Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors

Abstract

HER2-targeted therapies are approved only for HER2-positive breast and gastric cancers. We assessed the safety/tolerability and activity of the novel HER2-targeted antibody-drug conjugate trastuzumab deruxtecan (T-DXd) in 60 patients with pretreated, HER2-expressing (IHC ≥ 1+), non-breast/non-gastric or HER2-mutant solid tumors from a phase I trial (NCT02564900). Most common (>50%) treatment-emergent adverse events (TEAE) were nausea, decreased appetite, and vomiting. Two drug-related TEAEs were associated with fatal outcomes. The confirmed objective response rate (ORR) was 28.3% (17/60). Median progression-free survival (PFS) was 7.2 [95% confidence interval (CI), 4.8-11.1] months. In HER2-mutant non-small cell lung cancer (NSCLC), ORR was 72.7% (8/11), and median PFS was 11.3 (95% CI, 8.1-14.3) months. Confirmed responses were observed in six tumor types, including HER2-expressing NSCLC, colorectal cancer, salivary gland cancer, biliary tract cancer, endometrial cancer, and HER2-mutant NSCLC and breast cancer. Results suggest T-DXd holds promise for HER2-expressing/mutant solid tumors. SIGNIFICANCE: T-DXd demonstrated promising activity in a heterogeneous patient population with heavily pretreated HER2-expressing or HER2-mutant solid tumors, especially HER2-mutant NSCLC. The safety profile was generally acceptable. Interstitial lung disease can be severe and requires prompt monitoring and intervention. Further research of T-DXd is warranted to address these unmet medical needs.See related commentary by Rolfo and Russo, p. 643.This article is highlighted in the In This Issue feature, p. 627.

©2020 American Association for Cancer Research.

Figures

Figure 1.

Study design and patient disposition. Data cutoff for this analysis was February 2019. BC, breast cancer; CRC, colorectal cancer; EWOC, escalation with overdose control; GC, gastric cancer; mCRM, modified continuous reassessment method; PK, pharmacokinetics.

Figure 2.

Kaplan–Meier estimate for PFS for T-DXd (6.4 mg/kg) in patients with HER2-expresssing non-breast, non-gastric cancers or HER2-mutant advanced solid tumors. Data cutoff for this analysis was February 2019.

Figure 3.

Best percentage change in tumor size and tumor shrinkage over time (based on central laboratory assessment) after T-DXd in patients with NSCLC (A), colorectal cancer (B), or other cancers (C). HER2 expression and mutation values shown are based on central laboratory assessment. HER2 expression and mutation status at enrollment was determined via local assessment. Of the 60 patients, 51 were evaluable for tumor shrinkage. Eight patients did not have baseline measurable disease and 1 patient did not have a post-baseline tumor assessment. Data cutoff for this analysis was February 2019. Red lines denote 20% increase or 30% reduction in tumor size, respectively. Br, breast cancer; Ch, cholangiocarcinoma; E20, exon 20 insertion; En, endometrial cancer; Es, esophageal cancer; Ex, extraskeletal myxoid chondrosarcoma; Ga, gallbladder cancer; NE, not evaluated; Pc, pancreatic cancer; Pg, Paget disease; Sa, salivary duct carcinoma; SI, small-intestine adenocarcinoma; TM, single base pair substitution at transmembrane domain.