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Clinical Trial
. 2019 Nov 1;30(11):1821-1830.
doi: 10.1093/annonc/mdz291.

Ado-trastuzumab emtansine (T-DM1) in patients with HER2-amplified tumors excluding breast and gastric/gastroesophageal junction (GEJ) adenocarcinomas: results from the NCI-MATCH trial (EAY131) subprotocol Q

K L Jhaveri  1 , X V Wang  2 , V Makker  3 , S-W Luoh  4 , E P Mitchell  5 , J A Zwiebel  6 , E Sharon  7 , R J Gray  8 , S Li  8 , L M McShane  9 , L V Rubinstein  10 , D Patton  11 , P M Williams  12 , S R Hamilton  13 , B A Conley  14 , C L Arteaga  15 , L N Harris  14 , P J O'Dwyer  16 , A P Chen  17 , K T Flaherty  18
Affiliations
Clinical Trial

Ado-trastuzumab emtansine (T-DM1) in patients with HER2-amplified tumors excluding breast and gastric/gastroesophageal junction (GEJ) adenocarcinomas: results from the NCI-MATCH trial (EAY131) subprotocol Q

K L Jhaveri et al. Ann Oncol. .

Erratum in

Abstract

Background: The National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) is a national precision medicine study incorporating centralized genomic testing to direct refractory cancer patients to molecularly targeted treatment subprotocols. This treatment subprotocol was designed to screen for potential signals of efficacy of ado-trastuzumab emtansine (T-DM1) in HER2-amplified histologies other than breast and gastroesophageal tumors.

Methods: Eligible patients had HER2 amplification at a copy number (CN) >7 based on targeted next-generation sequencing (NGS) with a custom Oncomine AmpliSeq™ (ThermoFisher Scientific) panel. Patients with prior trastuzumab, pertuzumab or T-DM1 treatment were excluded. Patients received T-DM1 at 3.6 mg/kg i.v. every 3 weeks until toxicity or disease progression. Tumor assessments occurred every three cycles. The primary end point was centrally assessed objective response rate (ORR). Exploratory end points included correlating response with HER2 CN by NGS. The impact of co-occurring genomic alterations and PTEN loss by immunohistochemistry were also assessed.

Results: Thirty-eight patients were enrolled and 36 included in efficacy analysis. Median prior therapies in the metastatic setting was 3 (range 0-9; unknown in one patient). Median HER2 CN was 17 (range 7-139). Partial responses were observed in two (5.6%) patients: one mucoepidermoid carcinoma of parotid gland and one parotid gland squamous cell cancer. Seventeen patients (47%) had stable disease including 8/10 (80%) with ovarian and uterine carcinomas, with median duration of 4.6 months. The 6-month progression-free survival rate was 23.6% [90% confidence interval 14.2% to 39.2%]. Common toxicities included fatigue, anemia, fever and thrombocytopenia with no new safety signals. There was a trend for tumor shrinkage with higher levels of gene CN as determined by the NGS assay.

Conclusion: T-DM1 was well tolerated. While this subprotocol did not meet the primary end point for ORR in this heavily pre-treated diverse patient population, clinical activity was seen in salivary gland tumors warranting further study in this tumor type in dedicated trials.

Keywords: HER2-amplified; NCI-MATCH; NGS; T-DM1.

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Figures

Figure 1.
Figure 1.
ERBB2 amplification frequency: all tumors excluding breast and gastric/gastroesophageal junction tumors. This plot includes solid tumors (467/28 106 samples and 442/25 637 patients) with a minimum of 50 sequenced tumors and ERBB2 amplification > 0% using MSK-IMPACT assay. The numbers in the parentheses are the total number of sequenced tumors. (cBioPortal.org).
Figure 2.
Figure 2.
Consort diagram.
Figure 3.
Figure 3.
(A) Efficacy: Best% change from baseline (n = 28). Four patients had PD based on new lesions but data for the target lesions are not available so not included in this plot. (B) Treatment Duration in patients who achieved SD or PR. (C) Kaplan–Meier curve for progression-free survival. GYN, gynecological; CI, confidence interval; GI, gastrointestinal.
Figure 4.
Figure 4.
Correlation of best % change by ERBB2 copy number gain (n = 28). PR, partial response; SD, stable disease; PD, progressive disease.
Figure 5.
Figure 5.
Co-occurring genomic alterations with HER2 amplification using the NCI-MATCH assay color coded by variant type (left): copy number variant (purple), single nucleotide variant (red), indel (pink) and number of variants (top) for each eligible patient along with information regarding histology and best response on treatment (bottom): partial response (PR), stable disease (SD), progression of disease (PD), unevaluable (UE).
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