Optimal Therapeutic Strategy for PD-L1 Negative Metastatic Non-Small Cell Lung Cancer: A Decision-Making Guide Based on Clinicopathological and Molecular Features

Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17–48.

Article  PubMed  Google Scholar 

Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, et al. The 2015 World Health Organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol. 2015;10(9):1243–60.

Article  PubMed  Google Scholar 

Thai AA, Solomon BJ, Sequist LV, Gainor JF, Heist RS. Lung cancer. Lancet. 2021;398(10299):535–54.

Article  PubMed  Google Scholar 

Howlader N, Forjaz G, Mooradian MJ, Meza R, Kong CY, Cronin KA, et al. The effect of advances in lung-cancer treatment on population mortality. N Engl J Med. 2020;383(7):64–9.

Article  Google Scholar 

Rami-Porta R, Call S, Dooms C, Obiols C, Sánchez M, Travis WD, et al. Lung cancer staging: a concise update. Eur Respir J [Internet]. 2018 May;51(5). Available from: https://doi.org/10.1183/13993003.00190-2018

Jones GS, Baldwin DR. Recent advances in the management of lung cancer. Clin Med. 2018;18(Suppl 2):s41–6.

Article  Google Scholar 

Minguet J, Smith KH, Bramlage P. Targeted therapies for treatment of non-small cell lung cancer--recent advances and future perspectives. Int J Cancer. 2016;138(11):2549–61.

Article  CAS  PubMed  Google Scholar 

Havel JJ, Chowell D, Chan TA. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat Rev Cancer. 2019;19(3):133–50.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Baumeister SH, Freeman GJ, Dranoff G, Sharpe AH. Coinhibitory pathways in immunotherapy for cancer. Annu Rev Immunol. 2016;20(34):539–73.

Article  Google Scholar 

Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078–92.

Article  CAS  PubMed  Google Scholar 

Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018;379(21):2040–51.

Article  CAS  PubMed  Google Scholar 

Herbst RS, Baas P, Kim D-W, Felip E, Pérez-Gracia JL, Han J-Y, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540–50.

Article  CAS  PubMed  Google Scholar 

Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, 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. 2017;389(10066):255–65.

Article  PubMed  Google Scholar 

Vokes EE, Ready N, Felip E, Horn L, Burgio MA, Antonia SJ, et al. Nivolumab versus docetaxel in previously treated advanced non-small-cell lung cancer (CheckMate 017 and CheckMate 057): 3-year update and outcomes in patients with liver metastases. Ann Oncol. 2018;29(4):959–65.

Article  CAS  PubMed  Google Scholar 

• Garassino MC, Gadgeel S, Speranza G, Felip E, Esteban E, Dómine M, et al. Pembrolizumab plus pemetrexed and platinum in nonsquamous non-small-cell lung cancer: 5-year outcomes from the phase 3 KEYNOTE-189 study. J Clin Oncol. 2023 41(11):1992–8. 5-year outcomes from the phase 3 KEYNOTE-189 study, a randomized phase III which supports pembrolizumab plus pemetrexed-platinum as a standard of care in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations.

Rodríguez-Abreu D, Powell SF, Hochmair MJ, Gadgeel S, Esteban E, Felip E, et al. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Ann Oncol. 2021;32(7):881–95.

Article  PubMed  Google Scholar 

• Paz-Ares L, Ciuleanu T-E, Cobo M, Schenker M, Zurawski B, Menezes J, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Feb;22(2):198–211. Randomized, open-label, phase 3 trial that supports nivolumab plus ipilimumab with two cycles of chemotherapy as a first-line treatment option for patients with advanced NSCLC.

•• Reck M, Ciuleanu T-E, Cobo M, Schenker M, Zurawski B, Menezes J, et al. First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update. ESMO Open. 2021 Oct;6(5):100273. The CheckMate 9LA 2-year follow-up where nivolumab plus ipilimumab with two cycles of chemotherapy demonstrated durable efficacy benefits over chemotherapy with a manageable safety profile for advanced non-small-cell lung cancer.

