Three different regimens are recommended by the panel as options for subsequent treatment of mCRC with HER2 amplifications: fam-trastuzumab deruxtecan-nxki (T-DXd) monotherpay or trastuzumab in combination with either pertuzumab or lapatinib.

...Confirmed diagnosis of a malignancy harbouring HER2 amplification, or an appropriate activating mutation as defined by the MTB, using an analytically validated method....

A noninterventional study was conducted using patient-level data from MyPathway participants receiving PER-HER and real-world patients with HER2-amplified...The estimated HR for OS from the multivariate Cox proportional hazards model in the postweighting population was 0.729 (95% CI, 0.184 to 3.900). The results of sensitivity analyses were consistent with the primary analysis in terms of the point estimate of HR.

In MyPathway, patients with treatment-refractory HER2-amplified metastatic colorectal cancer (mCRC) were enrolled and received pertuzumab plus trastuzumab….In the post-weighting population, the hazard ratio (HR) for OS estimated by multivariate Cox regression model was 0.729 (95% CI: 0.184-3.900) and median survival in the PER/HER arm and the EC arm were 11.47 months (95% CI: 7.72-22.11) and 9.72 months (95% CI: 7.43-22.21), respectively....Despite a small sample size, the totality of findings suggests that the combination of pertuzumab and trastuzumab could have a potential benefit in OS for this population.

HER2 amplification was confirmed in tissue and/or ctDNA in 30 patients with mCRC. The study met the primary endpoint with a confirmed objective response rate of 30% in 27 tissue-positive patients and 28% in 25 ctDNA-positive patients, as compared to an objective response rate of 0% in a matched real-world reference population treated with standard-of-care salvage therapy....Pertuzumab plus trastuzumab showed similar efficacy in patients with mCRC with HER2 amplification in tissue or ctDNA, showing that ctDNA genotyping can identify patients who benefit from dual-HER2 blockade as well as monitor treatment response.

Among 75 pts screened, concordance of HER2 amp between tissue and ctDNA was 83%....The primary endpoint was met in each cohort of TRIUMPH, with confirmed ORR of 30% (95% CI 14-50%) in 27 tissue+ pts and 28% (12-49%) in 25 ctDNA+ pts....We demonstrate promising efficacy and safety of P+T for...mCRC pts with HER2 amp in either tumor tissue or ctDNA.

NON-SUPPORTIVE EVIDENCE: The confirmed ORR was 8.3% (2/24 partial responses [colorectal and cholangiocarcinoma], 90% CI 1.5-24%). There was one additional unconfirmed partial response (PR, urothelial cancer). Median PFS was 3.3 months (90% CI 2.0 - 4.6), 6-month PFS 23.3% (90% CI 13.6 – 40.1) and median OS 8.1 months (90% CI 5.5 - 12.4). Treatment-emergent adverse events were consistent with prior HP studies. There was no association between HER2 CN and response....HP had activity in a minority of tumours in this population, but did not meet the predefined efficacy benchmark for non-breast/gastroesophageal cancers with HER2 amplifications by NGS.

Thirty of 114 patients (26%; 95% CI, 19% to 35%) with HER2 amplification/overexpression had objective responses to treatment with trastuzumab plus pertuzumab (two CR, 28 PR). Objective responses were seen in nine primary tumor types: colorectal, bladder, biliary, salivary gland, NSCLC, pancreas, ovary, prostate, and skin (apocrine; Table 3).

Patients in this subset analysis were aged 18 years or older and had treatment-refractory, histologically confirmed HER2-amplified metastatic colorectal cancer...Patients received pertuzumab (840 mg loading dose, then 420 mg every 3 weeks, intravenously) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks, intravenously)...Among these 57 evaluable patients, as of Aug 1, 2017, one (2%) patient had a complete response and 17 (30%) had partial responses; thus overall 18 of 57 patients achieved an objective response (32%, 95% CI 20-45).

Normalized NADH/FAD ratio revealed significant metabolic response to panitumumab (-20%, G?=0.66) and trastuzumab/pertuzumab (-35%, G?=1.16) with insignificant effect of single agent trastuzumab (-14%, G?=0.46). Therapeutic dose escalation in a single PDCO of HER2 amplified CRC suggests improved sensitivity to EGFRi and dual HER2 targeting with trastuzumab/pertuzumab.