Risk and safety profile in checkpoint inhibitors on non-small-cell lung cancer: A systematic review

Figures & data

Figure 1. Flowchart diagrams of design and study selection procedure.

Figure 2. Flowchart of treatment regimens used in the studies papers.

Table 1. Characteristic of included studies.

First Author Publication year	ClinicalTrials.gov Clinical phase	Study sample	Tumour stage	Treatment regiment		Survival (median in months)	TEAE (total No)		CIP (yes/no)		CTCEA (Grade)
Brahmer et al., 2015^Citation6	NCT01642004 phase 3	272	IIIB-IV, NA	NIVO 3mg/kg IV Q2W	9.2			9		yes		3–4
				TXT 75 mg/m^2 IV Q3W	6.0
Shu et al., 2020^Citation32	NCT02716038 phase 2	30	IB-IIIA	ATE 1200 mg/kg IV Q3W	12.9			5		no		3–4
				NP 100 mg/m^2 IV Day1, 8, 15 Q3W	14.3
				CBP AUC 5 IV Q3W	17.9
Garon et al., 2015^Citation33	NCT01295827 phase 1	495	III-IV	PEM 2 or 10 mg/kg IV Q3W	10.9			4		yes		3–4
				PEM 10mg/kg IV Q2W
Gandhi et al., 2018^Citation34	NCT02578680 phase 3	616	III-IV	PEM 200 mg IV + PEME 500 mg/m^2 + CIS 75 mg/m^2 IV or CBP AUC 5 IV Q3W 4 cycles, then PEM 200 mg IV + PEME 500 mg/m^2 Q3W	12			11		no		3
				PEM 100 mg IV Q3W + SBRT	11.3
Rizvi et al., 2015^Citation35	NCT01721759 phase 2	117	IIIB-IV	NIVO 3 mg/kg IV Q2W	8.2			4		yes		1–2
Rizvi et al., 2020^Citation36	NCT02453282 phase 3	1118	IIIB-IV	DUR 20mg/kg IV Q4W	16.3			7		no		3–4
				DUR 20mg/kg IV Q4W + TREM 1mg/kg IV Q4W up to 4 doses	11.9#
				DUR 20mg/kg IV Q4W + PTX + CBD	12.9
Chen et al., 2020^27	NCT0223900 phase 1	241	IV	anti-CTLA-4 3 mg/kg IV Q3W 2 cycles + SBRT	10.7			8		no		3–4
	NCT02444741 phase 1+2			PEM 100 mg IV Q3W + SBRT	8.3
Planchard et al., 2020^Citation37	NCT02352948 phase 3	595	IV	DUR 10mg/kg IV Q2W	11.7			11		yes		3
				ERL 150mg PO QD + VIN 30 mg/m^2 IV Day1, 8, 15, 22 or GEM 1000 mg/m^2 IV Day1, 8, 15	6.8
				DUR 20mg/kg IV Q2W + anti-CTLA-4 1mg/kg IV Q4W, then DUR 10mg/kg IV Q2W	11.5
				DUR 10mg/kg IV Q2W up to year	10.1
				anti-CTLA-4 10mg/kg IV Q4W 24 weeks, then by Q12W up to 9 doses	6.9
				ERL 150mg PO QD + VIN 30 mg/m^2 IV Day1, 8, 15, 22 or GEM 1000mg/m^2 IV Day1, 8, 15	8.7
Soria et al., 2017^Citation38	NCT01750281 phase 2	212	III-IV	SEL 75mg PO BID + TXT 60 mg/m^2 IV Q3W	5.7			5		yes		3
				SEL 75mg PO BID + TXT 75 mg/m^2 IV Q3W	7.7
				Placebo PO BID + TXT 75 mg/m^2 IV Q3W	11.5