Marcus L, Fashoyin-Aje LA, Donoghue M, Yuan M, Rodriguez L, Gallagher PS, et al. FDA approval summary: pembrolizumab for the treatment of tumor mutational burden-high solid tumors. Clin Cancer Res. 2021;27(17):4685–9.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hellmann MD, Paz-Ares L, Bernabe Caro R, Zurawski B, Kim S-W, Carcereny Costa E, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med. 2019;381(21):2020–31.

Article  CAS  PubMed  Google Scholar 

•• Paz-Ares L, Vicente D, Tafreshi A, Robinson A, Soto Parra H, Mazières J, et al. A randomized, placebo-controlled trial of pembrolizumab plus chemotherapy in patients with metastatic squamous NSCLC: protocol-specified final analysis of KEYNOTE-407. J Thorac Oncol. 2020 Oct;15(10):1657–69. An update of the efficacy of pembrolizumab plus carboplatin and paclitaxel/nab-paclitaxel (chemotherapy) that significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus chemotherapy in patients with previously untreated metastatic squamous NSCLC (KEYNOTE-407 study).

Novello S, Kowalski DM, Luft A, Gümüş M, Vicente D, Mazières J, et al. Pembrolizumab plus chemotherapy in squamous non-small-cell lung cancer: 5-year update of the phase III KEYNOTE-407 Study. J Clin Oncol. 2023;41(11):1999–2006.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Yang Y, Wang Z, Fang J, Yu Q, Han B, Cang S, et al. Efficacy and safety of sintilimab plus pemetrexed and platinum as first-line treatment for locally advanced or metastatic nonsquamous NSCLC: a randomized, double-blind, phase 3 study (Oncology pRogram by InnovENT anti-PD-1-11). J Thorac Oncol. 2020;15(10):1636–46.

Article  CAS  PubMed  Google Scholar 

Zhou C, Wu L, Fan Y, Wang Z, Liu L, Chen G, et al. Sintilimab plus platinum and gemcitabine as first-line treatment for advanced or metastatic squamous NSCLC: results from a randomized, double-blind, phase 3 trial (ORIENT-12). J Thorac Oncol. 2021;16(9):1501–11.

Article  CAS  PubMed  Google Scholar 

West H, McCleod M, Hussein M, Morabito A, Rittmeyer A, Conter HJ, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(7):924–37.

Article  CAS  PubMed  Google Scholar 

Jotte R, Cappuzzo F, Vynnychenko I, Stroyakovskiy D, Rodríguez-Abreu D, Hussein M, et al. Atezolizumab in combination with carboplatin and nab-paclitaxel in advanced squamous NSCLC (IMpower131): results from a randomized phase III trial. J Thorac Oncol. 2020;15(8):1351–60.

Article  CAS  PubMed  Google Scholar 

Nishio M, Barlesi F, West H, Ball S, Bordoni R, Cobo M, et al. Atezolizumab plus chemotherapy for first-line treatment of nonsquamous NSCLC: results from the randomized phase 3 IMpower132 trial. J Thorac Oncol. 2021;16(4):653–64.

Article  CAS  PubMed  Google Scholar 

Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288–301.

Article  CAS  PubMed  Google Scholar 

Brahmer JR, Lee J-S, Ciuleanu T-E, Bernabe Caro R, Nishio M, Urban L, et al. Five-year survival outcomes with nivolumab plus ipilimumab versus chemotherapy as first-line treatment for metastatic non-small-cell lung cancer in CheckMate 227. J Clin Oncol. 2023;41(6):1200–12.

Article  CAS  PubMed  Google Scholar 

• Johnson ML, Cho BC, Luft A, Alatorre-Alexander J, Geater SL, Laktionov K, et al. Durvalumab with or without tremelimumab in combination with chemotherapy as first-line therapy for metastatic non-small-cell lung cancer: the phase III POSEIDON study. J Clin Oncol. 2023;41(6):1213–27. An open-label, phase III study that demonstrated the significant improvement of OS and PFS obtained with tremelimumab plus durvalumab and chemotherapy versus durvalumab plus chemotherapy and versus chemotherapy alone in metastatic NSCLC.

