Trodelvy Combination Shows Promise in Triple-Negative Breast Cancer: A Game-Changer for Gilead?

Gilead Sciences (GILD) has announced positive topline results from its Phase 3 ASCENT-04/KEYNOTE-D19 trial, a collaboration with Merck (MRK) evaluating the combination of Trodelvy (sacituzumab govitecan) and Keytruda (pembrolizumab) in first-line treatment for PD-L1-positive metastatic triple-negative breast cancer (mTNBC). The trial met its primary endpoint of progression-free survival (PFS), marking a potential paradigm shift in an aggressive cancer subtype with limited treatment options and a five-year survival rate of just 12%.

The Trial: A Breakthrough in mTNBC

The study randomized 443 patients to receive either Trodelvy plus Keytruda or standard chemotherapy (gemcitabine/carboplatin, paclitaxel, or nab-paclitaxel) combined with Keytruda. The Trodelvy-Keytruda arm demonstrated statistically significant and clinically meaningful improvement in PFS, as measured by blinded independent central review. While exact median PFS and hazard ratio data are pending, the results align with earlier signals from smaller trials, such as the 2022 Phase 2 study showing a 62% objective response rate (ORR) in mTNBC patients.

The safety profile was consistent with prior data: common side effects included neutropenia (49% in the Trodelvy arm) and diarrhea (11%), manageable through supportive care. No new safety signals emerged, a critical consideration given Trodelvy’s known profile in later-line settings.

Strategic Implications for Gilead

Trodelvy, a Trop-2-directed antibody-drug conjugate (ADC), is currently approved for third-line mTNBC and certain HR+/HER2- breast cancers. The ASCENT-04 results position it to move into first-line treatment for PD-L1-positive patients, a population of ~10,000 in the U.S. and EU5 by 2030. Analysts at Citi estimate this could boost Trodelvy’s peak sales to $3.2 billion, up from its current $1.2 billion in annual revenue.

The partnership with Merck also highlights the strategic value of combining ADCs with checkpoint inhibitors. Keytruda’s existing approval in first-line mTNBC (for CPS ≥10) provides a logical entry point, while Trodelvy’s mechanism—delivering the potent SN-38 payload to tumor cells—complements immune activation.

Competing ADCs and the Race for Market Share

Gilead faces stiff competition from emerging TROP-2 ADCs, including AstraZeneca/Daiichi Sankyo’s Datroway (sacituzumab deruxtecan) and Kelun-Biotech’s sacituzumab tirumotecan. Both are in late-stage trials for similar indications. For instance, Datroway’s Phase 3 TROPiCS-02 trial in second-line mTNBC met its PFS endpoint, though Trodelvy’s earlier-line data could differentiate it.

Gilead is countering with its own pipeline: the ASCENT-03 trial is evaluating Trodelvy vs. chemotherapy in first-line PD-L1-negative mTNBC, while ASCENT-05 explores it in early-stage TNBC with residual disease post-surgery. Positive results here could further expand Trodelvy’s addressable market.

The Bottom Line: A Risk-Adjusted Win for Gilead

While OS data remain immature, the PFS improvement alone is a major win for Gilead. The trial’s success could accelerate regulatory submissions, with a potential FDA decision by 2025. Even if OS data lag, the combination’s manageable safety profile and efficacy in a high-unmet-need setting may secure accelerated approval.

Conclusion: Positioning for Long-Term Oncology Growth

Trodelvy’s ASCENT-04 data underscore Gilead’s shift from its HIV/Hepatitis C roots toward oncology leadership. The $3.2 billion peak sales estimate hinges on Trodelvy’s expansion into first-line mTNBC and other tumor types, such as HR+/HER2- breast cancer (via the ASCENT-07 trial). With a 12% five-year survival rate in mTNBC, any therapy delaying progression or improving response rates has outsized patient and commercial value.

However, competition remains fierce. Investors should monitor OS data and the regulatory landscape, as well as Gilead’s ability to defend Trodelvy against rivals. For now, the ASCENT-04 results are a catalyst to watch, with Gilead poised to capitalize on a $3.2 billion opportunity—if it can sustain momentum in this crowded space.