Neoadjuvant atirmociclib plus letrozole versus letrozole alone in HR+/HER2− breast cancer: Results from FourLight-2, a randomized phase 2 window of opportunity study.

518 Background: In the neoadjuvant setting, endocrine therapy is a standard of care option in patients (pts) with HR+ breast cancer (BC). Atirmociclib (ATI, PF-07220060) is a potent and selective CDK4 inhibitor and has shown favorable tolerability and promising early activity as a first-line treatment in pts with HR+/HER2− metastatic BC. CDK4 selectivity is hypothesized to limit hematologic and gastrointestinal toxicities that may be dose-limiting; therefore, ATI may improve efficacy and tolerability. Ki-67 is a biomarker used to assess the antiproliferative activity of therapies. Complete cell cycle arrest (CCCA, defined as Ki-67-positive tumor cells ≤2.7%) in the neoadjuvant setting is correlated with less BC tumor recurrence. This phase 2 randomized global study evaluated the effects of ATI + letrozole (LET) and LET alone on Ki-67 expression in HR+/HER2− BC tumors after 14 days of treatment in the neoadjuvant setting (FourLight-2; NCT06465368). Methods: Postmenopausal women with HR+/HER2− BC and Ki-67 score of ≥10% per local assessment, primary tumor ≥1.5 cm, no prior systemic therapy for BC, and ECOG PS ≤1 were enrolled. Eligible pts were randomly assigned to ATI (300 mg, orally BID) + LET (2.5 mg, orally QD) or LET alone (2.5 mg, orally QD), for 14 days. Baseline breast lesion biopsy and on-treatment biopsy on day 14 were obtained. The primary endpoint was centrally-assessed CCCA rate at day 14; secondary endpoints included Ki-67 expression change, safety, ctDNA assessments, and PK. Results: 121 pts were randomized to ATI + LET (n = 59) or LET alone (n = 62) arms; median age was 66 y and 63 y; 90% and 92% had Stage I/II disease, respectively. In Ki-67 evaluable pts (n = 51 and n = 56), 77% and 70% had Ki-67 ≥20% at baseline (centrally assessed) and 71% and 80% had grade 1/2 tumor, respectively. At day 14, the proportion of pts who achieved CCCA was 88.2% (95% CI, 76.6–94.5) for ATI + LET and 17.9% (95% CI, 10.0–29.8) for LET alone, with median relative change of Ki-67 from baseline of -97.3% (range -99.8%, 34.0%) and -72.4% (range -98.3%, 139.9%) in each arm, respectively. CCCA was achieved at a higher rate with ATI + LET than LET alone across baseline subgroups (Table). The most common TEAEs with ATI + LET and LET alone, respectively, were diarrhea (19% and 2%), fatigue (15% and 10%), and nausea (14% and 5%) (all grade 1/2); no grade 3/4 treatment-related TEAEs or treatment discontinuations due to TEAEs were reported. Conclusions: ATI + LET demonstrated substantially greater antiproliferative effects than LET alone, with a tolerable safety profile in pts with HR+/HER2− BC, suggesting that ATI + LET may have value in early BC. Clinical trial information: NCT06465368 . Subgroup Analysis with CCCA, n (%) ATI + LETn = 51 LET alonen = 56 Tumor grade 1/2 32 (89) 9 (20) 3/X 13 (87) 1 (9) Primary tumor stage T1c 12 (80) 2 (11) T2 28 (93) 7 (22) T3/T4 5 (83) 1 (20) Baseline Ki-67 (central assessment) <20% 9 (90) 4 (27) ≥20% 35 (90) 6 (15)