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Review
. 2024 Aug 13;8(8):CD015495.
doi: 10.1002/14651858.CD015495.

Immune checkpoint inhibitors plus platinum-based chemotherapy compared to platinum-based chemotherapy with or without bevacizumab for first-line treatment of older people with advanced non-small cell lung cancer

Emeline Orillard  1   2 , Arjab Adhikari  3 , Reem S Malouf  4 , François Calais  5 , Corynne Marchal  6 , Virginie Westeel  2   7
Affiliations
Review

Immune checkpoint inhibitors plus platinum-based chemotherapy compared to platinum-based chemotherapy with or without bevacizumab for first-line treatment of older people with advanced non-small cell lung cancer

Emeline Orillard et al. Cochrane Database Syst Rev. .

Abstract

Background: Lung cancer is a cancer of the elderly, with a median age at diagnosis of 71. More than one-third of people diagnosed with lung cancer are over 75 years old. Immune checkpoint inhibitors (ICIs) are special antibodies that target a pathway in the immune system called the programmed cell death 1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway. These antibodies help the immune system fight cancer cells by blocking signals that cancer cells use to avoid being attacked by the immune system. ICIs have changed the treatment of people with lung cancer. In particular, for people with previously-untreated advanced non-small cell lung cancer (NSCLC), current first-line treatment now comprises ICIs plus platinum-based chemotherapy, rather than platinum-based chemotherapy alone, regardless of their PD-L1 expression status. However, as people age, their immune system changes, becoming less effective in its T cell responses. This raises questions about how well ICIs work in older adults.

Objectives: To assess the effects of immune checkpoint inhibitors (ICIs) in combination with platinum-based chemotherapy compared to platinum-based chemotherapy (with or without bevacizumab) in treatment-naïve adults aged 65 years and older with advanced NSCLC.

Search methods: We searched the Cochrane Lung Cancer Group Trial Register, CENTRAL, MEDLINE, Embase, two other trial registers, and the websites of drug regulators. The latest search date was 23 August 2023. We also checked references and searched abstracts from the meetings of seven cancer organisations from 2019 to August 2023.

Selection criteria: We included randomised controlled trials (RCTs) that reported on the efficacy and safety of adding ICIs to platinum-based chemotherapy compared to platinum-based chemotherapy alone for people 65 years and older who had not previously been treated. All data emanated from international multicentre studies involving adults with histologically-confirmed advanced NSCLC who had not received any previous systemic anticancer therapy for their advanced disease.

Data collection and analysis: We used standard methodological procedures expected by Cochrane. Our primary outcomes were overall survival and treatment-related adverse events (grade 3 or higher). Our secondary outcomes were progression-free survival, objective response rate, time to response, duration of response, and health-related quality of life (HRQoL).

Main results: We included 17 primary studies, with a total of 4276 participants, in the review synthesis. We identified nine ongoing studies, and listed one study as 'awaiting classification'. Twelve of the 17 studies included people older than 75 years, accounting for 9% to 13% of their participants. We rated some studies as having 'some concerns' for risk of bias arising from the randomisation process, deviations from the intended interventions, or measurement of the outcome. The overall GRADE rating for the certainty of the evidence ranged from moderate to low because of the risk of bias, imprecision, or inconsistency. People aged 65 years and older The addition of ICIs to platinum-based chemotherapy probably increased overall survival compared to platinum-based chemotherapy alone (hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.70 to 0.88; 8 studies, 2093 participants; moderate-certainty evidence). Only one study reported data for treatment-related adverse events (grade 3 or higher). The frequency of treatment-related adverse events may not differ between the two treatment groups (risk ratio (RR) 1.09, 95% CI 0.89 to 1.32; 1 study, 127 participants; low-certainty evidence). The addition of ICIs to platinum-based chemotherapy probably improves progression-free survival (HR 0.61, 95% CI 0.54 to 0.68; 7 studies, 1885 participants; moderate-certainty evidence). People aged 65 to 75 years, inclusive The addition of ICIs to platinum-based chemotherapy probably improved overall survival compared to platinum-based chemotherapy alone (HR 0.75, 95% CI 0.65 to 0.87; 6 studies, 1406 participants; moderate-certainty evidence). Only one study reported data for treatment-related adverse events (grade 3 or higher). The frequency of treatment-related adverse events probably increased in people treated with ICIs plus platinum-based chemotherapy compared to those treated with platinum-based chemotherapy alone (RR 1.47, 95% CI 1.02 to 2.13; 1 study, 97 participants; moderate-certainty evidence). The addition of ICIs to platinum-based chemotherapy probably improved progression-free survival (HR 0.64, 95% CI 0.57 to 0.73; 8 studies, 1466 participants; moderate-certainty evidence). People aged 75 years and older There may be no difference in overall survival in people treated with ICIs combined with platinum-based chemotherapy compared to platinum-based chemotherapy alone (HR 0.90, 95% CI 0.70 to 1.16; 4 studies, 297 participants; low-certainty evidence). No data on treatment-related adverse events were available in this age group. The effect of combination ICI and platinum-based chemotherapy on progression-free survival is uncertain (HR 0.83, 95% CI 0.51 to 1.36; 3 studies, 226 participants; very low-certainty evidence). Only three studies assessed the objective response rate. For time to response, duration of response, and health-related quality of life, we do not have any evidence yet.

