Abstract
Final analysis of multi-histology basket trial expansion of ado-trastuzumab emtansine in patients with HER2 amplified cancers.
Author
person
Dazhi Liu
Memorial Sloan Kettering Cancer Center, New York, NY
info_outline
Dazhi Liu, Vicky Makker, Darren J. Buonocore, Ronglai Shen, Rona Yaeger, Michelle S. Ginsberg, Randy Yeh, Amanda Johnson, Michael Offin, David B. Solit, Alexander E. Drilon, Charles M. Rudin, Mark G. Kris, Jorge S. Reis-Filho, Pedram Razavi, Sarat Chandarlapaty, Kanika Arora, Michael F. Berger, Alan Loh Ho, Bob T. Li
Full text
Authors
person
Dazhi Liu
Memorial Sloan Kettering Cancer Center, New York, NY
info_outline
Dazhi Liu, Vicky Makker, Darren J. Buonocore, Ronglai Shen, Rona Yaeger, Michelle S. Ginsberg, Randy Yeh, Amanda Johnson, Michael Offin, David B. Solit, Alexander E. Drilon, Charles M. Rudin, Mark G. Kris, Jorge S. Reis-Filho, Pedram Razavi, Sarat Chandarlapaty, Kanika Arora, Michael F. Berger, Alan Loh Ho, Bob T. Li
Organizations
Memorial Sloan Kettering Cancer Center, New York, NY, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical Center, New York, NY
Abstract Disclosures
Research Funding
Conquer Cancer Foundation of the American Society of Clinical Oncology
Conquer Cancer Foundation of the American Society of Clinical Oncology, U.S. National Institutes of Health
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.
Clinical status
Clinical
1 clinical trial
2 organizations
1 drug
1 target
Clinical trial
A Phase 2 Trial of Ado-Trastuzumab Emtansine for Patients With HER2 Amplified or Mutant CancersStatus: Recruiting, Estimated PCD: 2025-02-01
Organization
Memorial Sloan Kettering Cancer CenterTarget
HER2 (ERBB2)