Vergnenegre et al., 2020^Citation39	NCT03801304 phase 2	12	IV	ATE 1200mg IV Q3W + VIN 40mg PO QD Day1,3,5 Q3W	NA			4		no		1–2
Garassino et al., 2020^Citation40	NCT02087423 phase 2	444	III-IV	DUR 10mg/kg IV Q2W up to year	13.2			7		yes		3–4
Felip et al., 2020^Citation41	NCT02409368 phase 2	811	III-IV	NIVO 3mg/kg IV Q2W	10.0			6		yes		3–4
von Pawel et al., 2019^Citation42	NCT02008227 phase 3	1225	III-IV	ATE 1200 mg IV Q3W	11.9			15		yes		3
				TXT 75 mg/m^2 IV Q3W	16.0
Gettinger et al., 2015^Citation43	NCT00730639 phase 1	129	IV	NIVO 1 mg/kg IV Q2W 8 cycles up to 96 weeks	9.2			4		yes		3–5
				NIVO 3 mg/kg IV Q2W 8 cycles up to 96 weeks	14.9
				NIVO 10 mg/kg IV Q2W 8 cycles up to 96 weeks	9.2
Gettinger et al., 2021^Citation44	NCT02785952 phase 3	252	IV	NIVO 3mg/kg IV Q2W	10			10		yes		3
				NIVO 3mg/kg IV Q2W + anti-CTLA-4 1mg/kg IV 3 cycles	11
Herbst et al., 2020^Citation45	NCT02409342 phase 3	572	IV	ATE 1200mg/kg IV Q3W	20.2			6		yes		3–4
				CIS 75 mg/m^2 IV or CBP AUC 6 IV 4or6 cycles Q3W + PEME 500mg/m^2 IV Q3W	13.1
				CIS 75 mg/m^2 IV + GEM 1250 mg/m^2 IV Q3W or CBP AUC 5 IV Q3W 4or6 cycles + GEM 1000 mg/m^2 IV Q3W
Herbst et al., 2016^Citation46	NCT01905657 phase 2+3	1034	III-IV	PEM 2mg/kg IV Q3W	10.4			9		yes		3–4
				PEM 10mg/kg IV Q3W	12.7
				TXT 75 mg/m^2 IV Q3W	8.5
Fehrenbacher et al., 2016^Citation47	NCT01903993 phase 2	287	III-IV	ATE 1200mg IV Q3W	9.7			13		no		3
				TXT 75 mg/m^2 IV Q3W	12.6
Jabbour et al., 2021^Citation48	NCT03631784 phase 2	216	III	CBP AUC 6 IV + PTX 200 mg/m^2 IV + PEM 200 mg IV, then CBP AUC 2 IV + PTX 45 mg/m^2 IV QW 6 weeks, then PEM 200 mg IV Q3W + TRT 2 cycles	9.1^§			4		no		3–5
				CIS 75 mg/m^2 IV 3 cycles + PEME 500 mg/m^2 IV + PEM 200 mg IV Q3W + TRT 2+3 cycles, additional PEM 200 mg IV Q3W 14 cycles	7.7^§
Peters et al., 2019^Citation49	NCT02434081 phase 2	82	III	NIVO 360mg IV + SBRT	NA			3		yes		3–5
				Platinum-based IV 3 cycles
Hellmann et al., 2019^Citation50	NCT02477826 phase 3	1189	III-IV	NIVO 3 mg/kg IV Q2W + anti-CTLA-4 1 mg/kg IV Q6W	17.1			7		no		3–4
				NIVO 240mg IV Q2W
				Platinum-doublet Q3W 4 cycles	14.9
Besse et al., 2020^Citation51	NCT02451930 phase 1	71	III-IV	PEM 200 mg IV Q3W, then NECI 800 mg IV Day 1, 8 Q3W	NA			12		no		2
Borghaei et al., 2015^Citation52	NCT01673867 phase 3	582	III-IV	NIVO 3 mg/kg IV Q2W	12.2			14		no		3
				TXT 75 mg/m^2 IV Q3W	9.4
Wu et al., 2019^Citation53	NCT02613507 phase 3	504	III-IV	NIVO 3 mg/kg IV Q2W	12			8		yes		3
