Sacituzumab Govitecan/Pembrolizumab in HR+ Breast Cancer Show Nonsignificant PFS Increase

Ana C. Garrido-Castro, MD

In patients with hormone receptor–positive, HER2-negative metastatic breast cancer unselected by PD-L1 status, a numerical but statistically insignificant improvement in progression-free survival (PFS) was demonstrated with pembrolizumab (Keytruda) to sacituzumab govitecan-hziy (Trodelvy) compared with the antibody-drug conjugate (ADC) alone, according to findings from the phase 2 SACI-IO HR+ study (NCT04448886) presented at the 2024 ASCO Annual Meeting.¹

The doublet (n = 52) led to a median PFS of 8.12 months (95% CI, 4.51-11.12) vs 6.22 months (95% CI, 3.85-8.68) with the monotherapy (n = 52), equating to difference of 1.9 months (HR, 0.81; 95% CI, 0.51-1.28; P = .37). Although immature, at a median follow-up of 12.5 months, overall survival (OS) was not significantly improved in those who received the doublet vs the monotherapy, at a median of 18.52 months (95% CI, 16.55-not applicable [NA]) and 17.96 months (95% CI, 12.50-NA), respectively (HR, 0.65; 95% CI, 0.33-1.28; P = .21).

Moreover, in patients with PD-L1 positivity, defined as a combined positive score (CPS) of 1 or higher, a non-significant trend toward improved PFS and OS was observed in favor of the combination regimen.

“SACI-IO HR+ is the first randomized trial to report the efficacy of a topoisomerase I inhibitor ADC combined with an immune checkpoint inhibitor in breast cancer,” Ana C. Garrido-Castro, MD, a medical oncologist and codirector of the Triple-Negative Breast Cancer Working Group at Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School, in Boston, Massachusetts, said in a presentation of the data. “These results support further investigation of sacituzumab govitecan plus pembrolizumab in patients with PD-L1–positive, hormone receptor–positive, HER2-negative metastatic breast cancer.”

Sacituzumab govitecan—a TROP2–directed ADC with a topoisomerase 1 inhibitor payload, SN-38—is approved for use in patients with previously treated triple-negative and hormone receptor–positive, HER2-negative metastatic breast cancer. Previously, data from the phase 3 TROPiCS-02 study (NCT03901339) showed that treatment with the ADC (n = 272) led to improvements in PFS (HR, 0.66; 95% CI, 0.53-0.83; P = .0003) and OS (HR, 0.79; 95% CI, 0.65-0.96; P = .020) over chemotherapy (n = 271) in patients with hormone receptor–positive, HER2-negative metastatic breast cancer following two to four chemotherapy regimens for metastatic disease.^2,3

“Double-stand DNA breaks induced by SN-38 may activate cGAS-STING, stimulating type I interferon production and T-cell recruitment. SN-38 can enhance cytotoxic T-cell effector functions and deplete regulatory T cells,” Garrido-Castro explained. “Thus, we hypothesized that sacituzumab govitecan would synergize with the PD-1 inhibitor pembrolizumab via the combined restoration of T-cell effector functions, and that the combination would improve the efficacy of sacituzumab govitecan alone in hormone receptor–positive, HER2-negative metastatic breast cancer.”

The investigator-initiated, multicenter, open-label, randomized, phase 2 study enrolled patients with metastatic or locally advanced unresectable breast cancer who had hormone receptor–positive and HER2-negative disease.¹ Patients must have previously received at least 1 endocrine therapy for metastatic disease or have progressed on or within 12 months of adjuvant endocrine treatment. They could not have received more than 1 prior line of chemotherapy in the advanced setting. They could not have previously received topoisomerase I inhibitor ADC, irinotecan, or PD-1/PD-L1 inhibitor treatment, nor could they have known active brain metastases or leptomeningeal disease.

“This study was initially designed to enroll patients with PD-L1–positive tumors. However, due to the low prevalence of PD-L1 positivity in the pre-screening phase, the study was subsequently amended to allow any PD-L1 status,” Garrido-Castro noted.

