晚期非小细胞肺癌免疫治疗现状及未来方向

doi:10.19401/j.cnki.1007-3639.2022.06.002

摘要/Abstract

摘要：

肺癌仍然是中国发病率和死亡率最高的恶性肿瘤,其中非小细胞肺癌（non-small cell lung cancer,NSCLC）约占80%以上。以靶向程序性死亡[蛋白]-1（programmed death protein-1,PD-1）或程序性死亡[蛋白]配体-1（programmed death ligand-1,PD-L1）的免疫检查点抑制剂（immune checkpoint inhibitor,ICI）为基础的治疗已成为了晚期肺癌的标准治疗手段之一。本综述将对晚期NSCLC免疫治疗的现状予以梳理,探讨现阶段面临的问题与挑战,并思考与展望未来发展方向。

关键词: 非小细胞肺癌, 免疫检查点抑制剂, 免疫治疗

Abstract:

Lung cancer remains the malignant tumor with the highest morbidity and mortality in China, among which non-small cell lung cancer (NSCLC) accounts for more than 80%. Immune checkpoint inhibitors (ICIs)-based therapy targeting programmed death protein-1 (PD-1) or its ligand programmed death ligand-1 (PD-L1) has become one of the standard treatments for advanced NSCLC. This review, with the focus on advanced NSCLC, summarized the development of immunotherapy, discussed current problems, and challenges and proposed future directions.

Key words: Non-small cell lung cancer, Immune checkpoint inhibitor, Immunotherapy

中图分类号:

R734.2

苏春霞, 周彩存. 晚期非小细胞肺癌免疫治疗现状及未来方向[J]. 中国癌症杂志, 2022, 32(6): 478-486.

SU Chunxia, ZHOU Caicun. Current status and future directions of immunotherapy for advanced non-small cell lung cancer[J]. China Oncology, 2022, 32(6): 478-486.

