Small cell lung cancer patients treated with immune checkpoint inhibitor: a systematic literature review of treatment efficacy, safety and quality of life

Figures & data

Figure 1. Flow chart of selection process.

Table 1. Data extraction summary.

Line of therapy	Lead Author	Country	Intervention	Control	Type of ICI used	No. of patients (Male/Female)
First-line	Horn^7 et al. (2018)	USA	Atezolizumab + carboplatin and etoposide	Placebo + carboplatin and etoposide	Anti-PD-L1	403 (261/142)
	Reck^8 et al. (2013)	Germany	Ipilimumab + carboplatin and paclitaxel	Paclitaxel + carboplatin	Anti-CTLA-4	130 (NR)
	Reck^9 et al. (2016)	Germany	Ipilimumab + platinum and etoposide	Placebo + platinum and etoposide	Anti-CTLA-4	954 (643/311)
	Paz-Ares^10 et al. (2019)	Spain	Durvalumab + platinum and etoposide	Platinum and etoposide	Anti-PD-L1	573 (410/163)
	Rudin^11 et al. (2020)	USA	Pembrolizumab + etoposide and platinum	Placebo + etoposide and platinum	Anti-PD-1	453 (294/159)
	Mansfield^15 et al. (2020, PRO study)	USA	Atezolizumab + etoposide and carboplatin	Placebo + carboplatin and etoposide	Anti-PD-L1	403 (261/142)
	Goldman^16 et al. (2020, PRO study)	USA	Durvalumab + cisplatin and etoposide	Cisplatin + etoposide	Anti-PD-L1	972 (NR)
	Li^17 et al. (2019, CEA study)	China	Atezolizumab + carboplatin and etoposide	Carboplatin and etoposide	Anti-PD-L1	NR
	Zhou^18 et al. (2019, CEA study)	China (American perspective)	Atezolizumab + carboplatin and etoposide	Carboplatin and etoposide	Anti-PD-L1	NR
Second-line	Owonikoko^12 et al. (2021)	USA	Nivolumab + ipilimumab	Placebo	Anti-PD-1	834 (532/302)
	Spiegel^13 et al. (2021)	USA	Nivolumab	Topotecan or amrubicin	Anti-PD-1	569 (351/218)
	Pujol^14 et al. (2019)	France	Atezolizumab	Platinum + etoposide	Anti-PD-L1	73 (43/30)

ICI – Immune checkpoint Inhibitor; Anti-PD-L1 – Anti-Programmed Cell Death Ligand-1; Anti-PD-1 – Anti-Programmed Cell Death-1; Anti-CTLA-4 – Anti-cytotoxic T-lymphocyte-associated protein 4; CEA – Cost-effectiveness analysis; PRO – Patient reported outcome; NR – Not reported.

Table 2. Safety and efficacy studies: summary.

Serial no.	Lead Author	OS (median months)	HR (95% CI)	PFS (median months)	HR (95% CI)	ORR (%)
1	Horn^7	I–12.3; C–10.3	0.7* (0.54–0.91)	I–5.2; C–4.3	0.77* (0.62–0.96)	I–60.2; C–64.4
2a	Reck^8	I–12.5; C–10.5	0.93 (0.59–1.45)	I–6.4; C–5.3	0.64* (0.4–1.02)	I–71; C–53
2b	Reck^8	I–9.1; C–10.5	0.95 (0.59–1.54)	I–5.7; C–5.3	0.75 (0.48–1.19)	I–49; C–53
3	Reck^9	I–11; C–10.9	0.94 (0.81–1.09)	I–4.6; C–4.4	0.85* (0.75–0.94)	I–62; C–62
4	Paz-Ares^10	I–13; C–10.3	0.73* (0.59–0.91)	I–5.1; C–5.4	0.78 (0.65–0.94)	I–68; C–58*
5	Rudin^11	I–10.8; C–9.7	0.80 (0.64–0.98)	I–4.5; C–4.3	0.75^+ (0.61–0.91)	I–70.6; C–61.8
6	Owonikoko^12	I–9.2; C–9.6	0.92 (0.75–1.12)	I–1.7; C–1.4	0.72 (0.6–0.87)	I–9.1; C–4.2
7	Spiegel^13	I–7.5; C–8.4	0.86 (0.72–1.04)	I–1.4; C–3.8	1.41 (1.18–1.69)	C–13.7; I–16.5
8	Pujol^14	I–9.5; C–8.7	0.84 (0.45–1.58)	I–1.4; C–4.3	2.26* (1.30–3.93)	I–2.3; C–10

