Therapeutic strategies targeting the epidermal growth factor receptor signaling pathway in metastatic colorectal cancer

Table 1 Results of clinical trials based on RAS status

Therapy based on RAS status	Study	Design	Result	Ref.
RAS wild-type first-line therapy	CRYSTAL study	Cetuximab plus FOLFIRI vs FOLFIRI alone	The HR for PFS among patients with KRAS wild-type tumors was 0.68 (95%CI: 0.50 to 0.94), favoring the cetuximab-FOLFIRI group	Van Cutsem et al[4]
	OPUS study	Cetuximab plus FOLFOX-4 vs FOLFOX-4 alone	The median survival was 18.3 mo for patients receiving cetuximab plus FOLFOX-4 and 18.0 mo for FOLFOX-4 alone	Bokemeyer et al[5]
	COIN study	Cetuximab combined with the FOLFOX4 or XELOX regimen vs FOLFOX4 or XELOX regimen alone	The median survival was 19.6 mo vs 18.0 mo	Adams et al[6]
	PRIME study	Panitumumab combined with FOLFOX4 vs FOLFOX4 alone	In KRAS wild-type patients, panitumumab combined with FOLFOX4 significantly improved mPFS compared with FOLFOX4 alone, at 9.6 mo and 8.0 mo, respectively	Douillard et al[7]
RAS wild-type maintenance therapy	COIN-B study	Intermittent chemotherapy plus intermittent cetuximab therapy vs intermittent chemotherapy plus cetuximab maintenance therapy	mOS was 16.8 mo (95%CI: 14.5-22.6) in the intermittent cetuximab group vs 22.2 mo (18.4-28.9) in the continuous cetuximab group, and mPFS from week 12 was 3.1 mo (95%CI: 2.80-4.7) in the intermittent cetuximab group and 5.8 mo (4.9-8.6) with continuous cetuximab	Wasan et al[15]
	MACRO 2 TTD study	FOLFOX combined with cetuximab sequential cetuximab maintenance therapy vs FOLFOX combined with cetuximab	PFS at 9 mo was 60% vs 72%, and OS was 23 mo vs 27 mo. The objective response rate was 48% vs 39%	Aranda et al[16]
	MACBETH study	Modified FOLFOXIRI plus cetuximab, followed by cetuximab (arm A) vs bevacizumab maintenance (arm B)	10-mo PFR was 50.8% (90%CI: 39.5%-62.2%) in arm A and 40.4% (90%CI: 29.4%-52.1%) in arm B. The overall response rate was 71.6% (95%CI: 62.4%-79.5%)	Cremolini et al[17]
	VALENTINO study	Panitumumab plus fluorouracil and calcium folinate (arm A) vs panitumumab (arm B)	10-mo PFS rate was significantly higher in group A than in group B (59.9% vs 49.0%, P = 0.01). The mPFS was 12.0 mo and 9.9 mo, respectively. The OS rate at 18 mo was 66.4% and 62.4% (P = 0.60), respectively, with no significant difference	Pietrantonio et al[18]
	PANAMA (AIO KRK 0212) study	Panitumumab in combination with 5-FU vs 5-FU alone	RAS WT mCRC patients treated with 5-FU/LV + panitumumab maintenance therapy after FOLFOX + panitumumab induction therapy could have a superior outcome to 5-FU/LV maintenance therapy alone, with a PFS of 8.8 mo vs 5.7 mo (P = 0.014)	Modest et al[21]
RAS wild-type anti-EGFR-targeted agents rechallenge	CRICKET trial	Irinotecan and cetuximab as a third-line treatment for patients experiencing an initial response and then progression with a first-line irinotecan and cetuximab-containing therapy. Liquid biopsy samples were analyzed	The confirmed PR rate was 57% in patients with no RAS mutations detected in ctDNA. Patients with RAS wild-type ctDNA (n = 13) had significantly longer PFS than those with RAS-mutated ctDNA (n = 12), with a mPFS of 4.0 mo vs 1.9 mo (HR = 0.44, 95%CI: 0.18-0.98, P = 0.03), while no significant differences were reported in terms of OS (mOS: 12.5 mo vs 5.2 mo, HR = 0.58, 95%CI: 0.22-1.52, P = 0.24)	Cremolini et al[25]