参考文献 50

[1]	ZHENG R S,, ZHANG S W,, ZENG H M, et al. Cancer incidence and mortality in China, 2016[J]. J Natl Cancer Cent, 2022, 2(1): 1-9.
[2]	MOLINA J R,, YANG P,, CASSIVI S D, et al. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship[J]. Mayo Clin Proc, 2008, 83(5): 584-594. doi: 10.1016/S0025-6196(11)60735-0
[3]	YANG C Y,, YANG J C H,, YANG P C. Precision management of advanced non-small cell lung cancer[J]. Annu Rev Med, 2020, 71: 117-136. doi: 10.1146/annurev-med-051718-013524
[4]	RECK M,, RODRÍGUEZ-ABREU D,, ROBINSON A G, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small cell lung cancer[J]. N Engl J Med, 2016, 375(19): 1823-1833. doi: 10.1056/NEJMoa1606774
[5]	BRAHMER J R,, RODRIGUEZ-ABREU D,, ROBINSON A G, et al. LBA51 KEYNOTE-024 5-year OS update: first-line (1L) pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) in patients (pts) with metastatic NSCLC and PD-L1 tumour proportion score (TPS) ≥50%[J]. Ann Oncol, 2020, 31: S1181-S1182.
[6]	HERBST R S,, GIACCONE G,, DE MARINIS F, et al. Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC[J]. N Engl J Med, 2020, 383(14): 1328-1339. doi: 10.1056/NEJMoa1917346
[7]	JASSEM J,, DE MARINIS F,, GIACCONE G, et al. Updated overall survival analysis from IMpower110: atezolizumab versus platinum-based chemotherapy in treatment-naive programmed death-ligand 1-selected NSCLC[J]. J Thorac Oncol, 2021, 16(11): 1872-1882. doi: 10.1016/j.jtho.2021.06.019
[8]	SEZER A,, KILICKAP S,, GÜMÜŞ M, et al. Cemiplimab monotherapy for first-line treatment of advanced non-small cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial[J]. Lancet, 2021, 397(10274): 592-604. doi: 10.1016/S0140-6736(21)00228-2
[9]	RECK M,, RODRÍGUEZ-ABREU D,, ROBINSON A G, et al. Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non-small cell lung cancer with PD-L1 tumor proportion score ≥ 50[J]. J Clin Oncol, 2021, 39(21): 2339-2349. doi: 10.1200/JCO.21.00174
[10]	HWANG D M,, ALBAQER T,, SANTIAGO R C, et al. Prevalence and heterogeneity of PD-L1 expression by 22C3 assay in routine population-based and reflexive clinical testing in lung cancer[J]. J Thorac Oncol, 2021, 16(9): 1490-1500. doi: 10.1016/j.jtho.2021.03.028
[11]	GANDHI L,, RODRÍGUEZ-ABREU D,, GADGEEL S, et al. Pembrolizumab plus chemotherapy in metastatic non-small cell lung cancer[J]. N Engl J Med, 2018, 378(22): 2078-2092. doi: 10.1056/NEJMoa1801005
[12]	GADGEEL S,, GARASSINO M C,, ESTEBAN E, et al. KEYNOTE-189: OS update and progression after the next line of therapy (PFS2) with pembrolizumab + chemotherapy for metastatic nonsquamous NSCLC[J]. J Thorac Oncol, 2019, 14(11): S1153.
[13]	PAZ-ARES L,, LUFT A,, VICENTE D, et al. Pembrolizumab plus chemotherapy for squamous non-small cell lung cancer[J]. N Engl J Med, 2018, 379(21): 2040-2051. doi: 10.1056/NEJMoa1810865
[14]	PAZ-ARES L,, VICENTE D,, TAFRESHI A, 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]. J Thorac Oncol, 2020, 15(10): 1657-1669. doi: 10.1016/j.jtho.2020.06.015
[15]	ZHOU C C,, CHEN G Y,, HUANG Y C, et al. Camrelizumab plus carboplatin and pemetrexed versus chemotherapy alone in chemotherapy-naive patients with advanced non-squamous non-small cell lung cancer (CameL): a randomised, open-label, multicentre, phase 3 trial[J]. Lancet Respir Med, 2021, 9(3): 305-314. doi: 10.1016/S2213-2600(20)30365-9
[16]	YANG Y P,, WANG Z H,, FANG J, 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]. J Thorac Oncol, 2020, 15(10): 1636-1646. doi: 10.1016/j.jtho.2020.07.014
[17]	YANG Y P,, SUN J Y,, WANG Z H, et al. Updated overall survival data and predictive biomarkers of sintilimab plus pemetrexed and platinum as first-line treatment for locally advanced or metastatic nonsquamous NSCLC in the phase 3 ORIENT-11 study[J]. J Thorac Oncol, 2021, 16(12): 2109-2120. doi: 10.1016/j.jtho.2021.07.015