Gogishvili M, Melkadze T, Makharadze T, Giorgadze D, Dvorkin M, Penkov K, et al. Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: a randomized, controlled, double-blind phase 3 trial. Nat Med. 2022;28(11):2374–80.

Article  CAS  PubMed  PubMed Central  Google Scholar 

•• Di Federico A, De Giglio A, Gelsomino F, Sperandi F, Melotti B, Ardizzoni A. Predictors of survival to immunotherapy and chemoimmunotherapy in non-small cell lung cancer: a meta-analysis. J Natl Cancer Inst. 2023;115(1):29–42. A systematic analysis of 25 randomized trials that suggests taking into account clinicopathological data such as histology, sex and smoker status, and molecular features such as PD-L1 expression and tumor mutational burden to define the most beneficial first-line ICI-based option for advanced NSCLC patients.

Borghaei H, Langer CJ, Paz-Ares L, Rodríguez-Abreu D, Halmos B, Garassino MC, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced non-small cell lung cancer without tumor PD-L1 expression: a pooled analysis of 3 randomized controlled trials. Cancer. 2020;126(22):4867–77.

Article  CAS  PubMed  Google Scholar 

Ba H, Liu L, Peng Q, Chen J, Zhu Y-D. The relationship between blood-based tumor mutation burden level and efficacy of PD-1/PD-L1 inhibitors in advanced non-small cell lung cancer: a systematic review and meta-analysis. BMC Cancer. 2021;21(1):1220.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Rizvi NA, Cho BC, Reinmuth N, Lee KH, Luft A, Ahn M-J, et al. Durvalumab with or without tremelimumab vs standard chemotherapy in first-line treatment of metastatic non-small cell lung cancer: the MYSTIC phase 3 randomized clinical trial. JAMA Oncol. 2020;6(5):661–74.

Article  PubMed  PubMed Central  Google Scholar 

de Castro Junior G et al. HRLGKDNMWY-L. Association between tissue TMB (tTMB) and clinical outcomes with pembrolizumab monotherapy (pembro) in PD-L1-positive advanced NSCLC in the KEYNOTE-010 and -042 trials [Internet]. Available from: https://doi.org/10.1093/annonc/mdz394.077

Castellanos E, Snider J, Ali SM, Backenroth D, Albacker LA, Murugesan K, et al. Tumor mutational burden (TMB) and PD-L1 expression as predictors of response to immunotherapy (IO) in NSCLC. J Clin Oncol. 2019 37(15_suppl):2630 [Internet]. Available from: https://doi.org/10.1200/JCO.2019.37.15_suppl.2630

Zhang K, Hong X, Song Z, Xu Y, Li C, Wang G, et al. Identification of deleterious NOTCH mutation as novel predictor to efficacious immunotherapy in NSCLC. Clin Cancer Res. 2020;26(14):3649–61.

Article  CAS  PubMed  Google Scholar 

Scheffler M, Ihle MA, Hein R, Merkelbach-Bruse S, Scheel AH, Siemanowski J, et al. K-ras mutation subtypes in NSCLC and associated co-occuring mutations in other oncogenic pathways. J Thorac Oncol. 2019;14(4):606–16.

Article  CAS  PubMed  Google Scholar 

Landre T, Justeau G, Assié J-B, Chouahnia K, Davoine C, Taleb C, et al. Anti-PD-(L)1 for KRAS-mutant advanced non-small-cell lung cancers: a meta-analysis of randomized-controlled trials. Cancer Immunol Immunother. 2022;71(3):719–26.

Article  CAS  PubMed  Google Scholar 

Skoulidis F, Goldberg ME, Greenawalt DM, Hellmann MD, Awad MM, Gainor JF, et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov. 2018;8(7):822–35.

Article 

Comments (0)

No login
gif