Triple-negative breast cancer (TNBC) remains one of the most challenging and most malignant subtypes of breast cancer to treat. TNBC represents a heterogeneous group of diseases with distinct histologic, genomic, and immunologic characteristics, unified by their lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). The absence of these receptors precludes the use of endocrine or HER2-targeted therapies that have revolutionized outcomes in other breast cancer subtypes, leaving cytotoxic chemotherapy as the historical mainstay despite its limited therapeutic index and frequent toxicity. [1][2]
Although TNBC accounts for only about 15% of breast cancer diagnoses in the United States, it is responsible for a disproportionate share of breast cancer mortality, with a substantial proportion of patients ultimately developing distant metastases. Although recent advances in therapeutic strategies for TNBC are beginning to improve the outlook for many patients, a major unmet medical need remains.[3][4][5]
Exploratory PFS2 analysis from ASCENT-04/KEYNOTE-D19 reinforces the frontline role of Trop-2–directed ADC combination as FDA grants full approval for the indication
Over the last decade, novel drugs have been approved to treat TNBC, including poly(ADP-ribose polymerase inhibitors (PARPi). But this option benefits only a small subgroup of patients with TNBC and a pathogenic germline BRCA1 or BRCA2 variant. [3][4] Pembrolizumab (Keytruda®; Merck & Co/MSD) is the only approved PD-1 checkpoint inhibitor in combination with chemotherapy in the first-line setting and is a therapeutic option for approximately 40% of patients with PD-L1-positive tumors. [3][4]. To date, antibody-drug conjugates (ADCs), including sacituzumab govitecan-hziy (Trodelvy®, Gilead Sciences) and fam-trastuzumab deruxtecan-nxko-nxki (Enhertu®; Daiichi Sankyo and AstraZeneca), are considered the most important therapeutic advances. Despite their benefit, sacituzumab govitecan and trastuzumab deruxtecan are not specific for TNBC.
Trop-2
Trop-2, a transmembrane glycoprotein involved in calcium signaling and epithelial cell regulation, is overexpressed in the large majority of TNBC tumors while remaining comparatively low in normal epithelial tissue. That differential expression pattern has made Trop-2 an attractive target for ADC development, and it underlies the design of sacituzumab govitecan, a Trop-2–directed ADC that pairs a humanized IgG1 kappa antibody with SN-38, the active topoisomerase I–inhibiting metabolite of irinotecan, through a hydrolyzable linker. (see ADC Drugmap) This chemistry is intended to concentrate cytotoxic payload delivery within Trop-2–expressing tumor cells while limiting the systemic exposure associated with irinotecan-derived toxicity, particularly high-grade diarrhea.
ASCENT-04/KEYNOTE-D19: Primary Results
Sacituzumab govitecan’s role in previously untreated, PD-L1–positive metastatic TNBC was established in ASCENT-04/KEYNOTE-D19 (NCT05382286), a phase III trial that randomized 443 patients 1:1 to sacituzumab govitecan (10 mg/kg intravenously on days 1 and 8 of each 21-day cycle) plus pembrolizumab (200 mg on day 1, up to 35 cycles), or to investigator’s choice chemotherapy—single-agent paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin—plus pembrolizumab. Eligible patients had locally advanced, unresectable, or metastatic disease with PD-L1 combined positive score of 10 or higher by the 22C3 immunohistochemistry assay; prior anti–PD-(L)1 exposure in the curative setting was permitted.[6]
By blinded independent central review, the trial’s primary endpoint of progression-free survival (PFS) significantly favored the sacituzumab govitecan combination, with a median of 11.2 months compared with 7.8 months for chemotherapy plus pembrolizumab (hazard ratio [HR], 0.65; 95% CI, 0.51–0.84; P < .001), a 35% reduction in the risk of progression or death. Confirmed objective response rates (ORR) were similarly higher with the ADC-containing regimen. Overall survival data remained immature at the time of the primary analysis.[6][7]
PFS2 and Subsequent-Therapy Findings
Because overall survival data had not matured and a substantial proportion of chemotherapy-arm patients were expected to cross over to sacituzumab govitecan at progression, investigators examined progression-free survival after next line of treatment (PFS2)—defined as time from randomization to progression on subsequent therapy or death from any cause—along with time to first and second subsequent therapy, as exploratory endpoints. These data, presented by Kevin Kalinsky, MD, MS, FASCO, professor and director in the Division of Medical Oncology of the Department of Hematology and Medical Oncology at Winship Cancer Institute of Emory University, at the 2026 Annual Meeting of the American Society of Clinical Oncology (ASCO), used the same March 2025 data cutoff as the primary analysis, corresponding to a median follow-up of approximately 14 months.[6][7]
Despite a crossover rate of approximately 81% among chemotherapy-arm patients who progressed—the substantial majority of whom subsequently received sacituzumab govitecan either through the study or commercially—PFS2 continued to favor the frontline ADC combination. Median PFS2 was not yet reached in the sacituzumab govitecan plus pembrolizumab arm versus approximately 21.0 months in the chemotherapy plus pembrolizumab arm (HR, 0.67; 95% CI, 0.48–0.95), a 33% reduction in the risk of a PFS2 event. PFS2 event-free rates were 71.9% versus 53.0% at 18 months and 63.7% versus 45.6% at 24 months, respectively, favoring the sacituzumab govitecan arm.
