Table 2.
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.