CytomX emerges from masked obscurity

CytomX, once the also-ran in masked therapeutics, is now firmly established in investors’ minds as a key contender. This puts the spotlight on the company’s imminent catalyst, updated results from a phase 1 study of its lead asset, varsetatug masetecan, that are to determine the dose to be taken into a registrational trial.

The data, expected during the current quarter, relate to a trial in late-line colorectal cancer, and could also suggest whether varseta-M has a chance to move into earlier treatment settings. A key focus will be safety, given last year’s diarrhoea toxicity scare; that said, this barely dented the meteoric rise in CytomX stock.

The shares have climbed 640% over the past year, only coming off slightly in the past month. This has pushed CytomX’s market cap over $800m, putting it level with its rival Janux, which has had a reversal of fortune; Janux was the biotech that two years ago breathed new life into masked therapeutics, but recently saw its shares crash 49% on disappointing clinical data.

100 patients

Varseta-M is an ADC that targets EpCAM, and it’s only been a year since CytomX pivoted to it as its lead project. It showed its first signs of promise a few months later, with a 28% ORR among 18 patients given 7.2, 8.6 and 10.0mg/kg doses.

Now CytomX is looking for these data to hold up in many more patients. 73 had been enrolled as of last August, and the company says it hopes the dataset to comprise 100 when it gives the first-quarter update. For now all three doses are being investigated, but the aim is to select one for a registrational trial, and to reach agreement with the FDA over the design of such a study.

While it might be unrealistic to expect response rates to remain near 30%, there’s probably some leeway for the figure to fall off and still look competitive in this tough setting.

Some benchmarks for varseta-M in late-line colorectal cancer

Source: OncologyPipeline & academic literature.

CytomX’s ultimate goal is for varseta-M to be applicable to a biomarker-unselected colorectal cancer population, thanks to this cancer typically featuring high levels of EpCAM expression. However, hitting this target has been problematic, with gastrointestinal and liver toxicity scuppering Amgen’s T-cell engager solitomab, for instance.

Other antibody-based anti-EpCAM assets in clinical development, according to OncologyPipeline, include T-cell engagers from BioAtla (BA3182) and Lindis Biotech (catumaxomab), and a 4-1BB-co-stimulated MAb from Genmab and BioNTech (BNT314/GEN1059), but the database reveals no ADCs beyond varseta-M.

For its part CytomX says catumaxomab has validated the mechanism, though so far only in an oncology-adjacent setting, having been approved in the EU in malignant ascites; catumaxomab is being tested in non-muscle invasive bladder cancer.

The design of varseta-M is key to opening up the therapeutic window on EpCAM blockade; both the MAb’s EpCAM-binding domains are masked, to reduce activity in normal tissue. CytomX says a non-masked MAb or ADC isn’t expected to have a therapeutic window on account of its systemic toxicity.

However, varseta-M has shown diarrhoea toxicity and acute kidney injury, and these will be closely watched in the upcoming data reveal, being key to determining the molecule’s go-forward dose. CytomX says there’s been no sign of the pancreatitis or liver toxicity that have undone prior EpCAM work, and it has implemented prophylaxis for diarrhoea in phase 1 expansion.

Beyond the monotherapy setting for late-line colorectal cancer, CytomX wants to target first and second-line combinations to supplement such current standards of care as Folfox/Folfiri, Avastin, checkpoint blockade and BRAF inhibition. It plans to take a varseta-M/Avastin combo into phase 1 this month, with the trial informing development in early colorectal cancer treatment lines.

First, however, it has to show monotherapy activity continuing at or near previous levels, and without a repeat of the toxicity worries.