Authors' conclusions: Compared to platinum-based chemotherapy alone, adding ICIs to platinum-based chemotherapy probably leads to higher overall survival and progression-free survival, without an increase in treatment-related adverse events (grade 3 or higher), in people 65 years and older with advanced NSCLC. These data are based on results from studies dominated by participants between 65 and 75 years old. However, the analysis also suggests that the improvements reported in overall survival and progression-free survival may not be seen in people older than 75 years.

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Conflict of interest statement

Emeline Orillard has declared she has no conflict of interest.

Arjab Adhikari has declared that he has no conflict of interest.

Reem Malouf has declared that she has no conflict of interest.

Francois Calais has declared that he has no conflict of interest. He is Information Specialist for the Cochrane Lung Cancer Group and was not involved in the editorial process.

Corynne Marchal has declared that she has no conflict of interest. She is Managing Editor for the Cochrane Lung Cancer Group and was not involved in the editorial process.

Virginie Westeel reports ‘relationship/activity’ leading to personal payments with AMGEN (speaker bureau, consultancy fees, scientific committee, scientific advisory board and travel expenses); AstraZeneca (scientific advisory board, scientific committee, speaker bureau and travel expenses), Bristol‐Myers‐Squibb (speaker bureau and travel expenses), IPSEN Biopharmaceuticals Inc (board of experts), Janssen pharmaceuticals (travel expenses), Merck Sharp and Dohme (speaker bureau, scientific committee, travel expenses), Roche (scientific committee, speaker bureau and travel expenses, Sanofi (speaker bureau, travel expenses); VW is Coordinating Editor for the Cochrane Lung Cancer Group and was not involved in the editorial process.

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References

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References to studies excluded from this review

