Gilead's Trodelvy Suffers Fresh Setback in Lung Cancer Trial, Clearing Path for Rivals

Gilead Sciences (GILD) has suffered another clinical defeat for its flagship antibody-drug conjugate Trodelvy, after a phase 3 trial in first-line lung cancer failed — intensifying the race among Merck, AstraZeneca (AZN) and Daiichi Sankyo (DSNKY) to capture the indication.

Gilead and Merck & Co (MRK) said Monday they were terminating the phase 3 Evoke-03 trial, also known as Keynote-D46, following the recommendation of an independent data monitoring committee. The study was evaluating Trodelvy combined with Merck's immunotherapy Keytruda as a first-line treatment in patients with PD-L1-high non-small cell lung cancer, against Keytruda alone. The trial missed its progression-free survival endpoint at final analysis, and an interim review of overall survival suggested statistical significance was unlikely to be achieved. Gilead's shares fell around 2.7% on Tuesday.

The failure compounds a second-line NSCLC setback from more than two years ago, and raises serious questions about Trodelvy's commercial trajectory. Without a first-line lung cancer label, the drug's future rests largely on its triple-negative breast cancer franchise — a base that analysts say cannot justify the $21bn Gilead paid for Trodelvy's developer, Immunomedics. The company has already taken significant write-offs tied to the drug's earlier NSCLC failure and a bladder cancer market withdrawal in 2024.

Analysts at Jefferies (JEF) and Leerink Partners said the PFS miss was unexpected. Leerink cautioned that the result signaled outperforming Keytruda monotherapy as an entry point into first-line NSCLC "may not be as easy as it seems."

Attention now turns to rival TROP2 ADCs. Both analyst teams expressed continued optimism around sac-TMT, being developed by Merck in partnership with Kelun-Biotech. A subgroup analysis from the positive OptiTROP-Lung05 study linked sac-TMT plus Keytruda to a 53% PFS improvement over Keytruda alone in previously untreated Chinese patients with PD-L1-high NSCLC. Merck's phase 3 TroFuse-007 study is now testing the combination in a global population. Analysts noted sac-TMT showed numerically stronger efficacy than Trodelvy in the setting, while cautioning that no direct head-to-head comparison exists. A lower discontinuation rate — below 10% in Kelun's study versus 24% in Gilead's phase 2 Evoke-02 trial — may also favor sac-TMT.

AstraZeneca (AZN) and Daiichi Sankyo are also pursuing first-line NSCLC, with their phase 3 Avanzar trial of TROP2 ADC Datroway expected to report results this year. One of their studies, Tropion-Lung08, is evaluating Datroway alongside Keytruda in patients with first-line nonsquamous, PD-L1-high NSCLC; AZ has also developed a TROP2 biomarker to help optimize patient selection and improve trial success rates.

For Gilead, one phase 3 readout remains: the Ascent-GYN study in second-line endometrial cancer, also expected this year. Investor focus is meanwhile shifting toward the company's next ADC bet — TUB-040, a NaPi2b-targeting candidate acquired through its $3.15bn purchase of biotech Tubulis, which analysts believe holds best-in-class potential in ovarian cancer and possible upside in NSCLC.