				TXT 75 mg/m^2 IV Q3W	9.6
Wu et al., 2021^Citation54	NCT02220894 phase 3	1274	III-IV	PEM 200mg IV Q3W 35 cycles	20.1			10		no		3–5
				CBP AUC 5 Q3W + PTX 200mg/m^2 IV Q3W or TXT 75 mg/m^2 IV +PEME 500mg/m^2 IV Q3W	12.2
Kowanetz et al., 2018^Citation55	NCT01846416 phase 2	1092	III-IV	ATE 1200 mg IV Q3W				15		yes		1–2
	NCT01903993 phase 2			TXT 75 mg/m^2 IV Q3W	9.7
				ATE 1200mg IV Q3W	13.2
	NCT02031458 phase 2			ATE 1200mg IV Q3W
Sakai et al., 2020^Citation56	JIPANG-TR phase 3	374	II-IIIA	PEM 500mg/m^2 IV + CIS 75 mg/m^2 IV	52.5^§			NA		NA		NA
				VIN 25 mg/m^2 IV Day1,8 + CIS 80 mg/m^2 IV	72^§
Ready et al., 2019^Citation57	NCT02477826 phase 3	324	III-IV	NIVO 3mg/kg IV Q2W + anti-CTLA-4 1mg/kg IV Q6W	4.2			5		no		3–4
				NIVO 360mg IV Q3W + anti-CTLA-4 1mg/kg IV Q6W + Platinum doublet 2 cycles	8.7
Ouwens et al., 2021^Citation58	NCT02125461 phase 3	713	III	DUR 10mg/kg IV Q2W up to year	34.7			9		no		3
				Placebo Q2W up to year	22.9
Provencio et al., 2020^Citation59	NCT03081689 phase 2	46	IIIA	PTX 200mg/m^2 + CBP AUC 6 + NIVO 360mg Q3W, then surgery, followed by NIVO 240mg IV Q2W 4 months, followed by NIVO 480mg IV Q4W 8 months	24			6		yes		3–4
Osorio et al., 2017^Citation60	NCT01295827 phase 1	51	III-IV	PEM 1mg/kg IV Q2W	40			1		no		2
Paz-Ares et al., 2021^Citation61	NCT03215706 phase 3	719	IV	NIVO 360mg IV Q3W+ anti-CTLA-4 1mg/kg IV Q6W+ 2 Platinum-based IV Q3W 2 cycles	14.1			7		yes		3–4
				Cytostatics IV Q3W 4 cycles	10.7
Antonia et al., 2016^Citation62	NCT02000947 phase 1	102	III-IV	DUR 3, 10, 15 or 20mg/kg Q4W + TREM 1, 3 or 10mg/kg Q4W 6 cycles, then Q12W 3 cycles	47^§			5		no		3–4
Rudin et al., 2020^Citation63	NCT03066778 phase 3	453	III-IV	PEM 200mg IV Q3W 35 cycles + EP IV 4 cycles	10.8			6		yes		3–4
				Placebo 35 cycles + EP IV 4 cycles	9.7
Arrieta et al., 2020^Citation64	NCT02574598 phase 2	78	III-IV	PEM 200mg IV Day 8 Q3W + TXT 75 mg/m^2 IV Q3W	9^$			9		no		1–2
				TXT 75 mg/m^2 IV Q3W	5^$
Stratigos et al., 2021^Citation65	NCT03132636 phase 2	84	III-IV	CEM 350 mg IV Q3W 93 weeks	19^§			3		no		3–4
Middleton et al., 2020^Citation66	NCT02733159 phase 2	^Citation36	IV	PEM 200 mg IV Q3W maximum 2 years	NA			10		no		3–4
Reck et al., 2016^Citation7	NCT02142738 phase 3	305	III-IV	PEM 200 mg IV Q3W 35 cycles up to 2 years	8.0^‡			11		yes		3
				Platinum-based IV 4–6 cycles	6.3^‡

