In the first phase 3 trial to show the superiority of a TROP2-targeted antibody-drug conjugate and an immunotherapy agent in first-line triple-negative breast cancer (TNBC), Gilead Sciences’ Trodelvy has notched a much-needed win.
Trodelvy’s combination with Merck & Co.’s Keytruda was better than Keytruda and chemotherapy at prolonging the time before cancer returns or death in patients with previously untreated metastatic TNBC whose tumors express PD-L1, Gilead announced Monday.
The readout came from the phase 3 Ascent-04, or Keynote-D19, trial, which sets PD-L1 positivity cutoff at a combined positive score of at least 10, the same population that got Keytruda-chemo its FDA nod in this setting in 2020.
“These findings are the first to show the transformative potential of an antibody-drug conjugate combined with an immuno-oncology agent in early treatment lines of metastatic breast cancer,” Gilead’s newly minted chief medical officer, Dietmar Berger, M.D., Ph.D., said in a statement Monday.
Before the Trodelvy readout, a combination of Pfizer and Astellas’ Nectin-4 ADC Padcev and Keytruda won a full FDA approval in late 2023 as a first-line treatment for advanced bladder cancer. Also on Monday, AstraZeneca and Daiichi Sankyo said their HER2 ADC Enhertu and Roche’s monoclonal antibody Perjeta was successful in first-line HER2-positive breast cancer.
The positive first-line TNBC readout is a much-needed win for Trodelvy. The first-in-class drug is dealing with the market entrant of two other TROP2 ADCs, AZ and Daiichi’s Datroway in the U.S., and Kelun-Biotech’s Merck-partnered sacituzumab tirumotecan (sac-TMT) in China.
Trodelvy is also reeling from some clinical setbacks, including a high-profile flop in previously treated non-small cell lung cancer and another failed phase 3 that led to the withdrawal of an accelerated approval in bladder cancer.
Now, Gilead argues that the “significant and meaningful” improvement in progression-free survival as shown in Ascent-04 “further reinforces the potential of Trodelvy plus Keytruda as a much-needed new treatment option” in first-line, PD-L1-positive metastatic TNBC.
While data on the key secondary endpoint of overall survival was not mature, Gilead said there was an early sign of improvement with the Trodelvy-Keytruda combo.
The company will discuss the results with regulatory authorities. Despite existing treatment options, more than 50% of PD-L1-positive TNBC patients do not get to second-line treatments, Gilead pointed out.
Gilead has put Ascent-04’s addressable patient population at about 10,000 across the U.S. and EU5 countries in 2030, Citi analysts noted Monday. The Citi team has a more bullish view of Trodelvy’s potential, predicting the drug could reach peak sales of $3.2 billion by 2030, versus the consensus estimate of $2.9 billion.
Besides Ascent-04, Gilead expects a readout by June from the phase 3 Ascent-03 trial pitting Trodelvy against chemo in first-line, PD-L1-negative metastatic TNBC. The Ascent-05 study is testing Trodelvy and chemo as an adjuvant treatment in TNBC patients who have residual invasive disease after surgery and neoadjuvant therapy.
Trodelvy was once a main talking point for Gilead and its oncology ambition. But after several clinical flops, investors’ attention has lately turned back to the company’s bread-and-butter HIV business, especially the much-anticipated potential launch of the twice-yearly PrEP drug lenacapavir, as well as the Arcellx-partnered CD19 CAR-T candidate anito-cel.