Enhertu could fill a gastric hole
The first-line Destiny-Gastric05 trial includes a PD-L1-negative cohort.
The first-line Destiny-Gastric05 trial includes a PD-L1-negative cohort.
AstraZeneca and Daiichi’s HER2-targeting ADC Enhertu is already FDA-approved in second-line gastric cancer, but the companies have ambitions in first-line disease – and the latest pivotal study, Destiny-Gastric05, could help them hit a niche that the PD-(L)1 inhibitors cannot.
That’s because the trial, in HER2-positive patients, includes an exploratory cohort of patients with PD-L1 expression below 1%. The gastric cancer landscape has been shifting recently, and it’s becoming increasingly clear that the only place for checkpoint inhibitors is in PD-L1 expressers.
Destiny
A Keytruda/Herceptin/chemo combo gained accelerated US approval in 2021 in HER2-positive first-line gastric cancer regardless of PD-L1 status, but this was later restricted to PD-L1 ≥1% expressers. An adcom last year then made it clear that future stomach cancer approvals would be limited to PD-L1-positive patients.
The base case for Astra and Daiichi seems to be challenging the incumbents in this PD-L1-expressing population. The main cohort of Destiny-Gastric05, which began dosing this week, calls for PD-L1 levels of 1% or more.
In this arm, a combination of Enhertu, Keytruda and chemo will be pitted against Herceptin, Keytruda and chemo. 576 patients will be enrolled, according to Daiichi’s January third-quarter earnings presentation.
Meanwhile, in 150 PD-L1-negatives, the trial will evaluate Enhertu plus chemo, versus Herceptin plus chemo. The primary endpoint is progression-free survival, with overall survival as a key secondary.
The groups are also trialling another combo in first-line gastric cancer: the Artemide-Gastric01 trial, which began in early March, will test Enhertu alongside AstraZeneca’s anti-TIGIT x PD-1 MAb rilvegostomig and chemo in PD-L1 ≥1% expressers.
There’s plenty of doubt about TIGIT after various blow ups across the industry – only on Thursday BeiGene discontinued its contender ociperlimab – but this isn’t stopping Astra from starting new trials.
Phase 3 trials of Enhertu in gastric cancer
| Trial | Setting | Regimen | Primary endpoint | Note |
|---|---|---|---|---|
| Destiny-Gastric04 | 2nd-line, HER2+ve | Enhertu, vs Cyramza + paclitaxel | OS | Toplined positive Mar 2025; Enhertu already has full approval for post-Herceptin gastric cancer, based on Destiny-Gastric01 |
| Destiny-Gastric05 | 1st-line, HER2+ve (main cohort PD-L1 ≥1%; includes exploratory cohort in PD-L1 <1%) | Enhertu + chemo + Keytruda, vs Herceptin + chemo + Keytruda (exploratory cohort tests Enhertu + chemo, vs Herceptin + chemo) | PFS | 1st pt dosed Mar 2025; primary completion Jun 2028 |
| Artemide-Gastric01 | 1st-line, HER2+ve | Enhertu + rilvegostomig + chemo, vs Herceptin + Keytruda + chemo | PFS, OS | Started Mar 2025; primary completion Apr 2029 |
Source: OncologyPipeline & clinicaltrials.gov.
Destiny-Gastric05 seems like a surer bet. The new study has started not long after Astra and Daiichi reported that the second-line Destiny-Gastric04 was being unblinded at interim analysis, after Enhertu showed improved overall survival versus Cyramza and paclitaxel.
Enhertu received full FDA approval in relapsed gastric cancer in January 2021, based on ORR and OS from the phase 2 third-line Destiny-Gastric01 trial in Japan and South Korea, which had irinotecan or paclitaxel as control.
The global Destiny-Gastric04 should therefore shore up its position here; data will be disclosed at an unnamed upcoming medical meeting.
Now the drug needs to repeat the trick in first-line disease; a win in PD-L1 negatives would be the cherry on the cake.
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