Implications of recent neoadjuvant clinical trials on the future practice of radiotherapy in locally advanced rectal cancer

Table 2 Recent prospective clinical trials using immune checkpoint inhibitors as a component of neoadjuvant treatment for locally advanced rectal cancer

Trials	Identifier	Patients	Primary endpoint	Treatment	Results
VOLTAGE-A[16]	NCT02948348	cT3-4 Nany (regardless of MMR status)	pCR	CRT (cape) → Nivolumab #5 → TME (→ mFOLFOX6/CAPOX)	pCR: 30% for MSS, 60% for MSI-H
AVANA[17]	NCT03854799	cN+ or cT4 or high-risk cT3 (CRM ≤ 1 mm, ≤ 6 cm from AV, or T3c/d)	pCR	CRT (cape) + Avelumab #6 → TME	pCR: 23%
R-IMMUNE[18]	NCT03127007	Stage II or III	pCR, safety	CRT(5-FU) + Atezolizumab #4 → S	pCR: 24%
NRG-GI002[19]	NCT02921256	Stage II or III with at least 1 of the following criteria: cT3-4 ≤ 5 cm from AV, any cT4 or tumor within 3 mm of MRF, cN2, not candidates for sphincter-sparing surgery at presentation	Neoadjuvant rectal score	A: mFOLFOX6 #6 → CRT (cape) → TME; B: mFOLFOX6 #6 → CRT (cape) + Pembrolizumab #6 → TME	NAR score: 14.08 vs 11.53 (NS); pCR: 29.4% vs 31.9% (NS)
AVERECTAL[41,111,112]	NCT03503630	cT2N+ or cT3-4aNany	pCR	SCRT → mFOLFOX6 + Avelumab #6 → TME	pCR: 37.5%
Lin et al[42]	NCT04231552	Stage II or III	pCR	SCRT → CAPOX + Camrelizumab #2 →TME	pCR: 48.1% (13/27), 46.2% (12/26) for pMMR, 100% (1/1) for dMMR
TORCH[43,113] ongoing	NCT04518280	cT3-4 or cN+	cCR or pCR	A: SCRT → CAPOX + toripalimab #6 → TME or WW; B: CAPOX + toripalimab #2 → SCRT → CAPOX + toripalimab #4 → TME or WW	(Preliminary) cCR + pCR: 81.3% (13/16 MSS patients); group A (n = 7): cCR 1, pCR 4, near pCR 1; group B (n = 9): cCR 4, pCR 4
Cercek et al[20] ongoing	NCT04165772	cT3-4 or cN+ with dMMR or MSI-H	cCR, pCR, overall response	Dostarlimab #9 → if cCR → WW; if residual+ → CRT → WW (cCR) or TME (residual+)	cCR: 100%
PRIME-RT[45] ongoing	NCT04621370	cT3b+ or EMVI+ or CRM ≤ 2 mm or a low rectal tumor requiring abdomino-perineal excision	cCR or pCR	A: (SCRT → mFOLFOX6 #6) + durvalumab #4 → S or WW; B: (CRT → mFOLFOX6 #4) + durvalumab #4 → S or WW
EA2201[46] ongoing	NCT04751370	cT3-4 or cN+ with dMMR or MSI-H	pCR	Ipilimumab/Nivolumab #2 → SCRT → Ipilimumab/Nivolumab #2 → TME
Qiu[47] ongoing	NCT04636008	cT2 or higher with dMMR or MSI-H	Adverse reaction after neoadjuvant treatment and perioperative complications	SCRT + Sintilimab #3 → TME or WW

5-FU: 5-fluorouracil; AV: Anal verge; cape: Capecitabine; cCR: Clinical complete response; CRM: Circumferential resection margin; CRT: Chemoradiotherapy; dMMR: Deficient mismatch repair; EMVI: Extramural vascular invasion; MMR: Mismatch repair; MRF: Mesorectal fascia; MSI-H: High microsatellite instability; MSS: Microsatellite stable; NAR: Neoadjuvant rectal; NS: Not significant; pCR: Pathologic complete response; pMMR: Proficient mismatch repair; S: Surgery; SCRT: Short-course radiotherapy; TME: Total mesorectal excision; WW: Watch-and-wait.