[18]	LU S,, WANG J,, YU Y, et al. Tislelizumab plus chemotherapy as first-line treatment for locally advanced or metastatic nonsquamous NSCLC (RATIONALE 304): a randomized phase 3 trial[J]. J Thorac Oncol, 2021, 16(9): 1512-1522. doi: 10.1016/j.jtho.2021.05.005
[19]	ZHOU C,, REN S,, CHEN J, et al. Camrelizumab or placebo plus carboplatin and paclitaxel as first-line treatment for advanced squamous NSCLC (CameL-sq): a randomized, double-blind, multicenter, phase Ⅲ trial[J]. J Thorac Oncol, 2021, 16(4): S748.
[20]	WANG J,, LU S,, HU C, et al. Updated analysis of tislelizumab plus chemotherapy vs chemotherapy alone as first-line treatment of advanced squamous non-small cell lung cancer (SQ NSCLC)[J]. Ann Oncol, 2020, 31: S817.
[21]	ZHOU C C,, WU L,, FAN Y, 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]. J Thorac Oncol, 2021, 16(9): 1501-1511. doi: 10.1016/j.jtho.2021.04.011
[22]	ZHOU C C,, WANG Z P,, SUN Y P, et al. Sugemalimab versus placebo, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small cell lung cancer (GEMSTONE-302): interim and final analyses of a double-blind, randomised, phase 3 clinical trial[J]. Lancet Oncol, 2022, 23(2): 220-233. doi: 10.1016/S1470-2045(21)00650-1
[23]	WANG J,, WANG Z,, WU L, et al. CHOICE-01: a phase 3 study of toripalimab versus placebo in combination with first-line chemotherapy for advanced NSCLC[J]. J Thorac Oncol, 2021, 16(10): S927-S928.
[24]	RECK M,, JOTTE R,, CAPPUZZO F, et al. IMpower150: analysis of efficacy in patients (pts) with liver metastases (mets)[J]. Pneumologie, 2020, 74: S39-S39
[25]	YANG J C H,, LUFT A,, DE LA MORA JIMÉNEZ E, et al. Pembrolizumab (Pembro) with or without lenvatinib (Lenva) in first-line metastatic NSCLC with PD-L1 TPS ≥1% (LEAP-007): a phase Ⅲ, randomized, double-blind study[J]. Ann Oncol, 2021, 32: S1429-S1430.
[26]	NISHIO M,, PELED N,, ZER A, et al. Phase Ⅲ LEAP-006 safety Run-in (Part 1): 1L pembrolizumab (Pembro) + chemotherapy (Chemo) with lenvatinib (Len) for metastatic NSCLC[J]. Ann Oncol, 2020, 31: S848-S849.
[27]	REN S X,, HE J X,, FANG Y, et al. Camrelizumab plus apatinib in treatment-naive patients with advanced nonsquamous NSCLC: a multicenter, open-label, single-arm, phase 2 trial[J]. JTO Clin Res Rep, 2022, 3(5): 100312.
[28]	HAN B H,, CHEN J,, XIE Q, et al. A multicenter, randomized, phase 3 trial of penpulimab in combination with anlotinib or chemotherapy as first-line treatment in advanced NSCLC[J]. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer, 2021, 16(3): S650.
[29]	CHU T Q,, ZHONG R B,, ZHONG H, et al. Phase 1b study of sintilimab plus anlotinib as first-line therapy in patients with advanced NSCLC[J]. J Thorac Oncol, 2021, 16(4): 643-652. doi: 10.1016/j.jtho.2020.11.026
[30]	ZHAO S,, REN S X,, JIANG T, et al. Low-dose apatinib optimizes tumor microenvironment and potentiates antitumor effect of PD-1/PD-L1 blockade in lung cancer[J]. Cancer Immunol Res, 2019, 7(4): 630-643. doi: 10.1158/2326-6066.CIR-17-0640
[31]	HELLMANN M D,, PAZ-ARES L,, BERNABE CARO R, et al. Nivolumab plus ipilimumab in advanced non-small cell lung cancer[J]. N Engl J Med, 2019, 381(21): 2020-2031. doi: 10.1056/NEJMoa1910231
[32]	PAZ-ARES L G,, RAMALINGAM S S,, CIULEANU T E, et al. First-line nivolumab plus ipilimumab in advanced NSCLC: 4-year outcomes from the randomized, open-label, phase 3 CheckMate 227 part 1 trial[J]. J Thorac Oncol, 2022, 17(2): 289-308. doi: 10.1016/j.jtho.2021.09.010
[33]	PAZ-ARES L,, CIULEANU T E,, COBO M, 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[J]. Lancet Oncol, 2021, 22(2): 198-211. doi: 10.1016/S1470-2045(20)30641-0