Study participants (n = 110) were randomly assigned 1:1 to receive sacituzumab govitecan at 10 mg/kg on day 1 and 8 of every 21-day cycle with or without pembrolizumab at 200 mg on day 1 of every 21-day cycle. Treatment continued until disease progression or unacceptable toxicity.

The primary end point of the study was PFS in the intention-to-treat (ITT) population. Secondary end points included PFS in the PD-L1–positive subgroup; OS in the ITT and PD-L1–positive populations; objective response rate (ORR), duration of response (DOR), time to objective response (TTOR), and clinical benefit rate (CBR) in the ITT and PD-L1–positive populations; and safety. Exploratory end points will include correlative analyses and health-related quality of life assessment.

“With a 1-sided 0.1 type-I error and 80% power to detect a 3-month absolute difference in median PFS, corresponding to a hazard ratio of 0.65 at the time of final analysis, which was initially planned at 100 PFS events, or 9 months after the last patient was randomized, 110 patients would need to enroll,” she explained. “Upon further discussion with the data safety monitoring board, it was decided that the study would be amended so that the final PFS analysis would occur 2 months after the last patient was randomized due to the study accrual occurring over a longer period of time than initially anticipated and since we would not reach the prespecified 100 PFS events due to some patients coming off study therapy for reasons other than progressive disease.”

The data cutoff date for the analysis shared during the 2024 ASCO Annual Meeting was March 9, 2024, and had a median follow-up of 12.5 months. A total of 104 patients, spanning 5 clinical sites, began study therapy and were included in the assessment.

The median patient age was 57.0 years (range, 27.0-81.0). Most patients (98.1%) were female, White (80.8%), and had an estrogen receptor expression that was greater than or equal to 10% (95.2%). Regarding PD-L1 status, 60.6% of patients were negative, 38.5% had a CPS of 1 or higher, 31.7% had a CPS ranging from 1 to 9, 6.7% had a CPS of 10 or higher, and 1.0% were not tested. In terms of presentation at the time of diagnosis, 22.1% of patients had de novo metastatic breast cancer and 77.9% had recurrent metastatic breast cancer. Moreover, 77.9% and 8.7% of patients had liver or brain metastases, respectively, at baseline. More than half of patients (69.1%) previously received neoadjuvant/adjuvant chemotherapy and the majority (88.5%) received a prior CDK4/6 inhibitor in any setting. Moreover, 49.0% of patients received 1 prior chemotherapy regimen for metastatic breast cancer.

Additional efficacy findings showed that in the subset of patients with PD-L1–positive disease defined as a CPS of at least 1, the doublet (n = 16) led to a median PFS of 11.05 months (95% CI, 2.14-NA) vs 6.68 months (95% CI, 2.53-9.24) with the monotherapy (n = 24; HR, 0.62; 95% CI, 0.29-1.36; P = .23). In those with PD-L1–negative disease defined as a CPS under 1, the doublet (n = 35) resulted in a median PFS of 5.36 months (95% CI, 4.14-9.97) vs 5.07 months (95% CI, 3.85-NA) with the monotherapy (n = 28; HR, 1.06; 95% CI, 0.59-1.90; P = .84).

Again, OS data were not mature, but in PD-L1–positive patients, the median OS with the doublet was 18.52 months (95% CI, 16.88-NA) vs 12.50 months (95% CI, 11.97-NA) with the monotherapy (HR, 0.61; 95% CI, 0.18-2.04; P = .42). In the PD-L1–negative patients, the median OS in the respective arms was 16.55 months (95% CI, 14.64-NA) and 18.03 months (95% CI, 17.34-NA; HR, 0.68; 95% CI, 0.29-1.59; P = .38).

Garrido-Castro reported that the ORR, CBR, DOR, and TTOR did not significantly differ between the arms. The ORR achieved with pembrolizumab plus sacituzumab govitecan was 21.2% vs 17.3% with sacituzumab govitecan alone (P = .80). The median TTOR with the doublet was 2.3 months (95% CI, 1.8-8.7) vs 4.1 months (95% CI, 2.0-10.2) with the monotherapy (P = .68); the median DORs were 12.9 months (95% CI, 4.4-NA) and 4.5 months (95% CI, 4.5-NA), respectively (P = .31). The respective CBRs were 50.0% (95% CI, 35.8%-64.2%) and 46.2% (95% CI, 32.2%-60.5%; P = .84).

