Table 2.

Clinical Trials of Neoadjuvant combination Therapy

Therapeutic agent/authors	Included Patients	Regime	N	Outcomes	Grade ¾ irAEs
Ipilimumab, interferon alfa-2b Tarhini et al. 2018	Locally or regionally advanced	Arm A: ipi 3mg/kg q3 weeks × 2 doses + HDIFN (20 MU/m2/day) → surgery → ipi 3mg/kg q3 weeks × 2 doses then q12 weeks × 4 doses + HDIFN	15	cRR – 36% pCR – 32%	8 events
		Arm B: ipi 10mg/kg q3 weeks × 2 doses + HDIFN (20 MU/m2/day) → surgery → ipi 10mg/kg q3 weeks × 2 doses then q12 weeks × 4 doses + HDIFN	15		17 events
Ipilimumab, nivolumab Amaria et al. 2018	Resectable clinical stage III or oligometastatic stage IV	Arm A: nivo 3mg/kg q2 weeks × 4 doses → surgery → nivo 3mg/kg q2 weeks × 13 doses	12	Arm A:  ORR 25%  pCR 25%	8%
		Arm B: ipi 3mg/kg + nivo 1 mg/kg q3 weeks × 3 doses → surgery → nivo 3mg/kg up to 13 doses	11	Arm B:  ORR 73%  pCR 45%	73%
Ipilimumab, nivolumab OpACIN - Blank et al. 2018	Resectable clinical stage III	Arm A: surgery → ipi 3mg/kg + nivo 1mg/kg q3 weeks × 4 doses	10	NR	90%
		Arm B: ipi 3 mg/kg + nivo 1mg/kg q3 weeks × 2 doses → surgery → ipi 3 mg/kg + nivo 1mg/kg q3 weeks × 2 doses	10	cRR 78%  pCR 30%	90%
Ipilimumab, nivolumab OpACIN-neo - Rozeman et al. 2019	Resectable clinical stage III	Arm A: ipi 3mg/kg + concurrent nivo 1 mg/kg q3 weeks × 2 doses → surgery	30	cRR 63%  pCR 80%	40%
		Arm B: ipi 1mg/kg + concurrent nivo 3mg/kg q3 weeks × 2 doses → surgery	30	cRR 57%  pCR 77%	20%
		Arm C: ipi 3mg/kg × 2 doses → nivo 3mg/kg q3 weeks × 2 doses → surgery	26	cRR 35%  pCR 65%	50%

cRR – clinical response rate, pCR – pathology complete response, ORR – overall response rate, HDIFN – high-dose interferon alfa-2b, irAE – immune-related adverse events, NR – not reported, ipi – ipilimumab, nivo – nivolumab, pembro – pembrolizumab