Editor's Note: In this "Man Talks Breast Cancer: ASCO Special," Professor Man Li's team from The Second Affiliated Hospital of Dalian Medical University has selected the latest ASCO studies on HR+ advanced breast cancer, covering topics such as cross-line treatment with CDK4/6 inhibitors, novel ADCs combined with ICIs, and comparing CDK4/6 inhibitors + ET with chemotherapy in premenopausal women. These can provide more valuable insights for clinical practice.Study Overview
Background CDK4/6i+ET significantly improved the prognosis of HR+/HER2- breast cancer, but 25%-35% of patients do not benefit, and almost all eventually develop resistance, posing a significant challenge. KEYNOTE-756 and IMpassion031 successfully applied immunotherapy combined with chemotherapy in HR+/HER2- breast cancer. However, the optimal patient population and treatment combinations remain unclear. Sacituzumab govitecan (SG, TROP2 ADC) can theoretically enhance T-cell function by causing DNA double-strand breaks. Combining SG with pembrolizumab (Keytruda) may improve the prognosis of metastatic HR+/HER2- breast cancer.
Design and Results The SACI-IO HR+ study is a multicenter, randomized, open-label phase II trial, the first to evaluate the efficacy and safety of pembrolizumab combined with SG in metastatic HR+/HER2- breast cancer. Eligible patients were those with unresectable locally advanced or metastatic HR+/HER2- breast cancer, having received at least one line of endocrine therapy and up to one line of chemotherapy. Patients who had previously received topoisomerase I inhibitor ADCs, irinotecan, or PD-1/L1 inhibitors were excluded. 104 patients were randomly assigned 1:1 to receive SG plus pembrolizumab or SG monotherapy, with the primary endpoint being ITT population PFS.
38.5% of patients were PD-L1 positive (CPS≥1), but only 7 had CPS≥10. There were differences in PD-L1 positivity between groups (38.5% in the combination group vs. 46.2% in the monotherapy group). About two-thirds of patients received chemotherapy in the adjuvant or neoadjuvant setting, and 50% had first-line chemotherapy for advanced disease. Liver metastases were present in 80% of patients in both groups.
With a median follow-up of 12.5 months, median PFS was 8.12 months in the SG plus pembrolizumab group vs. 6.22 months in the SG monotherapy group (HR 0.81, 95% CI: 0.51-1.28, P=0.37); ORR was 21.2% vs. 17.3%. OS data were immature, with only 26 events, showing 18.52 months vs. 17.96 months (HR 0.65, 95% CI: 0.33-1.28). In the PD-L1 positive subgroup, PFS was 11.05 months vs. 6.68 months, and OS was 18.52 months vs. 12.5 months, but these differences were not statistically significant. Safety was consistent with previous reports, with no new safety signals.
Expert Commentary
- Study Design Interpretation The SACI-IO HR+ study is the first to evaluate pembrolizumab combined with SG in metastatic HR+/HER2- breast cancer. The phase II study did not pre-select for PD-L1 expression, resulting in a limited number of CPS≥1 and CPS≥10 patients, potentially affecting results. The OS data are immature, with only 26 death events, leading to a lack of observable OS benefit at this time.
- Clinical Practice Interpretation For metastatic HR+/HER2- breast cancer patients, CDK4/6-based first-line endocrine therapy should be the preferred strategy. However, post-endocrine progression, the selection of subsequent treatments is varied. Immunotherapy attempts in HR+/HER2- breast cancer are limited, but prior studies in triple-negative breast cancer (TNBC) suggest that immunotherapy benefits require precise selection of PD-L1 positive patients. The SACI-IO HR+ study confirms that SG combined with pembrolizumab is not universally effective in this population but shows potential benefits in PD-L1 positive patients. Future studies should focus on identifying which patients benefit from combined immunotherapy, considering PD-L1 levels, TMB, and TILs. Additionally, exploring resistance mechanisms and combining novel drugs targeting ESR1 mutations and other targets could improve outcomes for metastatic HR+/HER2- breast cancer patients.
