A triple-negative breast cancer face-off

The battle to become the best TROP2-targeting antibody-drug conjugate is increasingly seen as being between Merck & Co/Kelun’s sacituzumab tirumotecan and Daiichi Sankyo/AstraZeneca’s datopotamab deruxtecan. However, Gilead isn’t giving up on Trodelvy without a fight, as shown by the vast number of pivotal studies it’s now initiated.

One of these, Ascent-03 in front-line triple-negative breast cancer, will soon read out, and this catalyst gives Gilead another chance to show that its $21bn buyout of Trodelvy’s originator, Immunomedics, wasn’t money wasted. Still, competition isn’t far behind, and an analogous dato-dxd study, Tropion-Breast02, will yield data in the same second-half timeframe.

On the face of it, therefore, any success Trodelvy manages to score risks being neutralised by dato-dxd. In ER-positive breast cancer the two molecules have generated similar data, and if anything it’s the Merck/Kelun ADC that looks like the one to beat – albeit on the basis of early results.

Trodelvy is already approved for late-line TNBC, as well as for the ER-positive HER2-negative disease for which dato-dxd faces a February 2025 PDUFA date on the back of the Tropion-Breast01 trial. The two are also doing battle in second-line NSCLC, where dato-dxd has a December regulatory decision based on a benefit in non-squamous patients in Tropion-Lung01, while Gilead has played up a questionable subgroup in the Evoke-01 trial.

First line

Now the focus turns to early TNBC, a setting that’s been transformed by Keytruda, which is approved front line in patients whose tumours express PD-L1 at ≥10%, as well as in the perioperative setting as part of a chemo combo.

The availability of Keytruda explains the designs of Ascent-03 and Tropion-Breast02. Both global phase 3 trials are eligible only to patients who aren’t candidates for Keytruda, either by virtue of not expressing PD-L1 at ≥10%, by having received Keytruda in the periadjuvant setting, by having co-morbidities or because they’re based in a country where Keytruda isn’t available.

Tropion-Breast02 also lists as an exclusion criterion a history of interstitial lung disease or pneumonitis. This is an acknowledgment of dato-dxd’s most concerning toxicity, which is a major focus for any of this ADC’s clinical trial readouts.

Both studies enrol a broadly similar number of patients, and Tropion-Breast02 tests as co-primary endpoints progression-free and overall survival versus physician’s choice chemo (the options differ slightly versus Ascent-03). The Gilead trial, meanwhile, has set PFS as the sole primary, with OS appearing as the first listed secondary endpoint.

Though formally the trials’ completion dates are some years away, sellside analysts expect both to yield their first data in the second half. 

Given the prominence of saci-T it’s also worth considering how much of a threat the Kelun/Merck project poses in TNBC. This might be especially pertinent given that Merck owns Keytruda, and might thus see mileage in combining this drug with saci-T as part of a broader push into TNBC, including perhaps in PD-L1 expressers.

However, for now any threat seems some way off: in first-line TNBC the phase 3 effort is limited to Kelun’s China-focused Optitrop-Breast01 study; no other pivotal trials in first-line TNBC are under way, and Merck’s own Trofuse-012 concerns a Keytruda combo in adjuvant TNBC.

Gilead vs Astra/Daiichi in 1st-line TNBC

Source: OncologyPipeline.