Why SG Plus Pembrolizumab's Best Results May Come After First Progression

Updated analysis findings from the ASCENT-04 trial (NCT05382286) demonstrate that sacituzumab govitecan (SG, Trodelvy; Gilead Sciences, Inc) combined with pembrolizumab (pembro, Keytruda; Merck & Co) continues to deliver meaningful clinical benefit beyond initial disease progression in patients with previously untreated PD-L1–positive metastatic triple-negative breast cancer (mTNBC)—even in the context of significant crossover to SG in the comparator arm.

These data, presented at the 2026 American Society of Clinical Oncology Annual Meeting, may advance the standard of care by providing patients with a safe, efficacious therapeutic option following first disease progression.

TNBC and Trop-2

TNBC accounts for roughly 15% of all breast cancer diagnoses in the United States, yet it carries a disproportionate clinical burden with high malignancy and mortality rates. Approximately 45% of patients with TNBC develop distant metastases, including in the brain and other organs. TNBC is characterized by a higher tendency for recurrence and metastasis and a generally poorer prognosis.¹

Defined by the absence of estrogen receptor, progesterone receptor, and HER2 expression, TNBC is stripped of the molecular targets that underpin the most effective modern therapies—leaving clinicians with a narrower, less precise treatment toolkit than for other subtypes. Historically, treatment for TNBC involved antimetabolites, paclitaxel, and anthracyclines, but the toxic effects of these agents are harmful for patients, and outcomes remain poor.^1,2

The discovery of biomarkers in cancer has revolutionized the treatment and understanding of malignancies across the spectrum. In TNBC, Trop-2 has been identified as a promising target—occurring in approximately 88% of tumors. Trop-2 is a transmembrane glycoprotein that regulates calcium signaling and is broadly overexpressed across multiple epithelial tumor types.³

In normal tissue, Trop-2 plays a role in embryonic development, placental formation, and stem cell maintenance—and while it is present at low levels on healthy epithelial cells in organs such as the heart, liver, kidney, and lung, expression in malignant tissue is substantially higher. This differential creates a favorable therapeutic window: When Trop-2 is overexpressed, it functions as an oncogene, actively promoting tumor proliferation, invasion, and metastasis, while its limited expression in normal tissue reduces the risk of off-target toxicity. The precise mechanisms underlying TROP-2 upregulation in cancer cells are not yet fully elucidated, but researchers theorize that TROP-2 plays a crucial role in regulating cell proliferation and invasion.

Underlying Mechanism of SG

SG is a Trop-2-targeting antibody-drug conjugate and the first of its class to receive FDA approval for TNBC. The construct pairs an anti-Trop-2 IgG1 kappa antibody with SN-38—the active metabolite of irinotecan and a potent topoisomerase I inhibitor—via a proprietary hydrolyzable linker that enables targeted payload release at the tumor site. SN-38 exerts its cytotoxic effect by inducing double-stranded DNA breaks, but its clinical utility as a free agent has historically been constrained by the pharmacological limitations of its prodrug.

Irinotecan delivers SN-38 inefficiently, and the 100- to 1000-fold potency differential between the 2 compounds translates directly into toxicity, with approximately 1 in 3 patients experiencing grade 3 or 4 diarrhea. By conjugating SN-38 to a Trop-2-directed antibody, SG concentrates payload delivery within the tumor while substantially improving tolerability. Clinical data in TNBC have further demonstrated that this approach can outperform irinotecan even in patients with high homologous recombination repair activity and low-to-moderate Trop-2 expression, suggesting that targeted delivery itself—independent of receptor density—drives meaningful benefit.⁴

The ASCENT-04 Trial

ASCENT-04 data previously established that first-line SG plus pembro produced a statistically significant and clinically meaningful improvement in progression-free survival (PFS) over chemotherapy plus pembro in this population, with a median PFS of 11.2 months vs 7.8 months (HR, 0.65; 95% CI, 0.51-0.84; P < .001). With overall survival (OS) data still maturing, investigators turned to PFS2—time from randomization to progression on next-line therapy or death—as a more proximal measure of long-term clinical benefit. Because PFS2 captures the durability of first-line treatment effects into subsequent lines, it is considered a meaningful surrogate in settings where crossover or immature OS data limit direct interpretation.⁵

The trial randomly assigned 443 patients 1:1 to SG (10 mg/kg intravenously on days 1 and 8) plus pembro (200 mg on day 1, up to 35 cycles) in 21-day cycles, or to the investigator’s choice of chemotherapy—gemcitabine plus carboplatin, paclitaxel, or nab-paclitaxel—plus pembrolizumab. Patients in the chemotherapy arm who progressed were eligible to cross over to SG on study or could access it commercially in any subsequent line.⁵

SG Yielded Improved Survival Benefits

At a median OS follow-up of 14.0 months, 43% of patients in the SG plus pembro arm remained on study treatment compared with 23% in the chemotherapy arm—an early signal of the more durable disease control achieved with the experimental regimen. Among patients who discontinued and moved to subsequent therapy, the patterns were notably different between arms. In the SG plus pembro group, the most common subsequent treatments were taxanes, platinum chemotherapy, and capecitabine, each used in roughly a third of patients. In the chemotherapy arm, 81% of patients who moved to a subsequent line received SG, with taxanes and capecitabine each used by just 9%.⁵

Despite this substantial crossover, which would be expected to compress any OS advantage, PFS2 remained improved in the SG plus pembro group. Median time to first subsequent therapy was 17.3 months with SG plus pembro vs 9.8 months with chemotherapy plus pembro, a difference of more than 7 months. Median time to the second subsequent therapy had not yet been reached in the SG plus pembro arm, compared with 21.0 months in the chemotherapy arm.⁵

What This Means for TNBC Care

The PFS2 data from ASCENT-04 reinforce that the clinical benefit of first-line SG plus pembro extends well beyond initial progression. The fact that this advantage persisted despite most chemotherapy-arm patients subsequently receiving SG indicates the depth of benefit established early in treatment. Taken together with the primary PFS results, these findings further support SG plus pembrolizumab as a potential new standard of care for previously untreated PD-L1-positive mTNBC, while mature OS data are awaited to complete the picture.

REFERENCES

1. Triple-negative breast cancer. American Cancer Society. Updated January 25, 2025. Accessed June 2, 2026. https://www.cancer.org/cancer/types/breast-cancer/about/types-of-breast-cancer/triple-negative.html

2. Li XY, Li SQ, Xiang SL, et al. Antibody-drug conjugates in triple-negative breast cancer (2010-2024): a bibliometric analysis of global trends and clinical translation. Discov Oncol. 2025;16(1):1720. doi:10.1007/s12672-025-03426-x

3. Li T, Zhang T, Dang Y, Lin Y, Li X, Ling X. Trop2-based antibody-drug conjugates: emerging strategy and progress in triple-negative breast cancer therapy. Curr Oncol. 2026;33(2):92. doi:10.3390/curroncol33020092

4. Sakach E, Sacks R, Kalinsky K. Trop-2 as a therapeutic target in breast cancer. Cancers (Basel). 2022;14(23):5936. doi:10.3390/cancers14235936

5. Kalinsky K, Schmid P, Azambuja E, et al. Progression-free survival after next line of treatment (PFS2) and subsequent therapies (subs tx) in the ASCENT-04 study of participants (pts) with previously untreated PD-L1+ metastatic triple-negative breast cancer (mTNBC) treated with sacituzumab govitecan (SG) plus pembrolizumab (pembro) vs chemotherapy (chemo) plus pembro. Presented at: 2026 American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2026; Chicago, IL. Abstract LBA1006.