Gilead's Trodelvy Combination Shows Breakthrough in Aggressive Breast Cancer: A New Era in Oncology?

Gilead Sciences (NASDAQ: GILD) has announced a major milestone in oncology with its Phase 3 ASCENT-04/KEYNOTE-D19 trial, demonstrating that its antibody-drug conjugate (ADC) Trodelvy® (sacituzumab govitecan-hziy) combined with Merck’s immunotherapy Keytruda® (pembrolizumab) significantly improves progression-free survival (PFS) in patients with previously untreated, PD-L1-positive (CPS ≥10) metastatic triple-negative breast cancer (mTNBC). This breakthrough positions Trodelvy as a transformative first-line treatment option in a subtype of breast cancer with historically poor outcomes, reshaping both clinical practice and Gilead’s oncology growth trajectory.

Trial Results: A Major Milestone

The global, open-label Phase 3 trial enrolled 443 patients with unresectable locally advanced or metastatic mTNBC whose tumors expressed PD-L1 (CPS ≥10). Participants were randomized 1:1 to receive either:
- Trodelvy (10 mg/kg IV on Days 1 and 8 of a 21-day cycle) + Keytruda (200 mg IV on Day 1)
- Chemotherapy (gemcitabine/carboplatin, paclitaxel, or nab-paclitaxel) + Keytruda

The primary endpoint—PFS assessed by blinded independent central review (BICR)—was met with statistical and clinical significance, marking the first time a TROP-2 ADC combined with immunotherapy has shown superiority in first-line metastatic breast cancer. While overall survival (OS) data remains immature, an early trend toward improvement was observed in the Trodelvy-Keytruda arm.

Safety data aligned with known profiles of each agent, with no new safety signals. Common adverse events included neutropenia (64%, 49% Grade 3-4), diarrhea (64%, 11% Grade 3-4), and fatigue (51%). Prophylactic measures, such as G-CSF for neutropenia, are recommended to manage risks.

Clinical Significance and Market Potential

mTNBC accounts for 15% of breast cancers, but its five-year survival rate drops to 12% once metastatic. Current first-line options are limited, with over 50% of patients failing to progress beyond initial therapy. The ASCENT-04 results address this critical unmet need by offering a novel combination that eliminates chemotherapy in the first-line setting, a major advantage given the toxicity burden of traditional regimens.

Trodelvy’s mechanism—targeting the Trop-2 antigen with the SN-38 payload—allows targeted delivery to cancer cells and the tumor microenvironment, complementing Keytruda’s immune-checkpoint inhibition. This synergy could redefine treatment paradigms, especially for PD-L1+ tumors, which represent a subset of mTNBC with aggressive biology.

Gilead is advancing three Phase 3 trials to expand Trodelvy’s use:
- ASCENT-03: First-line mTNBC ineligible for PD-L1 testing.
- ASCENT-05: Early-stage TNBC with residual disease post-surgery.
- ASCENT-07: HR+/HER2- mBC after endocrine therapy.

The drug is also being tested in lung and gynecological cancers, leveraging its broad Trop-2 targeting.

Investment Considerations: Risks and Rewards

Gilead’s oncology pipeline has been a key growth driver, with Trodelvy already approved in over 50 countries for second-line mTNBC and generating $742 million in 2024 sales. The ASCENT-04 data could unlock a $3.2 billion peak sales opportunity by 2030, per Citi analysts, driven by first-line approvals and expanded indications.

Positive catalysts include:
- Regulatory submissions for first-line PD-L1+ mTNBC expected in late 2025.
- OS data maturation, which could solidify the combination’s long-term efficacy.
- Collaborations with Merck, deepening Trodelvy’s integration into immuno-oncology regimens.

Risks:
- Competition from AstraZeneca/Daiichi Sankyo’s Enhertu® (HER2 ADC) and emerging TROP-2 ADCs like Datroway.
- Reliance on U.S. markets, where mTNBC accounts for ~10,000 new cases annually (vs. ~50,000 total breast cancer cases).
- Need for managed care approvals to justify Trodelvy’s high cost (~$20,000/month).

Conclusion: A Paradigm Shift with Upside for Gilead

The ASCENT-04 trial represents a paradigm shift in mTNBC treatment, offering the first ADC-based combination to demonstrate first-line superiority in this aggressive subtype. With a 12% five-year survival rate and no effective options for PD-L1+ patients, Trodelvy-Keytruda’s PFS benefits and manageable safety profile address a critical gap.

Gilead’s stock has risen 87.56% over three years amid oncology growth, outpacing the broader market’s 5.9% gain. While the current share price ($80.00 as of April 2025) lags the consensus target of $112.74, the ASCENT-04 data could reaccelerate investor confidence. With Trodelvy’s pipeline expansion and potential label expansions, Gilead is well-positioned to capitalize on a $25 billion global ADC market, projected to grow at 12% CAGR through 2030.

For investors, the combination’s success underscores Gilead’s strategic pivot from hepatitis C dependence to oncology leadership. While risks remain, the ASCENT-04 breakthrough—paired with a robust pipeline—suggests a compelling long-term opportunity in a space where innovation is both urgent and highly valued.