Langer 2016 {published data only}
    1. Awad MM, Gadgeel SM, Borghaei H, Patnaik A, Chih-Hsin Yang J, Powell SF, et al. OFP01.02 KEYNOTE-021 cohort G long-term follow-up: first-line (1L) pemetrexed and carboplatin (PC) with or without pembrolizumab for advanced non squamous NSCLC. Journal of Thoracic Oncology 2021;16(S1):S8. [DOI: 10.1016/j.jtho.2020.10.034] - DOI - PubMed
    1. Borghaei H, Langer C, Gadgeel S, Papadimitrakopoulou V, Patnaik A, Powell S, et al. Pemetrexed-carboplatin plus pembrolizumab as first-line therapy for advanced nonsquamous nsclc: keynote-021 cohort g update. Journal of Thoracic Oncology 2017;11(12):S1791.
    1. Borghaei H, Langer CJ, Gadgeel S, Papadimitrakopoulou VA, Patnaik A, Powell SF. 24-month overall survival from KEYNOTE-021 cohort G: pemetrexed and carboplatin with or without pembrolizumab as first-line therapy for advanced nonsquamous non-small cell lung cancer. Journal of Thoracic Oncology 2018;14(1):124-9. [DOI: 10.1016/j.jtho.2018.08.004] - DOI - PubMed
    1. Borghaei H, Langer CJ, Gadgeel S, Papadimitrakopoulu VA, Patnaik A, Powell SF, et al. Updated results from KEYNOTE-021 cohort G: a randomized, phase 2 study of pemetrexed and carboplatin (PC) with or without pembrolizumab (pembro) as first-line therapy for advanced nonsquamous NSCLC. Annals of Oncology 2017;28(suppl 5):v636-7.
    1. Gadgeel SM, Stevenson J, Langer CJ, Gandhi L, Borghaei H, Patnaik A, et al. Pembrolizumab (pembro) plus chemotherapy as front-line therapy for advanced NSCLC: kEYNOTE-021 cohorts A-C. Journal of Clinical Oncology 2016;34(15 suppl):9016.
Li 2021 {published data only}
    1. Li F, Dong X. Pembrolizumab provides long-term survival benefits in advanced non-small cell lung cancer: the 5-year outcomes of the KEYNOTE-024 trial. Thoracic Cancer 2021;12(23):3085-7. - PMC - PubMed
Lynch 2010 {published data only}
    1. Lynch TJ, Bondarenko IN, Luft A, Serwatowski P, Barlesi R, Chacko RT, et al. Phase II trial of ipilimumab (IPI) and paclitaxel/carboplatin (P/C) in first-line stage IIIb/IV non-small cell lung cancer (NSCLC). Journal of Clinical Oncology 2010;28(15 suppl):7531.
Lynch 2012 {published data only}
    1. Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. Journal of Clinical Oncology 2012;30(17):2046-54. - PubMed
Reck 2012 {published data only}
    1. Reck M, Gonzalez-Mella P, Ahn MJ, Ghazal HH, Schneider CP, Jassem J. CA184-104: randomized, multicenter, double-blind, phase III trial comparing the efficacy of ipilimumab (Ipi) with paclitaxel/carboplatin (PC) versus placebo with PC in patients (pts) with stage IV/recurrent non-small cell lung cancer (NSCLC) of squamous histology. Journal of Clinical Oncology 2013;31:(15).
    1. Reck M, Lu H, Gribkoff G, Maier S, McGovern R, Cuillerot JM, et al. CA184-104: randomized, multicenter, double-blind, phase III trial comparing the efficacy of ipilimumab (Ipi) with paclitaxel/carboplatin (PC) versus placebo with PC in patients (pts) with stage IV/recurrent non-small cell lung cancer (NSCLC) of squamous histology. Journal of Clinical Oncology 2012;30(15 suppl):TPS7611.
Yang 2020 {published data only}
    1. NCT03607539. Efficacy and safety evaluation of sintilimab in patients with advanced or recurrent non-squamous NSCLC. https://clinicaltrials.gov/ct2/show/NCT03607539 2018.
    1. 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 non squamous NSCLC: a randomized, double-blind, Phase 3 study (Oncology pRogram by InnovENT anti-PD-1-11). Journal of Thoracic Oncology 2020;15(10):1636-46. [DOI: 10.1016/j.jtho.2020.07.014] - DOI - PubMed
    1. Zhang L, Yang Y, Wang Z, Fang J, Yu Q, Han B, et al. ID: 1329 ORIENT-11: sintilimab + pemetrexed + platinum as first-line therapy for locally advanced or metastatic non-squamous NSCLC. Journal of Thoracic Oncology 2020;15(10 Suppl):e41. [DOI: 10.1016/j.jtho.2020.08.002] - DOI
Zou 2022 {published data only}
    1. Zou J, Li C, Han Y, Xing Y, Zhan Y, Zuo C, Ren X. Efficacy of Camrelizumab in Advanced Non-Small-Cell Lung Cancer and Prognostic Analysis of Different PET/CT Features. Journal of Oncology 2022;2022:9942918. - PMC - PubMed

References to studies awaiting assessment

ORIENT‐12 2020 {published data only}
    1. Zhou C, Wu L, Fan Y, Wang Z, Liu L, Chen G, et al. ORIENT-12: sintilimab plus gemcitabine and platinum (GP) as first-line (1L) treatment for locally advanced or metastatic squamous non-small-cell lung cancer (sqNSCLC). Annals of Oncology 2020;31:S1186. [DOI: 10.1016/j.annonc.2020.08.2289] - DOI
    1. 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). Journal of Thoracic Oncology 2021;16(9):1501-11. [DOI: 10.1016/j.jtho.2021.04.011] - DOI - PubMed

