SHR-A1811 (antibody-drug conjugate) in advanced HER2-mutant non-small cell lung cancer: a multicenter, open-label, phase 1/2 study

Abstract

A dose-escalation and expansion, phase 1/2 study (ClinicalTrials.gov, NCT04818333) was conducted to assess the novel antibody-drug conjugate SHR-A1811 in pretreated HER2-altered advanced non-small cell lung cancer (NSCLC). Here, we report results from the phase 1 portion. Patients who had previously failed or were intolerant to platinum-based chemotherapy were enrolled and received SHR-A1811 intravenously at doses of 3.2 to 8.0 mg/kg every 3 weeks. Dose escalation followed a Bayesian logistic regression model that included overdose control, with subsequent selection of tolerable levels for dose expansion. Overall, 63 patients were enrolled, including 43 receiving a recommended dose for expansion of 4.8 mg/kg. All patients had HER2-mutant disease. Dose-limiting toxicity occurred in one patient in the 8.0 mg/kg dose cohort. Grade ≥ 3 treatment-related adverse events occurred in 29 (46.0%) patients. One patient in the 6.4 mg/kg cohort died due to interstitial lung disease. As of April 11, 2023, the 4.8 mg/kg cohort showed an objective response rate of 41.9% (95% CI 27.0-57.9), and a disease control rate of 95.3% (95% CI 84.2-99.4). The median duration of response was 13.7 months, with 13 of 18 responses ongoing. The median progression-free survival was 8.4 months (95% CI 7.1-15.0). SHR-A1811 demonstrated favourable safety and clinically meaningful efficacy in pretreated advanced HER2-mutant NSCLC.

Fig. 1

Trial profile. Study flowchart (a) and patient disposition (b) for phase 1 part of the trial are presented. TS was the primary analysis set for efficacy and safety. *Three patients (4.8 mg/kg, n = 2; 5.6 mg/kg, n = 1) with no evaluable pharmacokinetic data were excluded from PKPS. AE adverse event, BLRM Bayesian logistic regression model, PD progressive disease, PKPS pharmacokinetic parameter set, RP2D recommended phase 2 dose, SMC safety monitoring committee, TS treated set

Fig. 2

Pharmacokinetic profile of SHR-A1811 and total antibody (a) and free payload (b) after single dosing. Data are mean ± standard deviation. *Three enrolled patients (4.8 mg/kg, n = 2; 5.6 mg/kg, n = 1) had no evaluable pharmacokinetic data and were excluded from the analysis

Fig. 3

Tumor response. a Percentage change in target lesion over time in individual patients. b Best percentage change in target lesion from baseline in individual patients. * The patient was excluded from panel (a) as the first post-baseline tumor assessment was performed earlier than the specified time window due to clinical deterioration

Fig. 4

Biomarker analysis of ctDNA level within 6 months of treatment. a Maximum percent change in VAF and SoD during dosing relative to baseline. 25 patients (best response, PR, n = 12; SD, n = 13) with blood samples collected at both baseline and during dosing were included. b Linear correlation between ctDNA level within 6 months of treatment initiation and PFS. c Distributional differences in ctDNA levels between drug-resistant and drug-sensitive patients within 6 months of drug initiation. d Kaplan–Meier plot of PFS according to ctDNA clearance within 6 months. e Proportion of drug-resistant versus drug-sensitive patients according to ctDNA clearance within 6 months. Twenty-two patients (≥2 blood samples collected, or 1 sample collected due to recurrence or death within 6 months) were included in the analyses. PFS progression-free survival, PR partial response; SD stable disease; SoD sum of diameter, VAF variant allele frequency