*Statistically significant at p = .05, ⁺p = .006, a – phased ipilimumab, b – concurrent ipilimumab.

OS – Overall Survival; PFS – Progression Free Survival; ORR – Overall Response Rate; HR – Hazard ratio; 95% CI –Confidence Interval; I – Intervention; C – Control.

Horn L, Mansfield AS, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379(23):2220–2229.

 PubMed Web of Science ®Google Scholar

Reck M, Luft A, Szczesna A, et al. Phase III randomized trial of ipilimumab plus etoposide and platinum versus placebo plus etoposide and platinum in extensive-stage small-cell lung cancer [published correction appears in J Clin Oncol. 2019 Dec 1;37(34):3327]. J Clin Oncol. 2016;34(31):3740–3748.

 PubMed Web of Science ®Google Scholar

Reck M, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol. 2013;24(1):75–83.

 PubMed Web of Science ®Google Scholar

Paz-Ares L, Dvorkin M, Chen Y, CASPIAN investigators, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929–1939.

 PubMed Web of Science ®Google Scholar

Rudin CM, Salgia R, Wang X, et al. Randomized phase II study of carboplatin and etoposide with or without the bcl-2 antisense oligonucleotide oblimersen for extensive-stage small-cell lung cancer: CALGB 30103. J Clin Oncol. 2008;26(6):870–876.

 PubMed Web of Science ®Google Scholar

Mansfield AS, Każarnowicz A, Karaseva N, et al. Safety and patient-reported outcomes of atezolizumab, carboplatin, and etoposide in extensive-stage small-cell lung cancer (IMpower133): a randomized phase I/III trial. Ann Oncol. 2020;31(2):310–317.

 PubMed Web of Science ®Google Scholar

Goldman JW, Garassino MC, Chen Y, et al. Patient-reported outcomes with first-line durvalumab plus platinum-etoposide versus platinum-etoposide in extensive-stage small-cell lung cancer (CASPIAN): a randomized, controlled, open-label, phase III study. Lung Cancer. 2020;149:46–52.

 PubMed Web of Science ®Google Scholar

Li LY, Wang H, Chen X, et al. First-line atezolizumab plus chemotherapy in treatment of extensive small cell lung cancer: a cost-effectiveness analysis from China. Chin Med J (Engl). 2019;132(23):2790–2794.

 PubMed Web of Science ®Google Scholar

Zhou K, Zhou J, Huang J, et al. Cost-effectiveness analysis of atezolizumab plus chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer. Lung Cancer. 2019;130:1–4.

 PubMed Web of Science ®Google Scholar

Owonikoko TK, Park K, Govindan R, et al. Nivolumab and ipilimumab as maintenance therapy in extensive-disease small-cell lung cancer: CheckMate 451. J Clin Oncol. 2021;39(12):1349–1359.

 PubMed Web of Science ®Google Scholar

Spigel DR, Vicente D, Ciuleanu TE, et al. Second-line nivolumab in relapsed small-cell lung cancer: CheckMate 331. Ann Oncol. 2021;32(5):631–641.

 PubMed Web of Science ®Google Scholar

Pujol JL, Greillier L, Audigier-Valette C, et al. A randomized non-comparative phase II study of anti-programmed cell death-ligand 1 atezolizumab or chemotherapy as second-line therapy in patients with small cell lung cancer: Results from the IFCT-1603 trial. J Thorac Oncol. 2019;14(5):903–913.

 PubMed Web of Science ®Google Scholar