ASCO: Gilead Seeks Silver Lining in Failed Trodelvy Lung Cancer Trial, Awaits FDA Decision

Gilead Sciences has revealed data on Trodelvy, a TROP2-directed antibody-drug conjugate (ADC), in non-small cell lung cancer (NSCLC) patients, a release that previously led to a 10% drop in the company's stock price. The phase 3 EVOKE-01 study, which investigated Trodelvy in patients who did not respond to chemotherapy and PD-1/L1 immunotherapy, demonstrated a 16% reduction in the risk of death compared to the chemotherapy drug docetaxel. However, the overall survival benefit was not statistically significant. These findings were presented at the American Society of Clinical Oncology (ASCO) annual meeting and published in the Journal of Clinical Oncology.

Despite not meeting its primary endpoint, Gilead found a noteworthy positive sign in a subgroup of patients who had the highest unmet medical need, according to Bilal Piperdi, M.D., Vice President of Oncology Clinical Development. This subgroup analysis, which was pre-specified but not statistically powered, showed that Trodelvy reduced the risk of death by 25% in patients whose tumors did not respond to their previous PD-1/L1 therapy. These patients saw a median life expectancy increase of 3.5 months, reaching 11.8 months. However, in patients responsive to prior immunotherapy, Trodelvy performed worse than chemotherapy, showing a median overall survival of 9.6 months compared to 10.6 months for the chemotherapy group, indicating a 9% negative trend.

Approximately two-thirds of the trial population were unresponsive to immunotherapy, which reflects the real-world scenario where 40% to 50% of patients respond to first-line PD-1/L1 treatments. Piperdi highlighted that unresponsive patients generally have poor outcomes, suggesting that Trodelvy's 3.5-month improvement is clinically meaningful. However, the data showed that chemotherapy might have outperformed its usual efficacy in immunotherapy-responsive patients.

Gilead is now gathering the data and plans to consult with the FDA and oncologists to determine the future steps for Trodelvy. The FDA's approval based on a subgroup analysis is uncertain, as agency officials have indicated they would use such analyses to limit approval scope but not to salvage a failed trial.

Analysts from Leerink Partners have expressed skepticism about Trodelvy's approval prospects, given the primary endpoint miss. Nonetheless, the detailed findings from the EVOKE-01 trial could inform the broader TROP2 ADC class and influence Gilead’s development strategy.

Competition in the TROP2 ADC field is intensifying. AstraZeneca and Daiichi Sankyo recently reported that their TROP2 ADC, datopotamab deruxtecan (Dato-DXd), also failed to achieve statistical significance in overall survival in a similar NSCLC setting. However, their TROPION-Lung01 trial had a dual primary endpoint design and had previously shown statistical significance in progression-free survival (PFS), leading to an FDA application based on the PFS results in patients with nonsquamous tumors.

Trodelvy’s performance in the EVOKE-01 trial indicates it wouldn’t have shown a positive result even if PFS had been the primary endpoint, as it extended median PFS by just 0.2 months compared to chemotherapy, with an 8% reduction in the risk of tumor progression or death.

However, Trodelvy did show similar overall survival benefits between squamous and nonsquamous NSCLC patients, with death risk reductions of 17% and 13%, respectively. In patients with actionable genomic alterations (AGAs), Trodelvy reduced the risk of death by 48%, compared to an 11% reduction in those without AGAs, mirroring trends seen with Dato-DXd.

Given these results, the relatively modest benefits in the AGA-negative population, and the failed overall survival endpoints for both agents, the prospects for Dato-DXd’s ongoing FDA review remain uncertain. The FDA’s decision on Dato-DXd's NSCLC application is expected in December, while Gilead will provide regulatory updates on Trodelvy’s NSCLC application when appropriate.