Abbreviations: ATE - Atezolizumab, AUC – area under the curve, BID – twice a day, CBP – Carboplatin, CEM - Cemiplimab, CIP - checkpoint inhibitor pneumonitis, CIS - Cisplatin, CTCEA - the Common Terminology Criteria for Adverse Events, CTLA-4 - cytotoxic T lymphocyte associated protein 4, DUR – Durvalumab, EP - Etoposide and platinum, ERL - Erlotinib, GEM - Gemcitabine, IV – intravenous, NA – not applicable, NIVO - Nivolumab, N^o – number, NP - Nabpaclitaxel, PEM - Pembrolizumab, PEME - Pemetrexed, PO – peroral, PTX – Paclitaxel, QD – once a day, QxW – each x week, SBRT - Stereotactic body radiotherapy, TERM - Tremelimumab, TRT - Thoracic radiotherapy, TXT - Docetaxel, VIN - Vinorelbine, # - ns vs DUR study arm, § - treatment, no survival, $ - approximately because of still ongoing (median for both groups is 8.9 months), ‡ - objective response rate because overall survival was not reached.

Figure 3. The model of drug-based network and TEAEs. Fixed-effect and randomised-effect models on the study arms subgroups containing the total number of TEAEs. Forrest plots depict the risk ratio of the favourable treatments versus comparators. The standardised residuals of both models are displayed.

Figure 4. The model of drug-based network and TEAEs. Fixed-effect and randomised-effect models on the study arms subgroups grouped by these subgroups containing the total number of TEAEs. Forrest plots depict the risk ratio of the favourable treatments versus comparators. The standardised residuals of both models are displayed.

Figure 5. The model of drug-based network and TEAEs. Fixed-effect and randomised-effect models on the study arms subgroups containing the total number of TEAEs were moderated by CTCEA Grade (G-I against G-II). The models were grouped by CTCEA Grade and heterogeneity values was provided because of an analysis being run within each grade and an overall analysis across these grades as well as within groups and between groups. Forrest plots depict the risk ratio of the favours treatments versus comparators. The standardised residuals of both models are displayed.

Figure 6. Model on survival compared by CIP between studies. Fixed-effect and randomised-effect models on clinical trials (n=38) containing survival were compared by the presence of CIP. Forrest plots depict the risk ratio of the favours treatments versus comparators. The standardised residuals of both models are displayed.

Figure 7. Model on survival compared by ICI treatment effect. Fixed-effect and randomized-effect models containing quantifying the ICI treatment effect across studies using survival data by the log hazard rate. Forrest plots depict the risk ratio of the favorable treatments versus comparators. The standardized residuals of both models are displayed.

Figure 8. Models on survival compared by mortality across studies. Fixed-effect and randomised-effect models on mortality across studies investigated the total number of deaths in ICI subgroup against conventional drugs. Forrest plots depict the risk ratio of the favours treatments versus comparators. The standardised residuals of both models are displayed.

Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123–35. doi:10.1056/NEJMoa1504627.

 PubMed Web of Science ®Google Scholar

Shu C, Gainor J, Awad M, Chiuzan C, Grigg C, Pabani A, Garofano R, Stoopler M, Cheng S, White A, et al. Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2020;21(6):786–95. doi:10.1016/S1470-2045(20)30140-6.

 PubMed Web of Science ®Google Scholar

Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, et al. KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018–28. doi:10.1056/NEJMoa1501824.

 PubMed Web of Science ®Google Scholar

Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, et al. KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078–92. doi:10.1056/NEJMoa1801005.

 PubMed Web of Science ®Google Scholar

Rizvi NA, Mazières J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, Horn L, Lena H, Minenza E, Mennecier B, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015;16(3):257–65. doi:10.1016/S1470-2045(15)70054-9.

 PubMed Web of Science ®Google Scholar

Rizvi N, Cho B, Reinmuth N, Lee K, Luft A, Ahn M, van den Heuvel M, Cobo M, Vicente D, Smolin A, 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. doi:10.1001/jamaoncol.2020.0237.

