Table 2.

Anti-human epidermal growth factor receptor 2 (HER2) treatment strategies—phase II trials.

Study	Treatment	Setting	Endpoints	Patients Enrolled	Results	Safety/Toxicity Grade (G)	References
HERACLES1 A	Trastuzumab IV2 4 mg3/kg4 loading dose → 2 mg/kg qw5 + lapatinib 1000 mg/daily	KRAS6 exon 2 (codons 12 and 13) wt7 e and HER248+ mCRC9 refractory to standard of care (including cetuximab or panitumumab)	Primary endpoint: proportion of patients achieving OR610	27	OR = 30% (95% CI711 14–50), of which: CR12 = 4% (95% CI: 3–11) PR13 = 26% (95% CI: 9–43) SD14 44% (95% CI: 25–63)	-22% G3 (fatigue in four patients, skin rash in one patient, increased bilirubin concentration in one patient). -0% G4–G5 -0%SAE15	[30]
HERACLES B	Pertuzumab 840 mg loading dose →420 mg q3w16 + T-DM117 3.6 mg/Kg q3w	RAS18/BRAF19 wt HER2+ mCRC, PD20 after 5-FU21, oxaliplatin, irinotecan, and anti-EGFR22-containing regimens	Primary endpoint: ORR23 Secondary endpoint: PFS24	30	-ORR = 10% (95% CI: 0–28) – not significant; SD 70% (95% CI: 50–85); Disease control 80% -mPFS25 = 4.8 mos. (95% CI: 3.6–5.8). Higher HER2 IHC26 score (3+ vs.27 2+) associated with OR/SD ≥ 4 mos. [p = 0.03].	−6.6% G3 thrombocytopenia -G ≤2 events (mainly nausea and fatigue)	[31]
MOUNTAINEER28	Tucatinib 300 mg PO29 bid30 + standard doses of trastuzumab IV q3w	RAS wt HER2+ mCRC, prior treatment with 5-FU, oxaliplatin, irinotecan, and an anti-VEGF31	Primary endpoint: ORR	26 → 22 evaluable	-ORR = 55% (CR/PR = 12; SD = 5; PD = 5). -Clinical benefit rate (CR+PR+SD ≥4 months) = 64% -mPFS = 6.2 months (95% CI: 3.5-NE32). -mOS33 = 17.3 months (95% CI: 12.3-NE) -median duration of response: not reached	−9% G3 −0% G4/5 -most common TRAEs34: AST35 elevation (48%; all G1), ALT36 elevation (30%; all G1), and diarrhea (26%; G1/G2/G3 = 4%/17%/4%).	[32]
TRIUMPH37	Tissue and/or ctDNA38 confirmed RAS wt and HER2 amplified mCRC, refractory or intolerant to standard chemotherapy, including EGFR blockade	Trastuzumab + pertuzumab q3w	Primary endpoint: ORR, analyzed for two primary populations: tissue-positive and ctDNA-positive	19 → 18 evaluable	-tissue-positive group: ORR = 35% (95% CI: 14–62%); 1 CR and 5 PR -ctDNA positive group: ORR = 33% (95% CI: 12–62%); 1 CR and 4 PR) -mPFS for both groups = 4.0 months (95% CI  =  1.4–5.6 months and 1.3–5.6 months, respectively)	-1 patient: G3 decreased ejection fraction -1 patient: G3 infusion related reaction -safety profile consistent with previous reports	[33]

Note: ¹HERACLES = HER2 Amplification for Colo-rectaL cancer Enhanced Stratification; ²IV = intravenously; ³mg = milligrams; ⁴kg = kilograms; ⁵qw = once weekly; ⁶KRAS = Kirsten RAS oncogene homolog; ⁷wt = wild type; ⁴⁸HER2+ = human epidermal growth factor receptor 2; ⁹mCRC = metastatic colorectal cancer; ¹⁰OR = objective response; ¹¹CI: = confidence interval; ¹²CR = complete response; ¹³PR = partial response; ¹⁴SD = stable disease; ¹⁵SAE = serious adverse event; ¹⁶q3w = once every 3 weeks; ¹⁷T-DM1 = trastuzumab emtansine; ¹⁸RAS = rat sarcoma; ¹⁹BRAF = v-raf murine sarcoma viral oncogene homolog B1; ²⁰PD = progressive disease; ²¹5-FU = 5-fluorouracil; ²²anti-EGFR = anti-epidermal growth factor receptor; ²³ORR = objective response rate; ²⁴PFS = progression-free survival; ²⁵mPFS = median progression-free survival; ²⁶IHC = immunohistochemistry; ²⁷vs. = versus; ²⁸MOUNTAINEER = Phase II, Open Label Study of Tucatinib Combined with Trastuzumab in Patients with HER2+ Metastatic Colorectal Cancer; ²⁹PO = per os; ³⁰BID = bis in die; ³¹anti-VEGF = anti-vascular endothelial growth factor; ³²NE = not estimable; ³³mOS = median overall survival; ³⁴TRAEs = treatment related adverse events; ³⁵AST = aspartate aminotransferase; ³⁶ALT = alanine aminotransferase; ³⁷TRIUMPH = Multicenter Phase II study to evaluate efficacy and safety of combination therapy with trastuzumab and pertuzumab in patients with HER2-positive metastatic colorectal cancer; ³⁸ctDNA = circulating tumor DNA.