No lost causes at Xilio and Lyell

Despite recent unfavourable developments, two struggling biotechs, Xilio Therapeutics and Lyell Immunopharma, aren't about to give up on their lead projects, judging by plans revealed at their quarterly updates on Tuesday. However, both are proceeding cautiously, which given the precedent makes sense.

Xilio is maintaining a questionable claim that its lead, the masked anti-CTLA-4 MAb vilastobart, delivered "promising" phase 2 data, but has doubled down on plans to license it out for further development. And Lyell is planning a fresh phase 3 trial of the dual anti-CD19/CD20 Car-T therapy IMPT-314, but notably this won't include Car-relapsed patients, a setting in which Cargo Therapeutics crashed in January.

Xilio was thought to have been drawing a line under vilastobart, which at ASCO-GI managed a confirmed response rate of just 11% in combination with Tecentriq in MSS colorectal cancer, and 0% in patients with liver metastases (a common problem in this cancer), plus worrying toxicity.

This view was reinforced when the company surprised the markets with a discovery deal with AbbVie covering masked T-cell engagers, something that gave it a new focus plus a $52m eleventh-hour bailout. Despite this, on Tuesday Xilio insisted that it still had faith in vilastobart, promising an update from the phase 2 Tecentriq combo trial in mid-2025.

However, taking vilastobart development beyond this will depend on finding a partner. As such, it's understandable for Xilio to play up the phase 2 results, since they will drive any deal it manages to sign. Things to look for at the mid-year update include whether one unconfirmed response has been confirmed on subsequent scan, and whether any additional responses materialise.

Cargo crash

Meanwhile, Lyell came under the spotlight along with Cargo Therapeutics among companies seeking to develop Car-T therapies that might avert relapse in lymphoma patients, a common problem with marketed anti-CD19 Car-Ts.

Lyell acquired IMPT-314 last October in the takeover of ImmPACT Bio, itself seen as a pivot away from earlier disappointments in ROR1-targeting Car-T therapy. While IMPT-314 uses a bispecific anti-CD19/CD20 construct, Cargo's firicabtagene autoleucel hits CD22, and the latter's high-profile Firce-1 study blew up in January.

However, Firce-1 looked specifically at patients who had relapsed after a standard anti-CD19 Car like Yescarta, Kymriah or Breyanzi. For its part, IMPT-314 is being tested in those who have relapsed on other drugs, but are still naive to Car-T therapy.

It was in this latter setting that Lyell presented phase 1/2 data at last year's ASH, showing a 94% ORR (including a 71% three-month CR rate) among 17 patients who had received at least two prior therapy lines. A pivotal study in the same third-line-plus setting is to start this year, though it has yet to be entered on the clinicaltrials.gov registry.

On Tuesday Lyell added to this with plans to begin a second phase 3 "by early 2026", this one looking at second-line DLBCL. Neither pivotal study allows prior Car-T treatment, so IMPT-314 is being positioned as something better than a CD19 Car, rather than something that can rescue a patient who relapses on a CD19 Car, as was the case with firi-cel.

More information on the design of Lyell's phase 3 trials, especially whether they will include a CD19 Car as active comparator, are now awaited.