As Gilead's Trodelvy stumbles in first-line lung cancer, all eyes turn to Merck, AZ and Daiichi rivals

Following another phase 3 failure for Gilead Sciences’ Trodelvy, the race to bring a TROP2 antibody-drug conjugate (ADC) to patients with first-line non-small cell lung cancer (NSCLC) has narrowed. 

Monday, Merck & Co. and Gilead announced that they are pulling the plug on the phase 3 Evoke-03 trial, also known as Keynote-D46, following the recommendation of an external data monitoring committee. 

The study was evaluating Trodelvy, combined with Keytruda, as a first-line treatment in patients with PD-L1-high NSCLC versus Keytruda alone. 

The trial did not meet its progression-free survival endpoint at its final analysis, even though a positive trend was observed, according to the two companies. Additionally, an interim analysis of overall survival suggested the trial was unlikely to achieve statistical significance on this measure.

The Evoke-03 flop deals another major blow to the first-in-class TROP2 ADC following a second-line NSCLC trial setback more than two years ago. Gilead’s stock price dropped about 2.7% as of publication time Tuesday morning.

Without a win in first-line NSCLC, Trodelvy’s commercial future will mainly depend on its triple-negative breast cancer uses, which won’t be able to justify the $21 billion price tag that Gilead paid for the med’s developer, Immunomedics. Gilead already took major write-offs tied to Trodelvy’s second-line NSCLC failure and a market withdrawal in bladder cancer in 2024.

Trodelvy’s latest PFS miss surprised analysts at Jefferies and Leerink Partners. For the broader oncology industry, the Evoke-03 failure serves as a warning that “beating the easy [Keytruda] monotherapy standard-of-care (SoC) as an entry into 1L NSCLC may not be as easy as it seems,” the Leerink team wrote in a June 8 note.

Nevertheless, both teams of analysts remain hopeful that Merck’s rival TROP2 ADC, sac-TMT, could succeed in the same first-line NSCLC setting.

A subgroup analysis of the positive OptiTROP-lung05 study conducted by Merck’s partner, Kelun-Biotech, linked sac-TMT and Keytruda to a 53% PFS benefit over Keytruda alone in Chinese patients with previously untreated PD-L1-high NSCLC. Merck’s phase 3 TroFuse-007 study is testing that regimen in a global population.

Sac-TMT has shown numerically better efficacy than Trodelvy in the setting, the two analyst teams noted, while acknowledging that there’s no perfect direct comparison between the two agents in NSCLC. 

A potentially longer treatment duration may also benefit sac-TMT, the two teams both pointed out. Trodelvy showed much higher treatment-related discontinuations (24%) in Gilead’s phase 2 Evoke-02 trial than Kelun reported from OptiTROP-Lung05 (below 10%), Leerink noted.

Besides Merck, AstraZeneca and Daiichi Sankyo are also targeting the lucrative first-line NSCLC market, with the closely-watched phase 3 Avanzar trial of TROP2 ADC Datroway expected to read out this year. AZ has developed a TROP2-based biomarker in the partners’ first-line NSCLC trials to potentially increase the probability of their success. One of the studies, Tropion-Lung08, is testing Datroway alongside Keytruda in patients with first-line nonsquamous, PD-L1-high NSCLC.

Meanwhile, for Gilead, Trodelvy has one remaining phase 3 to read out. Data from the Ascent-GYN study in second-line endometrial cancer are expected this year.

As competition to Trodelvy mounts, including in breast cancer, Gilead investors’ attention will start to shift elsewhere. The California company recently agreed to buy ADC biotech Tubulis in a much cheaper deal than Immunomedics. For $3.15 billion upfront, Gilead is getting TUB-040, a NaPi2b ADC that analysts believe holds best-in-disease potential in ovarian cancer and potential upside in NSCLC, as well as a new ADC platform.