“Overall, the safety profile of sacituzumab govitecan with pembrolizumab was similar to that expected with either agent, with no new safety signals reported,” Garrido Castro said.

Any-grade treatment-emergent adverse effects (TEAEs) occurred in 98.1% of those given the doublet vs 96.2% of those given the monotherapy; these effects were related to treatment for 92.3% and 94.2% of patients, respectively. TEAEs resulted in discontinuation for 5.8% and 1.9% of patients, respectively. The most common TEAEs experienced by at least 15% of patients who received the combination included decreased neutrophil count (grade ≥2, 69.2%; grade 3/4, 53.8%), anemia (34.6%; 5.8%), decreased white blood cell count (26.9%; 23.1%), decreased lymphocyte count (15.4%; 11.5%), diarrhea (23.1%; 5.8%), nausea (28.8%; 3.8%), alopecia (42.3%; 0%), fatigue (38.5%; 1.9%), and anorexia (11.5%; 0%).

Immune-mediated AEs attributed to pembrolizumab in the combination arm included hypothyroidism (grade ≥2, 5.8%; grade 3/4, 0%), hypoalbuminemia (3.8%; 0%), increased alanine aminotransferase (3.8%; 1.9%), increased alkaline phosphatase (3.8%; 1.9%), increased aspartate aminotransferase (1.9%; 1.9%), acute kidney injury (1.9%; 1.9%), viral hepatitis (1.9%; 1.9%), adrenal insufficiency (1.9%; 0%), arthralgia (1.9%; 0%), increased blood bilirubin (1.9%; 0%), dyspnea (1.9%; 0%), pneumonitis (1.9%; 0%), and pruritus (1.9%; 0%).

The study had several limitations, according to Garrido-Castro, including that it was a phase 2 trial with a sample size that limited the ability to evaluate efficacy in prespecified subgroups, for example, among patients with PD-L1–positive tumors. Moreover, at 34% OS data maturity, additional follow-up is needed for OS analysis.

“Additional work is needed to investigate predictors of benefit from ADC and immune checkpoint inhibitor combination strategies in hormone receptor–positive, HER2-negative metastatic breast cancer,” Garrido-Castro concluded.

Disclosures: Dr Garrido-Castro disclosed receipt of honoraria from AstraZeneca and Daiichi Sanyo; serving in a consulting or advisory role for AstraZeneca, Daiichi-Sankyo, and Novartis; receiving research funding from 4D Path (Inst), AstraZeneca (Inst), Biovica (Inst), Bristol Myers Squibb (Inst), Daiichi Sanyo (Inst), Foundation Medicine (Inst), GileadSciences (Inst), Merck (Inst), Novartis (Inst), Precede Bio (Inst), and Zenith Epigenetics (Inst); and receiving support regarding travel, accommodations, and expenses from AstraZeneca, Daiichi Sanyo, Gilead Sciences, Merck, Novartis, and Roche/Genentech.

_References:

_{1. Garrido-Castro A, Kim, SE, Desrosiers J, et al. SACI-IO HR+: a randomized phase II trial of sacituzumab govitecan with or without pembrolizumab in patients with metastatic hormone receptor-positive/HER2-negative breast cancer. J Clin Oncol. 2024;42(suppl 17):LBA1004. doi:10.1200/JCO.2024.42.17_suppl.LBA1004}

_{2. Rugo HS, Bardia A, Marmé F, et al. Primary results from TROPiCS-02: a randomized phase 3 study of sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) in patients (pts) with hormone receptor–positive/HER2-negative (HR+/HER2-) advanced breast cancer. J Clin Oncol. 2022;40(suppl 17):LBA1001. doi:10.1200/JCO.2022.40.17_suppl.LBA1001}

_{3. Rugo HS, Bardia A, Marmé F, et al. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023;402(10411):1423-1433. doi:10.1016/S0140-6736(23)01245-X}