Neoadjuvant immune checkpoint inhibitors in high-risk stage III melanoma

Figures & data

Table 1. Neoadjuvant immunotherapy trials with published results

	Trial Name Registry Number	Phase	Treatment	Size N	Primary Endpoint(s)	Secondary Endpoint(s)	pCR	mPR	Radiographic Response
IPI	Tahrini A, 2014	I/II	Neoadj IPI 10mg/kg for 2 courses then adj IPI for 2 courses+IFNa	35	Safety, Biomarkers	PFS	0%	n/a	9%
	Tahrini A, 2018 NCT01608594	I/II	Neoad IPI 3 mg/kg or 10 mg/kg for 2 doses + high dose IFN, then adj IPI for 4 doses + high dose IFN (46 wks)	28	Safety	Efficacy	32%	39%	29% with 3 mg/kg vs. 43% with 10 mg/kg
PEMBRO	Huang AC, 2019 NCT02434354	I	Neoadj PEM (1 dose), then adj PEM (1 yr)	30	Safety	Biomarkers, efficacy	19%	30%	n/a
ICI COMNINATION	OpACIN Blank CU2018/ ESMO2020 NCT02437279	I	Arm A: adj NIVO + IPI (12 wks) Arm B: neoadj NIVO + IPI (6 wks), then adj NIVO + IPI (6 wks)	20	Biomarkers, safety, feasibility	RFS, safety	Arm B: 33%	Arm B: 78%	Arm B: 50%
	Amaria RN, 2018 (“MD Anderson study”) NCT02519322	II	Arm A: neoadj NIVO (6 wks), then adj NIVO (26 wks) Arm B: neoadj NIVO + IPI (6 wks), then adj NIVO (26 wks) Arm C: neoadj NIVO + RELA (4 wks), then adj NIVO + RELA (40 wks)	53	pRR	Biomarkers, cRR, RFS, OS, safety	Arm A: 25% Arm B: 45% Arm C: 59%	Arm A: n/a Arm B: n/a Arm C: 66%	Arm A: 25% Arm B: 73% Arm C: 57%
	OpACIN-neo Rozeman EA2019/ ESMO2020 NCT02977052	II	Arms A and B: neoadj NIVO + IPI (6 wks) (2 different regimens) Arm C: neoadj NIVO followed by neoadj IPI (6 wks)	110	Safety, cRR, pRR, RFS	Safety, biomarkers, RFS	Arm A: 47% Arm B: 57% Arm C: 23%	Arm A: 80% Arm B: 77% Arm C: 65%	Arm A: 63% Arm B: 57% Arm C: 35%
	CA209-8HF Cocorocchio E. ESMO2020	II	neoadj NIVO+IPI (12 wks), then adj NIVO (24 wks)	23	pCR	Safety, biomarkers, RFS.QoL, microbioma	53%	78%	n/a
Oncolytic –therapy + ICIs	Dummer R. NCT02211131	II	Neoadj T-VEC 6 doses (12 wks)	150	RFS	pCR, ORR, OS, Safety	22,8%	n/a	n/a
	Neo-C-Nivo NCT03618641	II	NIVO + CMP-001	34	mPR, safety	RFS, OS, ORR	50%	n/a	43%

Table 2. Ongoing neoadjuvant immunotherapy trials

Parameter	NCT03769155 (Phase 1)	NCT02519322 (Phase 2)	NCT03698019 (Phase 2)	NCT04013854 (Phase 2)	NCT02977052 (Phase 2, extension cohort)	NCT04495010 (Phase 2)
Studies	CA209-8N4 IRB00104273 NCI-2018-01229 Winship4400-18	2015–0041 NCI-2015-01520	NCI-2018-02107 S1801	CA209-74X UPCC 02619	OpACIN-neo CA209-701 M16OPN 2016–001984-35	CheckMate 7 UA 2020–000070-16
Design	PEP or PEP+Nivo or PEP+IPI or PEP+NIVO+IPI	NIVO or NIVO+IPI or NIVO+REL	Adj PEM or Neoadj + Adj PEM	Neoadj NIVO → Adj NIVO or NIVO+IPI (determined by pathological response)	NIVO+IPI	Neoadj NIVO+IPI → Adj NIVO or Neoadj NIVO+IPI → Adj NIVO or Observ vs adj NIVO
Population	Stage IIIB-D	Stage IIIB-IV	High-risk, Stage III/IV	Stage III	Stage III	Stage IIIB-D
Enrollment (estimated)	36	53	500	60	100–110	657
Primary endpoint	Biomarkers (CD8+ T cells)	Pathological RR	EFS	RFS	Safety, RR, RFS	EFS
Status (primary completion date)	Recruiting (Dec 2021)	Recruiting (Aug 2020)	Recruiting (Sep 2022)	Recruiting (Aug 2026)	Active, not recruiting (Jan 2020)	Not yet recruiting (Feb 2024)

adj, adjuvant; cRR, clinical response rate; EFS, event free survival; IPI, ipilimumab; neoadj, neoadjuvant; NIVO, nivolumab; OS, overall survival; PEM, pembrolizumab; PEP, pepinemab; RR, response rate; RFS, recurrence-free survival.

Table 3. Ongoing neoadjuvant immunotherapy trials plus other agents

Parameter	NCT02303951 (Phase 2)	NCT03554083 (Phase 2)	NCT02858921 (Phase 2)	NCT03259425 (Phase2)	NCT03618641 (Phase 2)
Studies	NEO-VC EADO_VC_NEO_1	NeoACTIVATE MC1776 NCI-2018-01018	NeoTrio MIA2015/176	Neo-NivoHF10 HCI1023-46	17–169
Design	VEM+COBI (cohort 1) VEM+COBI+ATEZO (chort 2)	COBI+ATEZO Or VEM+COBI+ATEZO	DB+TRAM + Concurrent o sequential PEM or PEM	NIVO+HF10 (oncolytic virus)	NIVO+CMP-001
Population	Stage IIIC/IV	High-risk, Stage III	Stage IIIB/C With BRAF mut	Stage IIIB/C or IVM1a	Stage IIIB-D with Clinically LN disease
Enrollment	90 (estimated)	30 (estimated)	60 (estimated)	7 (actual)	34 (actual)
Primary endpoint	Resectability rate	pCR, RFS	Pathological RR	Pathological response	Major pathological RR
Status (primary completion date)	Recruiting (Feb 2021)	Recruiting (Jun 2023)	Recruiting (Nov 2020)	Active, not recruiting (Sep 2018)	Active, not recruiting (Aug 2020)

adj, adjuvant; ATEZO, atezolizumab; cRR, clinical response rate; COBI, cobimetinib; DB, dabrafenib; EFS, event free survival; IPI, ipilimumab; neoadj, neoadjuvant; NIVO, nivolumab; OS, overall survival; PEM, pembrolizumab; PEP, pepinemab; RR, response rate; RFS, recurrence-free survival; TRAM, trametinib; VEM, vemurafenib.