 PubMed Web of Science ®Google Scholar

Planchard D, Reinmuth N, Orlov S, Fischer JR, Sugawara S, Mandziuk S, Marquez-Medina D, Novello S, Takeda Y, Soo R, et al. ARCTIC: durvalumab with or without tremelimumab as third-line or later treatment of metastatic non-small-cell lung cancer. Ann Oncol. 2020;31(5):609–18. doi:10.1016/j.annonc.2020.02.006.

 PubMed Web of Science ®Google Scholar

Soria JC, Fülöp A, Maciel C, Fischer JR, Girotto G, Lago S, Smit E, Ostoros G, Eberhardt WEE, Lishkovska P, et al. SELECT-2: aphase II, double-blind, randomized, placebo-controlled study to assess the efficacy of selumetinib plus docetaxel as a second-line treatment of patients with advanced or metastatic non-small-cell lung cancer. Ann Oncol. 2017;28(12):3028–36. doi:10.1093/annonc/mdx628.

 PubMed Web of Science ®Google Scholar

Vergnenegre A, Monnet I, Bizieux A, Bernardi M, Chiapa AM, Léna H, Chouaïd C, Robinet G. Open-label phase II trial to evaluate safety and efficacy of second-line metronomic oral vinorelbine-atezolizumab combination for stage-IV non-small-cell lung cancer - VinMetAtezo trial, (GFPC‡ 04-2017). Future Oncol. 2020;16(4):5–10. doi:10.2217/fon-2019-0730.

 PubMed Web of Science ®Google Scholar

Chiara Garassino M, Cho B-C, Kim J-H, Mazières J, Vansteenkiste J, Lena H, Corral Jaime J, Gray JE, Powderly J, Chouaid C, et al. Final overall survival and safety update for durvalumab in third- or later-line advanced NSCLC: the phase II ATLANTIC study. Lung Cancer. 2020;147:137–42. doi:10.1016/j.lungcan.2020.06.032.

 PubMed Web of Science ®Google Scholar

Felip E, Ardizzoni A, Ciuleanu T, Cobo M, Laktionov K, Szilasi M, Califano R, Carcereny E, Griffiths R, Paz-Ares L, et al. CheckMate 171: a phase 2 trial of nivolumab in patients with previously treated advanced squamous non-small cell lung cancer, including ECOG PS 2 and elderly populations. Eur J Cancer. 2020;127:160–72. doi:10.1016/j.ejca.2019.11.019.

 PubMed Web of Science ®Google Scholar

von Pawel J, Bordoni R, Satouchi M, Fehrenbacher L, Cobo M, Han JY, Hida T, Moro-Sibilot D, Conkling P, Gandara DR, et al. Long-term survival in patients with advanced non-small-cell lung cancer treated with atezolizumab versus docetaxel: results from the randomised phase III OAK study. Eur J Cancer. 2019;107:124–32. doi:10.1016/j.ejca.2018.11.020.

 PubMed Web of Science ®Google Scholar

Gettinger SN, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA, Powderly JD, Heist RS, Carvajal RD, Jackman DM, et al. Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol. 2015;33(18):2004–12. doi:10.1200/JCO.2014.58.3708.

 PubMed Web of Science ®Google Scholar

Gettinger S, Redman M, Bazhenova L, Hirsch F, Mack P, Schwartz L, Bradley J, Stinchcombe T, Leighl N, Ramalingam S, et al. Nivolumab plus ipilimumab vs nivolumab for previously treated patients with stage IV squamous cell lung cancer: the lung-MAP S1400I phase 3 randomized clinical trial. JAMA Oncol. 2021;7(9):1368–77. doi:10.1001/jamaoncol.2021.2209.

 PubMed Web of Science ®Google Scholar

Herbst R, Giaccone G, de Marinis F, Reinmuth N, Vergnenegre A, Barrios C, Morise M, Felip E, Andric Z, Geater S. et al. Atezolizumab for first-line treatment of PD-L1–selected patients with NSCLC. N Engl J Med. 2020;383(14):1328–39. doi:10.1056/NEJMoa1917346.