The subsequent-therapy endpoints followed a consistent pattern. Median time to first subsequent therapy was 17.3 months with frontline sacituzumab govitecan plus pembrolizumab versus 9.8 months with chemotherapy plus pembrolizumab (HR, 0.59; 95% CI, 0.46–0.76). Median time to second subsequent therapy was not reached in the sacituzumab govitecan arm versus 21.0 months in the comparator arm (HR, 0.82; 95% CI, 0.59–1.14). At data cutoff, 43% of patients in the sacituzumab govitecan arm remained on first-line treatment, compared with 23% in the chemotherapy arm.
Treatment patterns after progression diverged markedly between arms: among chemotherapy-arm patients who received a subsequent line of therapy, the substantial majority received sacituzumab govitecan, whereas patients who progressed on frontline sacituzumab govitecan more often received taxanes, platinum-based chemotherapy, or capecitabine (Xeloda®; Cheplapharm). No new safety signals were identified relative to the primary analysis; consistent with each agent’s known profile, diarrhea occurred more frequently with sacituzumab govitecan, while anemia, thrombocytopenia, and peripheral neuropathy occurred more frequently with chemotherapy.[6]
At the 2026 ASCO Annual Meeting, Kalinsky framed the persistence of a PFS2 benefit despite extensive crossover as evidence of a durable treatment effect attributable to earlier use of sacituzumab govitecan, potentially reflecting the combined immunogenic effects of pairing an ADC with checkpoint inhibition, and supporting continued use of the frontline combination as later-line sequencing does not appear to replicate the same magnitude of benefit.[7]
A Cautionary Statistical Perspective
In post-ASCO comments, the exploratory nature of PFS2 as an endpoint drew scrutiny from the invited discussant, Meredith M. Regan, ScD, a biostatistician and professor of medicine at Dana-Farber Cancer Institute and Harvard Medical School, who was not involved in the ASCENT-04/KEYNOTE-D19 study.[6][7]
After reviewing data from previous studies, Regan questioned the broader use of PFS2 in trials comparing first-line regimens, noting that the endpoint’s definition varies across studies and that FDA guidance on oncology endpoints does not incorporate PFS2 into benefit-risk assessment. In her view, PFS2 and subsequent-therapy endpoints do not isolate the treatment effect attributable specifically to first-line therapy, given the heterogeneity of subsequent treatments across arms, and the existing evidence is insufficient to support PFS2 as a surrogate for overall survival in metastatic breast cancer. Regan suggested that PFS2 could become more informative if the field converged on a standardized definition and analytic approach across trials, an effort she said would benefit from pooling individual patient data.[6][7]
Regulatory Context
The exploratory analysis was presented against a shifting regulatory backdrop. On June 24, 2026, the FDA approved sacituzumab govitecan-hziy for two related but distinct indications in TNBC under Project Orbis, the agency’s framework for concurrent international review. The first, based on the outcomes of the ASCENT-03 trial (NCT05382299), covers sacituzumab govitecan as monotherapy for first-line treatment of unresectable locally advanced or metastatic TNBC in patients who are not candidates for PD-1 or PD-L1 inhibitor–based therapy. The second, supported by ASCENT-04/KEYNOTE-D19, covers sacituzumab govitecan in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex®; Merck & Co/MSD) for first-line treatment of adults with unresectable locally advanced or metastatic TNBC whose tumors express PD-L1 (CPS ≥ 10) as determined by the PD-L1 IHC 22C3 pharmDx assay developed by Agilent Technologies and approved by the FDA. [10]
