Table 1.

Select Neoadjuvant Immunotherapy Trials

Trial/Year	Tumor Type	Phase	No.	1° Endpoint	Intervention	Results	Surgical Delay/Complication Data	Biomarker Analysis
KEYNOTE 522 2020(6)	TNBC	3	1174	pCR EFS	Pembrolizumab + chemotherapy v placebo + chemotherapy	pCR 64.8% in IO arm v 51.2% in placebo arm 18 mo EFS HR 0.63	No	Yes; 20% difference in PDL1 +/− subgroups, but benefit seen in both groups
IMpassion031 2020(8)	TNBC	3	333	pCR in all-randomized and PDL1+ subgroup	Atezolizumab + chemotherapy v placebo + chemotherapy	pCR all randomized: 17% rate difference (95% CI 6–27; p=0.0044) pCR in PDL1+: 20% rate difference (95% CI 4–35; p=0.02)	No	Yes; pCR in PDL1+ is co-primary endpoint; PDL1+ pCR 53/77 (69%, 9% CI 57–79) in experimental arm; 37/75 (49%, 38–61) in placebo + chemo arm
NeoTRIP Michelangelo 2022 (10)	TNBC	3	280	EFS Secondary endpoint: pCR	Non-anthracycline chemotherapy +/− atezolizumab	EFS follow up ongoing pCR: OR 1.18 (95% CI 0.74–1.89, p 0.48); did not reach statistical significance	Disease progression in 8 patients	Yes; 7.6% increase in pCR in PDL1+ disease (OR 2.68, 1.64–2.65, p<0.0001)
Ademuyiwa et al 2022 (11)	TNBC	2	67	pCR TIL percentage	Chemotherapy +/− atezolizumab	pCR: 36.8% treatment difference in IO + chemo arm (95% CI 8.5–56.6%, p=0.018)	No data	Yes; pCR increase in both PDL1 + and – patients TIL percentages higher in IO arm
GeparNuevo 2022 (12)	TNBC	2	174	pCR	Durvalumab v placebo 2 weeks prior to chemo, then durvalumab v placebo x 12 weeks, with nab-paclitaxel followed by durvalumab v placebo alone	pCR: effect seen in window group. OR 2.22, 95% Ci (1.06–4.64, p=0.035)	99% of patients underwent surgery, no data on surgical complications	Yes; Higher pCR rate with higher sTILs in both arms; trend toward higher pCR in PDL1 +
CheckMate 816 2022 (18)	NSCLC	3	358	EFS pCR	Nivolumab + platinum-based chemotherapy v. chemotherapy alone	Median EFS 31.6 mo in neoadjuvant IO arm v 20.8 in chemo arm (HR 0.63; 97.38% CI 0.43–0.91, p=0.0005) pCR 24% in NA-IO arm, 2.2% in chemo arm (OR 13.94, 99% CI 3.49–55.75, p<0.001)	Surgery delayed in 3.4% of patients receiving nivo and 5.1% of patients receiving chemo alone	Yes; ctDNA clearance higher in those receiving IO. EFS longer in patients with ctDNA clearance
NADIM 2022 (19)	NSCLC	2	46	PFS at 24 months	Nivolumab + carboplatin/paclitaxel	24 month PFS 77.1%	No surgery delays	Yes; no significant associations with PDL1 and TMB. Reduced PFS with STK11, KEAP1, RB1, EGFR
NEOSTAR 2021 (20)	NSCLC	2	44	MPR	Nivolumab alone v Nivolumab + ipilimumab	MPR in combo group: 38% MPR in nivo arm: 22%
KEYNOTE 671 2023 (21)	NSCLC	3	797	EFS OS	Perioperative treatment. Chemo + pembrolizumab v placebo x 4 cycles, surgery, adjuvant pembrolizumab v placebo	24 mo EFS: 62.4% in pembro group, 40.% in placebo group (HR 0.58, CI 0.46–0.72, p<0.001) 24 mo OS: 80.9% in the pembro arm, 77.6% in the placebo group (p=0.02)	3.8% of patients in pembro arm and 6.5% of patients in the placebo group did not undergo surgery due to progression of disease	Yes; higher PD-L1 expression with lower HR for progression, recurrence cand death; but all subgroups benefitted
Uppaluri et al 2020 (26)	HNSCC	2	36	AEs Pathologic tumor response	Pembrolizumab	AEs: no Grade 3–4 AEs prior to surgery pTR-2 in 22% and pTR01 in 22%	No surgical delays/complications	Yes; positive correlation between pTR and PDL1 expression
Schoenfeld et al 2020 (27)	HNSCC	2	29	Safety Volumetric response	Nivolumab monotherapy v nivolumab + ipilimumab	Safety: Gr 3–4 irAEs in 2 nivo patients and 5 nivo+ipi patients Volumetric response nivo: 50% Volumetric response nivo + ipi: 53%	No surgical delays	Yes; PDL1 did not correlate with volumetric or pathologic response
IMCISION 2021 (28)	HNSCC	1b/2a	32	Feasibility to resect no later than week 6 (phase 1b) Primary tumor pathological response (phase 2a)	Nivolumab monotherapy; nivolumab + ipilimumab	No surgical delay in any patient MPR 35% in combo arm MPR 17% in nivo monotherapy arm	Included as primary endpoint, no delays	Yes; AID/APOBEC-associated mutation profile