 PubMed Web of Science ®Google Scholar

Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, 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. doi:10.1016/S0140-6736(15)01281-7.

 PubMed Web of Science ®Google Scholar

Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, et al. POPLAR study group. atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016;387(10030):1837–46. doi:10.1016/S0140-6736(16)00587-0.

 PubMed Web of Science ®Google Scholar

Jabbour SK, Lee KH, Frost N, Breder V, Kowalski DM, Pollock T, Levchenko E, Reguart N, Martinez-Marti A, Houghton B, et al. Pembrolizumab plus concurrent chemoradiation therapy in patients with unresectable, locally advanced, stage III non-small cell lung cancer: the phase 2 KEYNOTE-799 nonrandomized trial. JAMA Oncol. 2021;7(9):1–9. doi:10.1001/jamaoncol.2021.2301.

 PubMed Web of Science ®Google Scholar

Peters S, Felip E, Dafni U, Belka C, Guckenberger M, Irigoyen A, Nadal E, Becker A, Vees H, Pless M, et al. Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-radiotherapy regimen in stage III non-small cell lung cancer-the ETOP NICOLAS trial. lung cancer. Lung Cancer. 2019;133:83–7. doi:10.1016/j.lungcan.2019.05.001.

 PubMed Web of Science ®Google Scholar

Hellmann M, Paz-Ares L, Bernabe Caro R, Zurawski B, Kim S, Carcereny Costa E, Park K, Alexandru A, Lupinacci L, de la Mora Jimenez E, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019;381(21):2020–31. doi:10.1056/NEJMoa1910231.

 PubMed Web of Science ®Google Scholar

Besse B, Garrido P, Cortot AB, Johnson M, Murakami H, Gazzah A, Gil M, Bennouna J. Efficacy and safety of necitumumab and pembrolizumab combination therapy in patients with stage IV non-small cell lung cancer. Lung Cancer. 2020;142:63–9. doi:10.1016/j.lungcan.2020.02.003.

 PubMed Web of Science ®Google Scholar

Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627–39. doi:10.1056/NEJMoa1507643.

 PubMed Web of Science ®Google Scholar

Wu Y-L, Lu S, Cheng Y, Zhou C, Wang J, Mok T, Zhang L, Tu H-Y, Wu L, Feng J, et al. Nivolumab versus docetaxel in a predominantly Chinese patient population with previously treated advanced NSCLC: CheckMate 078 randomized phase III clinical trial. J Thorac Oncol. 2019;14(5):867–75. doi:10.1016/j.jtho.2019.01.006.

 PubMed Web of Science ®Google Scholar

Wu YL, Zhang L, Fan Y, Zhou J, Zhang L, Zhou Q, Li W, Hu C, Chen G, Zhang X, et al. Randomized clinical trial of pembrolizumab vs chemotherapy for previously untreated Chinese patients with PD-L1-positive locally advanced or metastatic non–small-cell lung cancer: KEYNOTE-042 China study. Int J Cancer. 2021;148(9):2313–20. doi:10.1002/ijc.33399.

 PubMed Web of Science ®Google Scholar

Kowanetz M, Zou W, Gettinger SN, Koeppen H, Kockx M, Schmid P, Kadel EE 3rd, Wistuba I, Chaft J, Rizvi NA, et al. Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti-PD-L1). Proc Natl Acad Sci USA. 2018;115(43):10119–26. doi:10.1073/pnas.1802166115.

 PubMed Web of Science ®Google Scholar

Sakai K, Tsuboi M, Kenmotsu H, Yamanaka T, Takahashi T, Goto K, Daga H, Ohira T, Ueno T, Aoki T, et al. Tumor mutation burden as a biomarker for lung cancer patients treated with pemetrexed and cisplatin (the JIPANG-TR). Cancer Sci. 2020;112(1):388–96. doi:10.1111/cas.14730.

