A nectin-4 antibody-drug conjugate through 395 patients, with the efficacy still to come

Design

Multicentre, single-arm phase 1 trial with Bayesian optimal interval dose escalation and expansion stages, at 39 hospitals

Population

395 pretreated adults with advanced solid tumours, all Chinese, ECOG 0-1; median age 59 years, median follow-up 7.2 months

Primary outcome

Safety, dose-limiting toxicity, maximum tolerated dose and recommended phase 2 dose

Effect

One dose-limiting toxicity (grade 4 thrombocytopenia at 10 mg/kg); maximum tolerated dose not reached; grade 3-4 treatment-related events 54% (neutropenia 30%, leucopenia 19%, anaemia 17%); serious treatment-related events 25%; two treatment-related deaths

Nectin-4 is the target of enfortumab vedotin in urothelial cancer, and is expressed across other solid tumours. SHR-A2102 pairs a fully human nectin-4 antibody with a topoisomerase I inhibitor payload on a cleavable linker — the payload class that has driven recent antibody-drug conjugate success.

This phase 1 trial ran at 39 hospitals in China and treated 395 patients across dose escalation, pharmacokinetic expansion and efficacy expansion: 197 with non-small-cell lung cancer, 77 with oesophageal squamous cell carcinoma, 68 with breast cancer, 26 with head and neck squamous cell carcinoma and 27 with other tumours. Doses ran from 2 to 10 mg/kg every three weeks. Only one dose-limiting toxicity occurred — grade 4 thrombocytopenia at 10 mg/kg — and the maximum tolerated dose was not reached.

Toxicity was haematological and substantial: grade 3-4 treatment-related events in 54%, most commonly neutropenia (30%), leucopenia (19%) and anaemia (17%). Serious treatment-related events occurred in 25%, pneumonia being the commonest at 5%, and two patients died of treatment-related causes.

The interpretation section describes promising activity, but this report does not give response rates, so nothing about efficacy can be stated here. What it establishes is a tolerable dose range across several tumour types, which is what phase 1 is for.

• No change to practice; this is dose-finding
• Expect haematological toxicity to dominate if this class reaches later trials
• Every participant was Chinese and treated in China; tolerability elsewhere is untested
• Note that pneumonia was the commonest serious treatment-related event
• Watch for the phase 2 readouts, which are where activity will be quantified

Why it matters

It extends a target proven in urothelial cancer into lung, oesophageal and breast disease, where the question of activity is now testable.

Don't overread it

This is a single-arm phase 1 trial with no control group and no response rates in the available report.

The statistics, in plain English

A maximum tolerated dose that is not reached means the trial ran out of planned doses before it ran out of tolerability, so the ceiling is unknown rather than high. Fifty-four per cent grade 3-4 treatment-related events is a large figure but comes from a heavily pretreated population in which marrow reserve is already reduced. The absence of reported response rates in this record means no efficacy claim can be assessed, and none is made here.

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