Wise-Draper et al 2022 (29)	HNSCC	2	92	One year DFS	Pembrolizumab, 1 cycle, 3	DFS 97% in intermediate-risk group; 66% in high-risk group	33 (36%) patients with surgical complications: dehiscence, fistulas and/or infections	Yes: PD-L1 expression not associated with DFS
NICHE 2020 (35)	Colorectal	2	40	Safety and feasibility	Ipilimumab x 1, nivolumab x 2	Treatment tolerated by all patients; no surgical delays	No surgical delays (primary endpoint)	Yes; CD8+ PD-L1+ T cell infiltration
Cercek et al 2022 (36)	Rectal	2	12	Sustained clinical response 12 months after completion of treatment pCR after dostarlimab therapy w/ or w/o surgery or chemoradiotherapy	Single agent dostarlimab	12/12 patients (100%; 95% CI 74–100) with CR	No patients underwent surgery or chemoradiotherapy	Yes; PD-L1 protein and CD8+ T lymphocytes found in higher levels in tumor-free rectal mucosa after 6 months compared to mid-treatment
Ferrarotto et al 2021(38)	CSCC	2	20	ORR	cemiplimab	ORR: 30%, all partial responses	All patients underwent surgery as planned	Yes; responders had higher levels of IFN-g and TILs
Gross et al 2022 (40)	CSCC	2	79%	pCR	cemiplimab	pCR: 51% of patients, MPR 13%	2 patients progressed to inoperable disease; 1 patient progressed and lost to follow up	Yes; PDL1 and TMB data acquired, but no clear association
Amaria et al 2018 (44)	Melanoma	2	23	ORR pCR TRAE	Nivolumab monotherapy v Ipilimumab + nivolumab	ORR combo group: 73% pCR combo group: 45% Grade 3 irAEs combo group: 73%	Trial stopped early due to early observation of progression in nivolumab alone group with high rates of trAEs in combination group	Yes; responders trended toward higher TMB and T-cell clonality
OpACIN 2018 (45)	Melanoma	1b	20	Safety Feasibility Immune activating capacity	Ipilimumab/nivolumab neoadjuvant-adjuvant v adjuvant only	Safety: 90% of patients in each arm with Gr 3–4 AEs Feasibility: surgery performed	Feasibility included as a co-primary endpoint	Yes; sTILs expansion included as co-primary endpoint
OpACIN-neo 2019 (47)	Melanoma	2	86	Grade 3–4 Toxicity pCR and radiologic objective response	A.Ipilimumab 3 mg/kg + nivolumab 1 mg/kg; B.Ipilimumab 1 mg/kg + nivolumab 3 mg/kg; 3. ipilimumab 3 mg//kg followed by nivolumab 3 mg/kg	Grade 3–4 irAEs observed in 40% Group A, 20% Group B 50% group C Radiologic objective response: 63% Group A, 57% Group B, 35% in Group C pCR: 80% Group A, 77% group B, 65% Group C	No cases attributed to neoadjuvant therapy	Yes; IFN-g signature associated with relapse, but not pCR
Huang et al 2019 (48,49)	Melanoma	1b	27	Pathologic response; Immunologic response DFS	Pembrolizumab, single dose	29% pCR or MPR Increase in circulating TILs, associated with path response DFS: 63% at 2 years 100% 5 year OS in responders	No delays or unexpected complications	Yes; included as primary endpoint
SWOG S1801 2023 (50)	Melanoma	2	313	EFS in ITT population	Neoadjuvant-adjuvant or adjuvant only pembrolizumab	2 yr. EFS 72% in NA-A group, 49% in adjuvant-only group	1 patient with toxic effects, 12 patients with disease progression evidence of disease.	No; Data collected but to be published in separate analysis
ABACUS 2019 (53)	MIBC	2	95	Pathologic compete response	Atezolizumab, 2 cycles	pCR 31%	62% surgical complications; 1 post-op death	Yes; tumor CD8+ immune phenotypes, PD-L1, TMB
PURE-01 2018 (54)	MIBC	2	50	Pathologic compete response	Pembrolizumab, 3 cycles	pCR 42%	50% surgical complications	Yes; PD-L1, immune expression assay
NABUCCO 2020 (56)	MIBC	2	24	Feasibility to resect	Ipilimumab x 2, nivolumab x 2	23/24 (95%) patients underwent surgery at pre-defined time 46% with pCR	1 patient with surgical delay due to immune-related hemolysis	Yes; PD-L1, immune expression assay