References to ongoing studies

Han 2021 {published data only}
    1. Han B, Chen J, Xie Q, Yao W, Shi H, Zhao Y, et al. P80.01 A multicenter, randomized, phase 3 trial of penpulimab in combination with anlotinib or chemotherapy as first-line treatment in advanced NSCLC. Journal of Thoracic Oncology 2021;16(3 Suppl):S650. [DOI: 10.1016/j.jtho.2021.01.1189] - DOI
Han 2022 {published data only}
    1. Han B, Jiao S, Chen J, Wang Z, Zhao Y, Zhang G, et al. 59 MO - Final analysis of AK105-302: A randomized, double-blind, placebo-controlled, phase III trial of penpulimab plus carboplatin and paclitaxel as first-line treatment for advanced squamous NSCLC. Annals of Oncology 2022;16 (Suppl 1):100102.
JPRN‐UMIN000021136 {published data only}
    1. JPRN-UMIN000021136. A phase III study of platinum doublet chemotherapy with or without nivolumab for the patients with chemo-naive, advanced non-small cell lung cancer (WJOG8615L). rctportal.niph.go.jp/en/detail?trial_id=UMIN000021136 (date registered: 22 February 2016).
Kuon 2022 {published data only}
    1. Kuon J, Bozorgmehr F, Schneider MA, Krisam J, Lasitschka F, Serke M, et al. Durvalumab in frail and elder patients with stage four NSCLC: the DURATION trial. Annals of Oncology 2018;19(Suppl 8):viii546-7. [DOI: 10.1093/annonc/mdy292.129] - DOI
    1. Kuon JB, Blasi M, Kokowski K, Faehling M, Schuette W, Christoph DCC, et al. DURATION - a phase II randomized trial in older / frail patients (pts) with advanced non-small cell lung cancer (NSCLC) comparing chemotherapy (CTX, 4 cycles) with CTX (2 cycles) and consecutive durvalumab (D): top-line early efficacy endpoints. Annals of Oncology 2022;33:S1021‐2.
    1. NCT03345810. Durvalumab in frail and elderly patients with stage four non-small cell lung cancer: study protocol of the randomized phase II DURATION trial. clinicaltrials.gov/ct2/show/NCT03345810 (first posted 17 November 2017). - PMC - PubMed
Lu S 2021 {published data only}
    1. Lu S, Chand A, Vaz De Melo Sette C, Bondarenko I, Fang H, Shankar S, et al. P79.03 A phase 3 study of the PD-1 inhibitor retifanlimab (INCMGA00012) plus platinum-based chemotherapy in 1L mNSCLC: POD1UM-304. Journal of Thoracic Oncology 2021;16(3):S646-7. [DOI: 10.1016/j.jtho.2021.01.1182] - DOI
NCT02477826 {published data only}
    1. Borghaei H, Hellmann MD, Paz-Ares LG, Ramalingam SS, Reck M, O'Byrne KJ, et al. Nivolumab (Nivo) + platinum-doublet chemotherapy (chemo) versus chemo as first-line (1L) treatment (Tx) for advanced non-small cell lung cancer (NSCLC) with <1% tumor PDL1 expression: results from CheckMate 227. Journal of Clinical Oncology 2018;36(15):9001.
    1. NCT02477826. An investigational immuno-therapy trial of nivolumab, or nivolumab plus ipilimumab, or nivolumab plus platinum-doublet chemotherapy compared to platinum doublet chemotherapy in patients with stage IV non-small cell lung cancer (NSCLC). clinicaltrials.gov/ct2/show/NCT02477826 (first posted 23 June 2015).
    1. Paz-Ares L, Brahmer J, Hellmann MD, Reck M, O'Byrne K, Borghaei H, et al. CheckMate 227: a randomized, open-label phase 3 trial of nivolumab nivolumab plus ipilimumab, or nivolumab plus chemotherapy versus chemotherapy in chemotherapy-naïve patients with advanced non-small cell lung cancer (NSCLC). Annals of Oncology 2017;28:iii50-1.
    1. Paz-Ares L, Ciuleanu TE, Yu X, Salman P, Pluzanski A, Nagrial A, et al. Nivolumab (NIVO) 1 platinum-doublet chemotherapy (chemo) versus chemo as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (NSCLC): checkMate 227-part 2 final analysis. Annals of Oncology 2019;30(Suppl 11):xi67-8. [DOI: 10.1093/annonc/mdz453.004] - DOI
NCT03786692 {published data only}
    1. NCT03786692. Phase II randomized trial of carboplatin+pemetrexed+bevacizumab+/- atezolizumab in stage IV NSCLC. https://clinicaltrials.gov/ct2/show/NCT03786692 2018.
NCT03977194 {published data only}
    1. NCT03977194. Study of atezolizumab in elderly patients with advanced non-small-cell lung cancer and receiving monthly carboplatin with weekly paclitaxel chemotherapy. clinicaltrials.gov/ct2/show/NCT03977194 (first posted 6 June 2019).
NCT04033354 {published data only}
    1. EUCTR2019-003064-50PL. Phase III study of HLX10 in combination with chemotherapy versus chemotherapy alone as first-line therapy for locally advanced or metastatic squamous non-small cell lung cancer (NSCLC). trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2019-003064-50-PL (date of registration: 17 March 2020).
    1. NCT04033354. A randomized, double-blind, placebo controlled phase III study to investigate efficacy and safety of first-line treatment with HLX10 + chemotherapy (carboplatin-nanoparticle albumin bound (nab) paclitaxel) in patients with stage IIIB/IIIC or IV NSCLC. clinicaltrials.gov/ct2/show/NCT04033354 (first posted 26 July 2019).

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