	JACCRO CC-08 trial	Irinotecan plus cetuximab rechallenge as third-line treatment in KRAS wild-type mCRC patients who achieved clinical benefit with first-line cetuximab-containing therapy	The 3-mo PFS rate was 44.1%. The mPFS and OS were 2.4 mo and 8.2 mo, respectively. The response and DCR were 2.9% and 55.9%, respectively	Masuishi et al[26]
	CAPRI 2 GOIM trial	FOLFIRI + cetuximab (first line); FOLFOX + cetuximab (second line); irinotecan + cetuximab (third line)	Ongoing	Martini et al[28]
	WJOG8916G trial	TAS-102 in combination with cetuximab	DCR was 54%, PR was 3.6%, and mPFS was 2.4 mo. Patients with wild-type RAS, BRAF, EGFR, PIK3CA, ERBB2, and MET genes had a DCR of 75% vs 39% (P = 0.02), respectively, compared to mutant patients. mPFS was 4.7 mo vs 2.1 mo (P < 0.01)	Izawa et al[29]
	Phase II single-arm study	Cetuximab and palbociclib in KRAS-WT mCRC treated with ≥ 2 prior lines of therapy	The 4-mo DCR was 20%, which did not fulfill the prespecified 4-mo DCR rate. mPFS was 1.8 mo and mOS was 6.6 mo	Sorah et al[32]
	CAVE Trial	Cetuximab plus avelumab as a rechallenge strategy in patients with RAS wild-type metastatic colorectal cancer	The mOS was 17.3 mo for wild-type and 10.4 mo for ctDNA mutant patients (HR = 0.49, P = 0.02), with a PFS of 4.1 mo and 3.0 mo (HR = 0.42, P = 0.004), respectively	Martinelli et al[33]
	CAVE 2 study	Avelumab plus cetuximab as a reinvigorating strategy in pre-treated patients with RAS and BRAF WT mCRC	Ongoing	Napolitano et al[34]
	CRACK study	Cetuximab rechallenge combined with liposomal irinotecan and camrelizumab	The ORR was 25%, and the DCR was 75%. The mPFS and OS were 6.9 mo and 15.1 mo, respectively	Quan et al[36]
NeoRAS wild-type	C-­PROWESS trial	Panitumumab plus irinotecan therapy for patients with NeoRAS mCRC	Ongoing	Osumi et al[40]
KRAS G12C mutation	CodeBreaK100 trial	Sotorasib	The ORR was 9.7%	Fakih et al[44]
	CodeBreaK300 trial	Sotorasib (960 mg daily in arm A and 240 mg daily in arm B) with panitumumab vs chemotherapy	HR = 0.49 (95%CI: 0.30-0.80, P = 0.006) in the sotorasib 960 + panitumumab group and HR = 0.58 (95%CI: 0.36-0.93, P = 0.03) in the sotorasib 240 + panitumumab group, and OS data was immature	Pietrantonio et al[45]
	KRYSTAL-1 study	Adagrasib (MRTX849) alone vs adagrasib plus cetuximab	In the adagrasib monotherapy group, the ORR and DCR were 19% and 86%, respectively, while the mPFS was 5.6 mo. In the cetuximab–adagrasib group, a higher ORR of 46% and DCR of 100% were observed, and the mPFS was 6.9 mo	Yaeger et al[46]

ORR: Overall response rate; mPFS: Median progression-free survival; OS: Overall survival; DCR: Disease control rate; HR: Hazard ratio; PFS: Progression-free survival; RAS: Rat sarcoma; KRAS: Kirsten RAS; ctDNA: Circulating tumor DNA; mCRC: Metastatic colorectal cancer; BRAF: B-type RAF.