Table 7.

Key Papers Describing First Line Therapy in Metastatic Pulmonary LCNEC.

Study	Study Design	Patient population	Total Patients	Treatment	Outcomes	Other
Le Treut et al.(103)	Prospective, phase II, single arm study of etoposide and cisplatin	Stage IV/IIIB LCNEC	42 patients (29 patients with LCNEC by centralized pathology review)	Etoposide/Cisplatin	For whole cohort median OS 7.7 months, ORR 38%, 64% DCR, at 1 year OS was 26.8%. LCNEC cases proven on central review, ORR 34%.
Niho et al. (14)	Prospective, phase II, single arm study of irinotecan and cisplatin	Advanced pulmonary LCNEC	44 patients (30 patients with pure LCNEC)	Irinotecan/ Cisplatin	ORR in pure LCNEC was 46.7%, median OS 12.6 months. 1 year OS was 62.1%, 2 year OS was 18.4%.
Derks et al. (104)	Retrospective review	Stage IV chemotherapy treated LCNEC patients	207 patients	3 groups of chemotherapy regimens reviewed:	Median OS 7.3 months. NSCLC-t group with median OS of 8.5 months vs median OS of 5.9 months in NSCLC-t group and 6.7 months in SCLC-t group.
				“NSCLC-pt” Platinum based therapy with gemcitabine, docetaxel, paclitaxel or vinorelbline, most platinum/gemcitabine (N=60) “NSCLC-t” Platinum and pemetrexed (N=20) “SCLC-t” Platinum and etoposide (N=64)
Derks et al. (105)	Retrospective review	Patients with stage IV LCNEC	232 cases (148 confirmed on pathology review, 79 with chemotherapy regimens available)	3 regimens compared:	LCNEC with wild type RB1 gene showed significantly longer OS when treated with platinum with gemcitabine / taxane (9.6 months) as compared to platinum / etoposide (5.8 months).
				Platinum with gemcitabine / taxane Platinum and etoposide Platinum/ pemetrexed
Zhuo et al. (106)	Retrospective review	Patients with advanced stage LCNEC, analyzed by molecular subgroups	63 patients (54 patients with advanced stage disease receiving first line chemotherapy)	3 regimens compared:	ORR from all chemotherapy regimens was 46.7% in SCLC- like LCNEC as compared to 25.6% in NSCLC- like LCNEC. In SCLC-like LCNEC RR (75%) to platinum/etoposide was higher than platinum/ pemetrexed (0%). In NSCLC-like LCNEC there was no difference in RR between the three chemotherapy regimens, however platinum/etoposide regimens were associated with longer PFS (5.2 months) than platinum/gemcitabine/taxane (2.5 months).
				Platinum with gemcitabine / taxane Platinum and etoposide Platinum/ pemetrexed

RFA, recurrence free survival; OS, overall survival; LCNEC, Large cell neuroendocrine carcinoma; SCLC, Small cell Lung Cancer; DFS, Disease free survival; NSCLC, Non-small cell lung cancer; DCR, Disease control rate; ORR, Overall response rate.