Pembrolizumab plus gosatuzumab shows non-significant trend towards improved PFS in HR+ breast cancer

Addition of pembrolizumab to gosatuzumab in patients with hormone receptor-positive, HER2-negative metastatic breast cancer who are not selected by PD-L1 status, based on data from the phase 2 SACI-IO HR+ study (NCT04448886) govitecan), there was a numerical improvement in progression-free survival (PFS) compared with the antibody-drug conjugate (ADC) alone, but it was not statistically significant.

The median PFS in the dual therapy group (n=52) was 8.12 months (95% CI, 4.51-11.12), while the median PFS in the monotherapy group (n=52) was 6.22 months( span>95% CI, 3.85-8.68), equivalent to a difference of 1.9 months (HR, 0.81; 95% CI, 0.51-1.28; P=0.37). Although premature, overall survival (OS) was not significantly improved with dual therapy versus monotherapy at a median follow-up of 12.5 months, with a median follow-up of 18.52 months. (95% CI, 16.55, not applicable [NA]) and 17.96 months (95% CI, 12.50-NA) (HR, 0.65; 95% CI, 0.33-1.28; P=0.21). Additionally, in patients who were PD-L1 positive (defined as a composite positive score [CPS] of 1 or higher), a nonsignificant trend toward improved PFS and OS in favor of the combination regimen was observed.

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. These results support further study of gosatuzumab plus pembrolizumab in patients with PD-L1-positive, hormone receptor-positive, HER2-negative metastatic breast cancer.

Gosatuzumab is a TROP2-directed ADC with the topoisomerase 1 inhibitor payload SN-38, approved for 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 patients with hormone receptor-positive, HER2-negative metastatic breast cancer who received two to four metastatic therapies compared with chemotherapy (n=271) After disease chemotherapy, ADC treatment (n=272) improved PFS (HR, 0.66; 95%CI, 0.53-0.83; P=0.0003) and OS (HR, 0.79; 95%CI: 0.65-0.96; P=0.020).

Investigator-initiated multicenter, open-label, randomized,The Phase 2 study enrolled patients with metastatic or locally advanced unresectable breast cancer and hormone receptor-positive and HER2-negative disease. Patients must have received at least 1 prior endocrine therapy for metastatic disease or progressed on adjuvant endocrine therapy within 12 months. In senior settings, they cannot receive more than 1 previous dose of chemotherapy. They had not previously received treatment with the topoisomerase I inhibitor ADC, irinotecan, or PD-1/PD-L1 inhibitors and had no known active brain metastases or leptomeningeal disease.

Study participants (n=110) were randomized 1:1 to receive 10 mg/kg of gosatuzumab on days 1 and 8 of each 21-day cycle, with or without 200 mg of pembrolizumab on day 1 of each 21-day cycle. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint of the study is PFS in the intention-to-treat (ITT) population. Secondary endpoints include PFSITT in the PD-L1-positive subgroup and OS in the PD-L1-positive population; objective response rate (ORR), duration of response (DOR), objective time to response (TTOR), clinical benefit rate (CBR), and safety in the ITT and PD-L1-positive populations. Exploratory endpoints will include correlation analyzes and health-related quality of life assessments.

Additional efficacy findings showed that in the subset of patients with PD-L1-positive disease (defined as a CPS of at least 1), the median PFS in the dual-therapy arm (n=16) was 11.05 months (95% CI, 2 .14-NA), while the median PFS in the monotherapy group (n = 24; HR, 0.62; 95% CI, 0.29-1.36; P = 0.23) was 6.68 months (95% CI, 2.53-9.24). Among those with PD-L1-negative disease defined as CPS less than 1, median PFS was 5.36 months (95% CI, 4.14-9.97) in the dual-therapy group (n=35) compared with 5.07 months (95% CI, 3.85-NA) in the monotherapy group (n=28; HR, 1.06; 95% CI, 0.59-1.90; P=0.84).

Again, OS data are immature, but in PD-L1-positive patients, the median OS with dual therapy was 18.52 months (95% CI, 16.88-NA), compared with 12.50 months (95% CI, 11.97-NA) with monotherapy (HR, 0.61; 95% CI, 0.18-2.04; P=0.42). Among PD-L1-negative patients, the median OS of each group 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=0.38).

There were no significant differences in ORR, CBR, DOR and TTOR between the two groups. The ORR of pembrolizumab plus gosatuzumab was 21.2%, compared with gosatuzumab aloneThe ORR is 17.3%. The median TTOR was 2.3 months (95% CI, 1.8-8.7) in the dual-therapy group and 4.1 months (95% CI, 2.0-10.2) in the monotherapy group; the median DOR was 12.9 months (95% CI, 4.4-NA) and 4.5 months (95% CI, 4.5-NA), respectively. The relative risks of the two were 50.0% (95%CI, 35.8%-64.2%) and 46.2% (95%CI, 32.2%-60.5%) respectively.

Overall, the safety profiles of pembrolizumab and gosatuzumab were similar to expected for either drug, with no new safety signals reported.

Among patients who received dual therapy, 98.1% of patients experienced a treatment-emergent adverse effect (TEAE) of any grade compared with 96.2% of patients who received monotherapy; these effects were associated with treatment in 92.3% and 94.2% of patients, respectively. TEAEs resulted in discontinuation in 5.8% and 1.9% of patients, respectively. The most common TEAEs experienced by at least 15% of patients receiving the combination included decreased neutrophil count, anemia, decreased white blood cell count, decreased lymphocyte count, diarrhea, nausea, alopecia, fatigue, and anorexia.

Immune-mediated AEs in the pembrolizumab combination groupAEs included hypothyroidism, hypoalbuminemia, increased alanine aminotransferase, increased alkaline phosphatase, increased aspartate aminotransferase, acute kidney injury, viral hepatitis, adrenal insufficiency, arthralgia, increased blood bilirubin, dyspnea, pneumonia, and pruritus.