Gilead's Trodelvy Fails to Unseat Keytruda in Frontline NSCLC, Casting Doubt on Unselected ADC+IO Strategy

MSD and Gilead Terminate Phase III NSCLC Trial

MSD and Gilead Sciences have terminated their Phase III KEYNOTE-D46/EVOKE-03 study (NCT05609968) evaluating a combination of Trodelvy (sacituzumab govitecan) and Keytruda (pembrolizumab) for frontline, PD-L1-expressing non-small cell lung cancer (NSCLC). The decision was based on an external data monitoring committee's prediction that the combination would not significantly improve overall survival (OS) compared to Keytruda alone. While an additive numerical benefit to progression-free survival (PFS) was observed, it did not reach statistical significance. This marks a setback for Gilead's plans to expand Trodelvy's indications, though it will not impact other ongoing studies.

• The Phase III KEYNOTE-D46/EVOKE-03 study, combining Gilead's Trodelvy and MSD's Keytruda for frontline PD-L1-expressing NSCLC, was terminated. An external data monitoring committee concluded the combination would not significantly improve overall survival (OS) versus Keytruda alone. Although an additive numerical benefit was seen for progression-free survival (PFS), it lacked statistical significance.
• This trial termination is a notable setback for Gilead's strategy to broaden Trodelvy's indications, both as a monotherapy and in combination for solid tumors. Despite this, Gilead stated the result would not impact other ongoing studies, including the ASCENT-05 trial for adjuvant triple-negative breast cancer and late-stage monotherapy trials for extensive stage small cell lung cancer (ES-SCLC) and metastatic endometrial cancer.
• For MSD, the outcome represents a minor setback in its efforts to expand Keytruda's role ahead of its anticipated market exclusivity loss in 2028. The company is actively fortifying its pipeline, notably with the Kelun Biotech-developed TROP2-targeting ADC sacituzumab tirumotecan (sac-TMT), which has shown Phase III success in late-stage NSCLC and endometrial cancer and is forecast to achieve blockbuster status by 2029.

Frontline NSCLC: A Reality Check for ADC-ICI Combinations

The recent decision by MSD and Gilead to halt their Phase III KEYNOTE-D46/EVOKE-03 study for sacituzumab govitecan plus pembrolizumab in frontline PD-L1-expressing non-small cell lung cancer (NSCLC) sends a clear signal across the oncology development landscape. While sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate (ADC), has demonstrated impressive efficacy in other challenging indications like triple-negative breast cancer and urothelial carcinoma, its combination with the immune checkpoint inhibitor (ICI) pembrolizumab failed to show a statistically significant overall survival (OS) benefit over pembrolizumab alone in this specific setting.

This outcome underscores the formidable challenge of improving upon highly effective existing standards of care. Pembrolizumab monotherapy has set a high bar in frontline PD-L1-positive NSCLC, and any new combination must demonstrate a clear and substantial advantage to justify its use, especially considering potential additive toxicities. The observation of a numerical, but not statistically significant, progression-free survival (PFS) benefit without translating into OS improvement highlights a critical risk: early efficacy signals may not always predict long-term patient benefit, and the balance of efficacy and safety in combination regimens is paramount. Furthermore, research indicates that Trop-2 expression, the target for sacituzumab govitecan, did not correlate with greater clinical efficacy in a related NSCLC study, suggesting that target expression alone may not be a sufficient predictive biomarker for this combination in NSCLC.

For companies developing ADCs and ICI combinations, this event reinforces the need for rigorous trial design, careful patient selection, and a deep understanding of tumor biology to identify synergistic pathways. While this specific combination in frontline NSCLC did not succeed, the broader promise of ADCs remains strong, as evidenced by their success in other cancers and the continued exploration of novel targets and combination strategies. The path forward will likely involve more nuanced approaches to precision oncology, ensuring that combination therapies deliver truly transformative benefits.