A nectin-4 antibody-drug conjugate in phase 1: cytopenias dominated toxicity

Design

Multicentre, single-arm, phase 1 dose-escalation and expansion trial

Population

395 patients with pretreated advanced solid tumours, 39 hospitals in China

Primary outcome

Safety, dose-limiting toxicity and recommended phase 2 dose

Effect

Grade 3-4 treatment-related AEs 54%; serious 25%; 2 treatment-related deaths

SHR-A2102 is an antibody-drug conjugate that targets nectin-4 and carries a topoisomerase I inhibitor. This single-arm phase 1 trial at 39 Chinese hospitals treated 395 patients with pretreated advanced solid tumours, half with non-small cell lung cancer, at 2 to 10 mg/kg every three weeks.

The maximum tolerated dose was not reached, and 6 and 8 mg/kg were taken forward. Grade 3 to 4 treatment-related adverse events occurred in 54%, most often low neutrophils (30%), low white cells (19%) and anaemia (17%). Serious treatment-related events occurred in 25%, most often pneumonia, and two patients died of treatment-related causes.

The abstract describes activity as promising without giving response rates. This is early-phase work; its relevance is as a signal of where the antibody-drug conjugate pipeline is heading.

• Expect marked myelosuppression with topoisomerase I inhibitor payload conjugates; monitor counts closely.
• Watch for pneumonia and treat infections early in patients on these agents.
• Consider trial referral for pretreated patients with good performance status where nectin-4 conjugates are being studied.
• Do not infer efficacy from a phase 1 safety report.

Why it matters

Nectin-4 is expressed across several common solid tumours, which makes this class worth watching beyond urothelial cancer.

Don't overread it

Phase 1 data establish dose and toxicity, not efficacy.

The statistics, in plain English

A single-arm phase 1 trial has no comparison group, so it can describe toxicity but cannot show benefit. Median follow-up was only about seven months.

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