[34]	JOHN T,, SAKAI H,, IKEDA S, et al. First-line (1L) nivolumab (NIVO) + ipilimumab (IPI) + chemotherapy (chemo) in Asian patients (pts) with advanced non-small cell lung cancer (NSCLC) from CheckMate 9LA[J]. Ann Oncol, 2020, 31: S847-S848.
[35]	JOHNSON M,, CHO B C,, LUFT A, et al. Durvalumab ± tremelimumab + chemotherapy as first-line treatment for mNSCLC: results from the phase 3 POSEIDON study[J]. J Thorac Oncol, 2021, 16(10): S844.
[36]	ABREU D R,, RECK M,, ŞENDUR N, et al. Pembrolizumab plus ipilimumab or placebo in previously untreated metastatic NSCLC with PD-L1 tumor proportion score ≥50%: KEYNOTE-598 3-year follow-up[J]. Ann Oncol, 2022, 33: S30-S31.
[37]	MARUHASHI T,, SUGIURA D,, OKAZAKI I M, et al. LAG-3: from molecular functions to clinical applications[J]. J Immunother Cancer, 2020, 8(2): e001014.
[38]	HODI F S,, TAWBI H A,, LIPSON E J, et al. Relatlimab (RELA) + nivolumab (NIVO) vs NIVO in previously untreated metastatic or unresectable melanoma: additional efficacy in RELATIVITY-047[J]. Ann Oncol, 2021, 32: S867-S868.
[39]	MORGENSZTERN D,, CHAUDHRY A,, IANNOTTI N, et al. RELATIVITY-104: First-line relatlimab (RELA) + nivolumab (NIVO) with chemotherapy vs NIVO with chemotherapy in stage Ⅳ or recurrent non-small cell lung cancer (NSCLC): a phase Ⅱ, randomized, double-blind study[J]. Ann Oncol, 2021, 32: S1030.
[40]	CHAUVIN J M,, ZAROUR H M. TIGIT in cancer immunotherapy[J]. J Immunother Cancer, 2020, 8(2): e000957.
[41]	CHO B C,, ABREU D R,, HUSSEIN M, et al. Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line treatment for PD-L1-selected non-small cell lung cancer (CITYSCAPE): primary and follow-up analyses of a randomised, double-blind, phase 2 study[J]. Lancet Oncol, 2022, 23(6): 781-792. doi: 10.1016/S1470-2045(22)00226-1
[42]	MARIN-ACEVEDO J A,, KIMBROUGH E O,, LOU Y Y. Next generation of immune checkpoint inhibitors and beyond[J]. J Hematol Oncol, 2021, 14(1): 45. doi: 10.1186/s13045-021-01056-8
[43]	PAZ-ARES L,, KIM T M,, VICENTE D, et al. Bintrafusp Alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in second-line treatment of patients with NSCLC: results from an expansion cohort of a phase 1 trial[J]. J Thorac Oncol, 2020, 15(7): 1210-1222. doi: 10.1016/j.jtho.2020.03.003
[44]	WU L,, CHEN B,, YAO W, et al. A phase Ⅰb/Ⅱ trial of AK104 (PD-1/CTLA-4 bispecific antibody) in combination with anlotinib in advanced NSCLC[J]. Ann Oncol, 2021, 32: S1006.
[45]	HONG M H,, CLUBB J D,, CHEN Y Y. Engineering CAR-T cells for next-generation cancer therapy[J]. Cancer Cell, 2020, 38(4): 473-488. doi: 10.1016/j.ccell.2020.07.005
[46]	QU J J,, MEI Q H,, CHEN L J, et al. Chimeric antigen receptor (CAR)-T-cell therapy in non-small cell lung cancer (NSCLC): current status and future perspectives[J]. Cancer Immunol Immunother, 2021, 70(3): 619-631. doi: 10.1007/s00262-020-02735-0
[47]	YILMAZ A,, CUI H W,, CALIGIURI M A, et al. Chimeric antigen receptor-engineered natural killer cells for cancer immunotherapy[J]. J Hematol Oncol, 2020, 13(1): 168. doi: 10.1186/s13045-020-00998-9
[48]	GOULDING J,, BLUM R,, HANCOCK B, et al. Abstract 1591: FT536: preclinical development of a novel off-the-shelf CAR-MICA/B NK cell immunotherapy combined with radiation and antibody treatments as a first-of-kind pan-cancer targeting strategy[J]. Cancer Res, 2021, 81(13_Supplement): 1591. doi: 10.1158/1538-7445.AM2021-1591
[49]	HEMMINKI O,, DOS SANTOS J M,, HEMMINKI A. Oncolytic viruses for cancer immunotherapy[J]. J Hematol Oncol, 2020, 13(1): 84. doi: 10.1186/s13045-020-00922-1
[50]	SAXENA M,, VAN DER BURG S H,, MELIEF C J M, et al. Therapeutic cancer vaccines[J]. Nat Rev Cancer, 2021, 21(6): 360-378. doi: 10.1038/s41568-021-00346-0