Final analysis of multi-histology basket trial expansion of ado-trastuzumab emtansine in patients with HER2 amplified cancers.

Abstract

3025 Background: Human epidermal growth factor receptor 2 ( HER2, ERBB2) amplification occurs in 5% of non-breast non-gastric solid tumors. Ado-trastuzumab emtansine (T-DM1) showed preliminary efficacy in patients with HER2 amplified lung, endometrial, salivary gland, biliary tract and ovarian cancers, but the extent of its differential effects across histologies is unknown. Methods: Patients with HER2 amplified solid tumors were enrolled and received treatment 3.6mg/kg IV every 3 weeks. The primary endpoint was overall response rate (ORR) using RECIST v1.1 or PERCIST. A basket trial expansion used a Simon two stage optimal design applied to each of 5 histology cohorts with type I error rate under 2%, power of 90%, H0 10%, H1 40%, with family-wise error rate at 10%. After first stage, lung, salivary gland and endometrial cohorts were expanded to 23 patients. The null hypothesis was rejected for each cohort separately, if at least 6 responses were observed in each cohort. Secondary endpoints included duration of response (DOR), progression-free survival (PFS) and toxicity. HER2 amplification was identified by fluorescence in situ hybridization (FISH), or next generation sequencing (NGS). Correlative studies were performed using tissue immunohistochemistry (IHC). Plasma cell-free DNA (cfDNA) was collected throughout study treatment. Results: 88 patients with 8 unique cancer types were treated across 5 cohorts of HER2 amplified lung, salivary gland, colorectal, endometrial and other cancers. The median age was 66 (26-90). Median line of prior therapy was 2 (1-7). ORR was 33% (29/87 including 11 CRs, 95% CI 24-44%), including 47% (9/19) for lung cancers, 87% (13/15, 8 CRs) for salivary gland cancers, 22% (5/23, 3 CRs) for endometrial cancers, 12% (1/8) for biliary cancers, 14% (1/7) for ovarian cancers. Median DOR was 9.7 months (95% CI 4.8, 20.2), median PFS was 2.76 months (95% CI 2.53, 5.39). There were 8 (9%) G3 treatment related toxicities. HER2 fold change corrected for purity and ploidy by FACETS algorithm correlated with response (p=0.04) and PFS>=3 months (p=0.0037). HER2 amplification by NGS correlated with HER2/CEP17≥2 by FISH (67/71 tested) and IHC3+ (54/68 tested). We observed persistent HER2 amplification in plasma cfDNA during acquired resistance and progression on T-DM1 in patients with salivary gland cancers. Conclusions: Ado-trastuzumab emtansine showed promising efficacy in patients with HER2 amplified lung and salivary gland cancers as identified by NGS, meeting the primary endpoint. However, its efficacy did not meet prespecified response rate in patients with HER2 amplified endometrial, colorectal and other cancers. Histologic lineage differences in HER2 amplified cancers affect response and translational research is critical for further drug development. Clinical trial information: NCT02675829 .

Molecular Targeting of the Human Epidermal Growth Factor Receptor-2 (HER2) Genes across Various Cancers

“…T-DM1 showed only minimal activity in HER2-positive endometrial cancers in a phase II basket trial, with an ORR of 22% [133,140]. T-DXd is currently being evaluated in another basket trial of HER2-positive tumors, DESTINY-PanTumor02, which includes endometrial carcinoma (NCT04482309).…”

“…The phase IIa MyPathway basket trial of trastuzumab with pertuzumab in 39 patients with previously treated HER2-amplified and/or -overexpressed metastatic BTC showed an ORR of 23%, with DOR of 10.8 months, PFS of 4 months and OS of 10.9 months [84]. On the other hand, the phase II multi-histology basket trial of T-DM1 showed low activity, with an ORR of 12% in BTC [133,140]. T-DXd was also evaluated in the phase II Japanese HERB trial, with an ORR of 36.4%, PFS of 4.4 months and OS of 7.1 months in 22 patients with HER2-positive BTC refractory to a gemcitabine-based regimen [154].…”

Genomic Profiling and Molecular Characterisation of Metastatic Urothelial Carcinoma

“…The first one that was approved for clinical use was trastuzumab-emtansine (TDM-1), composed by an anti-HER2 monoclonal antibody (trastuzumab) linked to an anti-microtubule agent (DM-1) [69]. Although promising in preclinical activity, in a basket trial, TDM-1 did not show a response in UC patients [70]. A new multicentric, phase II clinical trial is ongoing to evaluate TDM-1 monotherapy or in combination with other drugs in UC [71].…”

Molecular Targeting the Human Epidermal Growth Factor Receptor-2 (HER2) Genes Across Various Cancer

“…T-DM1 showed only minimal activity in HER2 positive endometrial cancers in a phase II basket trial, with an ORR of 22% [132,142]. T-DXd is currently being evaluated in another basket trial of HER2-positive tumors, DESTINY-PanTumor02, which includes endometrial carcinoma (NCT04482309).…”

“…The phase IIa MyPathway basket trial of trastuzumab with pertuzumab in 39 patients with previously treated HER2 amplified and/or overexpressed metastatic BTC showed ORR of 23% with DOR of 10.8 months, PFS of 4 months and OS of 10.9 months [157]. On the other hand, the phase II multi-histology basket trial of T-DM1 showed low activity with ORR of 12% in BTC [132,142]. T-DXd was also evaluated in the phase II Japanese HERB trial with ORR of 36.4%, PFS of 4.4 months and OS of 7.1 months in 22 patients with HER2-positive BTC refractory to a gemcitabine-based regimen [158].…”