 PubMed Web of Science ®Google Scholar

Ready N, Hellmann MD, Awad MM, Otterson GA, Gutierrez M, Gainor JF, Borghaei H, Jolivet J, Horn L, Mates M, et al. First-line nivolumab plus ipilimumab in advanced non-small-cell lung cancer (CheckMate 568): outcomes by programmed death ligand 1 and tumor mutational burden as biomarkers. J Clin Oncol. 2019;37(12):992–1000. doi:10.1200/JCO.18.01042.

 PubMed Web of Science ®Google Scholar

Ouwens M, Darilay A, Zhang Y, Mukhopadhyay P, Mann H, Ryan J, Dennis PA. Assessing the influence of subsequent immunotherapy on overall survival in patients with unresectable stage III non-small cell lung cancer from the PACIFIC study. Curr Ther Res Clin Exp. 2021;95:100640–50. doi:10.1016/j.curtheres.2021.100640.

 PubMed Web of Science ®Google Scholar

Provencio M, Nadal E, Insa A, García-Campelo MR, Casal-Rubio J, Dómine M, Majem M, Rodríguez-Abreu D, Martínez-Martí A, De Castro Carpeño J, et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial. The Lancet Oncology. 2020;21(11):1413–22. doi:10.1016/S1470-2045(20)30453-8.

 PubMed Web of Science ®Google Scholar

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. 2017;28(3):583–9. doi:10.1093/annonc/mdw640.

 PubMed Web of Science ®Google Scholar

Paz-Ares L, Ciuleanu TE, Cobo M, Schenker M, Zurawski B, Menezes J, Richardet E, Bennouna J, Felip E, Juan-Vidal O, 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;22(2):198–211. doi:10.1016/S1470-2045(20)30641-0.

 PubMed Web of Science ®Google Scholar

Antonia S, Goldberg SB, Balmanoukian A, Chaft JE, Sanborn RE, Gupta A, Narwal R, Steele K, Gu Y, Karakunnel JJ, et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol. 2016;17(3):299–308. doi:10.1016/S1470-2045(15)00544-6.

 PubMed Web of Science ®Google Scholar

Rudin CM, Awad MM, Navarro A, Gottfried M, Peters S, Csőszi T, Cheema PK, Rodriguez-Abreu D, Wollner M, Yang JC, et al. KEYNOTE-604 Investigators. Pembrolizumab or placebo plus etoposide and platinum as first-line therapy for extensive-stage small-cell lung cancer: randomized, double-blind, phase III KEYNOTE-604 study. J Clin Oncol. 2020;38(21):2369–79. doi:10.1200/JCO.20.00793.

 PubMed Web of Science ®Google Scholar

Arrieta O, Barrón F, Ramírez-Tirado LA, Zatarain-Barrón ZL, Cardona AF, Díaz-García D, Yamamoto Ramos M, Mota-Vega B, Carmona A, Peralta Álvarez MP, et al. Efficacy and safety of pembrolizumab plus docetaxel vs docetaxel alone in patients with previously treated advanced non-small cell lung cancer: the PROLUNG phase 2 randomized clinical trial. JAMA Oncol. 2020;6(6):856–64. doi:10.1001/jamaoncol.2020.0409.

 PubMed Web of Science ®Google Scholar

Stratigos AJ, Sekulic A, Peris K, Bechter O, Prey S, Kaatz M, Lewis KD, Basset-Seguin N, Chang ALS, Dalle S, et al. Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an open-label, multi-centre, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):848–57. doi:10.1016/S1470-2045(21)00126-1.

 PubMed Web of Science ®Google Scholar

Middleton G, Brock K, Savage J, Mant R, Summers Y, Connibear J, Shah R, Ottensmeier C, Shaw P, Lee SM, et al. Pembrolizumab in patients with non-small-cell lung cancer of performance status 2 (PePS2): a single arm, phase 2 trial. LancetLancet Respir Med. 2020;8(9):895–904. doi:10.1016/S2213-2600(20)30033-3.

 PubMed Web of Science ®Google Scholar

Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, et al. KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823–33. doi:10.1056/NEJMoa1606774.

 PubMed Web of Science ®Google Scholar