Both applications were reviewed under the FDA’s Assessment Aid framework and were approved one month ahead of the FDA’s goal date, with the agency collaborating with regulatory counterparts in Australia, Israel, Brazil, Canada, and Switzerland. The primary ASCENT-04/KEYNOTE-D19 results supporting this approval were also published in the New England Journal of Medicine (NEJM), with overall survival data reported as still maturing at the time of publication.[8][9][10][11]
The prescribing information for sacituzumab govitecan-hziy carries a boxed warning for diarrhea and neutropenia, along with warnings and precautions addressing hypersensitivity and infusion-related reactions, nausea and vomiting, reduced UGT1A1 activity*, and embryo-fetal toxicity. This safety profile is consistent with the adverse event pattern observed in the PFS2 analysis and underscores the importance of proactive management of gastrointestinal and hematologic toxicity in patients receiving long-term frontline therapy. [11]
Clinical Implications
Taken together with the primary PFS results, the PFS2 and subsequent-therapy data provide additional, if methodologically contested, support for using sacituzumab govitecan plus pembrolizumab in the frontline setting for PD-L1–positive metastatic TNBC rather than reserving the ADC for later lines of therapy.
The persistence of benefit despite extensive crossover suggests that earlier exposure to the combination confers an advantage not fully recaptured when sacituzumab govitecan is introduced only after chemotherapy failure, though the statistical limitations of PFS2 as an endpoint warrant caution in overinterpreting its magnitude. With full FDA approval now in place and overall survival data continuing to mature, this regimen is positioned as a standard first-line option for the roughly 40% of patients with PD-L1–positive metastatic TNBC, pending confirmation of a durable survival advantage.
Note:* UGT1A1 activity refers to the function of the UDP-glucuronosyltransferase 1A1 enzyme, which is responsible for metabolizing and eliminating toxins, drugs, and bilirubin from the body. Reduced UGT1A1 activity impairs the body’s ability to process these substances, resulting in mild jaundice and an increased risk of chemotherapy-related toxicity. [13]
Clinical Trials
Study of Sacituzumab Govitecan-hziy Versus Treatment of Physician’s Choice in Patients With Previously Untreated Locally Advanced Inoperable or Metastatic Triple-Negative Breast Cancer (ASCENT-03) – ClinicalTrials.gov ID NCT05382299
Study of Sacituzumab Govitecan-hziy and Pembrolizumab Versus Treatment of Physician’s Choice and Pembrolizumab in Patients With Previously Untreated, Locally Advanced Inoperable or Metastatic Triple-Negative Breast Cancer (ASCENT-04) – ClinicalTrials.gov ID NCT05382286
Highlights of Prescribing Information
Sacituzumab govitecan-hziy (Trodelvy®, Gilead Sciences)[Prescribing Information]
Fam-trastuzumab deruxtecan-nxko-nxki (Enhertu®; Daiichi Sankyo and AstraZeneca)[Prescribing Information]
Pembrolizumab (Keytruda®; Merck & Co/MSD)[Prescribing Information]
Pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex®; Merck & Co/MSD)[Prescribing Information]
Capecitabine (Xeloda®; Cheplapharm)[Prescribing Information]
References
[1] American Cancer Society. Triple-negative breast cancer. Updated January 25, 2025. Online. Last accessed on September 2, 2026
[2] Derakhshan F, Reis-Filho JS. Pathogenesis of Triple-Negative Breast Cancer. Annu Rev Pathol. 2022 Jan 24;17:181-204. doi: 10.1146/annurev-pathol-042420-093238. PMID: 35073169; PMCID: PMC9231507.
