Nakamura Y: Biomarkers for immune checkpoint inhibitor-mediated tumor response and adverse events. Front Med (Lausanne). 6(119)2019.PubMed/NCBI View Article : Google Scholar
15	Schildhaus HU: Predictive value of PD-L1 diagnostics. Pathologe. 39:498–519. 2018.PubMed/NCBI View Article : Google Scholar
16	Lagos GG, Izar B and Rizvi NA: Beyond tumor PD-L1: Beyond tumor PD-L1: Emerging genomic biomarkers for checkpoint inhibitor immunotherapy. Am Soc Clin Oncol Educ Book. 40:1–11. 2020.PubMed/NCBI View Article : Google Scholar
17	Chindaprasirt J: Sarcopenia in cancer patients. Asian Pac J Cancer Prev. 16:8075–8077. 2015.PubMed/NCBI View Article : Google Scholar
18	Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, Jatoi A, Loprinzi C, MacDonald N, Mantovani G, et al: Definition and classification of cancer cachexia: An international consensus. Lancet Oncol. 12:489–495. 2011.PubMed/NCBI View Article : Google Scholar
19	Roch B, Coffy A, Jean-Baptiste S, Palaysi E, Daures JP, Pujol JL and Bommart S: Cachexia-sarcopenia as a determinant of disease control rate and survival in non-small lung cancer patients receiving immune-checkpoint inhibitors. Lung Cancer. 143:19–26. 2020.PubMed/NCBI View Article : Google Scholar
20	Nishioka N, Uchino J, Hirai S, Katayama Y, Yoshimura A, Okura N, Tanimura K, Harita S, Imabayashi T, Chihara Y, et al: Association of sarcopenia with and efficacy of anti-PD-1/PD-L1 therapy in non-small-cell lung cancer. J Clin Med. 8(450)2019.PubMed/NCBI View Article : Google Scholar
21	Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al: New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 45:228–247. 2009.PubMed/NCBI View Article : Google Scholar
22	U.S. Department of Health and Human Services, National Institutes of Health National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE). Version 4.0. https://www.eortc.be/services/doc/ctc/. Accessed September 1, 2018.
23	Shiroyama T, Nagatomo I, Koyama S, Hirata H, Nishida S, Miyake K, Fukushima K, Shirai Y, Mitsui Y, Takata S, et al: Impact of sarcopenia in patients with advanced non-small cell lung cancer treated with PD-1 inhibitors: A preliminary retrospective study. Sci Rep. 9(2447)2019.PubMed/NCBI View Article : Google Scholar
24	Peixoto da Silva S, Santos JMO, Costa E Silva MP, Gil da Costa RM and Medeiros R: Cancer cachexia and its pathophysiology: Links with sarcopenia, anorexia and asthenia. J Cachexia Sarcopenia Muscle. 11:619–635. 2020.PubMed/NCBI View Article : Google Scholar
25	Sanders KJ, Hendriks LE, Troost EG, Bootsma GP, Houben RM, Schols AM and Dingemans AM: Early weight loss during chemoradiotherapy has a detrimental impact on outcome in NSCLC. J Thorac Oncol. 11:873–879. 2016.PubMed/NCBI View Article : Google Scholar
26	Ross PJ, Ashley S, Norton A, Priest K, Waters JS, Eisen T, Smith IE and O'Brien ME: Do patients with weight loss have a worse outcome when undergoing chemotherapy for lung cancers? Br J Cancer. 90:1905–1911. 2004.PubMed/NCBI View Article : Google Scholar
27	Petruzzelli M and Wagner EF: Mechanisms of metabolic dysfunction in cancer-associated cachexia. Genes Dev. 30:489–501. 2016.PubMed/NCBI View Article : Google Scholar
28	Flint TR, Janowitz T, Connell CM, Roberts EW, Denton AE, Coll AP, Jodrell DI and Fearon DT: Tumor-Induced IL-6 reprograms host metabolism to suppress anti-tumor immunity. Cell Metab. 24:672–684. 2016.PubMed/NCBI View Article : Google Scholar
29	Katakami N, Uchino J, Yokoyama T, Naito T, Kondo M, Yamada K, Kitajima H, Yoshimori K, Sato K, Saito H, et al: Anamorelin (ONO-7643) for the treatment of patients with non-small cell lung cancer and cachexia: Results from a randomized, double-blind, placebo-controlled, multicenter study of Japanese patients (ONO-7643-04). Cancer. 124:606–616. 2018.PubMed/NCBI View Article : Google Scholar
30	Osorio JC, Ni A, Chaft JE, Pollina R, Kasler MK, Stephens D, Rodriguez C, Cambridge L, Rizvi H, Wolchok JD, et al: Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. Ann Oncol. 28:583–589. 2017.PubMed/NCBI View Article : Google Scholar