Astra tentatively takes Tigit pivotal

Bispecifics targeting Tigit and CTLA4 head into phase 3 development, as the developer follows Bristol out of IL-12.

The Tigit mechanism has much to prove this year, but Astrazeneca has apparently seen enough to push on. The PD-1/Tigit bispecific rilvegostomig, previously codenamed AZD2936, will move into pivotal development this year, the developer announced today.

Rilvegostomig is currently being tested in the phase 1/2 Artemide-01 trial – Astra has guided to readout in 2024 – but the trial is open label and the developer has presumably gleaned promising signals. A much bolder plan was unveiled for volrustomig, its PD-1/CTLA-4 bispecific, which is heading into five new phase 3 studies in 2023.

The more cautious approach with rilvegostomig is understandable given Tigit’s unproven potential. Susan Galbraith, Astrazeneca’s head of oncology R&D, acknowledged that overall survival data are awaited, presumably a reference to the Roche Skyscraper-01 study of tiragolumab.

She told a press conference that the next wave of immuno-oncology combinations are likely to result in greater patient segmentation, and that the Tigit-blocking pathway could become particularly important at the higher end of PD-L1 expression. Astra is also betting that bispecifics, rather than molecules that hit a single target, will be more convenient.

“You don’t get an added toxicity penalty and that enables further combination, which is an important part of our strategy overall,” she said.

That combination approach is likely to be on show when the pivotal programme for volrustomig, formerly called MEDI5752, is unveiled. The project is currently in two phase 1 trials in various solid tumours – again, the drugmaker has guided to data in 2024 – while pivotal settings will include NSCLC.

Astrazeneca's bispecific push 
Project Ongoing trials Data? Pivotal plan
Volrustomig (PD-1/CTLA-4) Advanced renal cell carcinoma, + Inlyta or Lenvima; advanced solid tumours, +/-chemo 2024 Five phase 3s planned in 2023 across key tumour types, incl NSCLC (vs SOC regimens)
Rilvegostomig (PD-1/Tigit) Artemide-01 (NSCLC monotherapy in CPI experienced and naïve) 2024 New phase 3 planned in 2023
AZD7789 (PD-1/Tim3) NSCLC and other tumours; R/R Hodgkin lymphoma  >2024 None detailed
Source: Company communications.

Another new combination trial unveiled today will see Imfinzi plus the Daiichi Sankyo-partnered ADC datopotamab deruxtecan against Keytruda in first-line NSCLC. The study, called Avanzar, will stratify for a Trop2 biomarker. Readout of the second-line Tropion-Lung01 study, which tests the ADC versus docetaxel, is probably the biggest catalyst for the drug maker, and its Japanese partner, this year.

Other notable pipeline updates today include the dropping of a second IL-12 asset, the phase 1 gene therapy MEDI9253; a Moderna-partnered projected was ditched last year. Ms Galbraith said neither project was showing appropriate efficacy to push on, and that the moves do not reflect any disbelief in IL-12 as an important cytokine. This is notable considering Bristol Myers Squibb also exited this area this week.

Outside of oncology, Mene Pangalos, head of biopharmaceuticals R&D, confirmed that Astra would not be pursuing roxadustat for anaemia associated with chronic kidney disease in the US. Fibrogen had hinted as much in filings last year, and given the FDA’s reluctance to approve these agents, and the huge burden of proof that would be required to change the agency's mind, the decision is not entirely surprising.

Astrazeneca has plenty of other places to put its money – it plans to start more than 30 phase 3 trials in 2023. 

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