[3] Li Y, Zhang H, Merkher Y, Chen L, Liu N, Leonov S, Chen Y. Recent advances in therapeutic strategies for triple-negative breast cancer. J Hematol Oncol. 2022 Aug 29;15(1):121. doi: 10.1186/s13045-022-01341-0. PMID: 36038913; PMCID: PMC9422136.
[4] Riaz F, Gruber JJ, Telli ML. New Treatment Approaches for Triple-Negative Breast Cancer. Am Soc Clin Oncol Educ Book. 2025 Jun;45(3):e481154. doi: 10.1200/EDBK-25-481154. Epub 2025 Jun 3. PMID: 40460322.
[5] El Gazzar WB, Albakri KA, Hasan H, Badr AM, Farag AA, Saleh OM. Poly(ADP-ribose) polymerase inhibitors in the treatment landscape of triple-negative breast cancer (TNBC). J Oncol Pharm Pract. 2023 Sep;29(6):1467-1479. doi: 10.1177/10781552231188903. Epub 2023 Aug 9. PMID: 37559370.
[6] Kalinsky K, Schmid P, de Azambuja E, Loi S, Kim SB, Yam C, Rapoport BL, Im SA, Pistilli B, McHayleh W, Cescon DW, Watanabe J, Lara A, Freitas-Junior R, Lortholary A, Caldwell K, Huo Y, Lai C, Tolaney SM. 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 ASCO Annual Meeting; May 29–June 2, 2026; Chicago, IL. J Clin Oncol 44, 2026 (suppl 17; abstr LBA1000)
[7] Haelle T. New Frontline Standard or Not? Triple-Negative Breast Cancer Data Spark Debate. Oncology News Central/Health Central. June 8, 2026. Online. Last accessed on September 2, 2026
[8] de Azambuja E, Kalinsky K, Loi S, Kim SB, Yam C, Rapoport BL, Im SA, Pistilli B, McHayleh W, Cescon DW, Watanabe J, Lara A, Freitas-Junior R, Bofill JS, Afshari M, Gary D, Wang L, Lai C, Schmid P. Sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro in previously untreated PD-L1–positive advanced triple-negative breast cancer (TNBC): Primary results from the randomized phase 3 ASCENT-04/KEYNOTE-D19 study. Journal of Clinical Oncology, 2025, 43: 17_suppl, LBA109.
[9] Tolaney SM, de Azambuja E, Kalinsky K, Loi S, Kim SB, Yam C, Rapoport B, Im SA, Pistilli B, Mchayleh W, Cescon DW, Watanabe J, Bañuelas MAL, Freitas-Junior R, Salvador Bofill J, Afshari M, Gary D, Wang L, Lai C, Schmid P; ASCENT-04/KEYNOTE-D19 Clinical Trial Investigators. Sacituzumab Govitecan plus Pembrolizumab for Advanced Triple-Negative Breast Cancer. N Engl J Med. 2026 Jan 22;394(4):354-366. doi: 10.1056/NEJMoa2508959. PMID: 41564397.
[10] Fiero MH, Shah M, Amiri-Kordestani L. Is Progression-Free Survival 2 Ready for Prime Time in US Food and Drug Administration Regulatory Decision Making? J Clin Oncol. 2026 Jul 10;44(20):1865-1868. doi: 10.1200/JCO-26-00226. Epub 2026 Mar 30. PMID: 41911517.
[11] U.S. Food and Drug Administration. FDA approves sacituzumab govitecan-hziy as monotherapy and in combination with pembrolizumab for first-line treatment of triple-negative breast cancer. June 24, 2026. Online. Last accessed on September 2, 2026.
[12] Li T, Zhang T, Dang Y, et al. Trop2-based antibody-drug conjugates: emerging strategy and progress in triple-negative breast cancer therapy. Curr Oncol. 2026;33(2):92.
[13] Szeląg-Pieniek S, Kucak J, Malinowski D, Oswald S, Droździk M, Kurzawski M. The Impact of UGT1A1 Genetic Variability on Enzyme Expression in Liver Pathology. Genes (Basel). 2026 May 21;17(5):589. doi: 10.3390/genes17050589. PMID: 42195046; PMCID: PMC13205437.
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