Abstract PD13-03: Ribociclib, everolimus, exemestane triplet therapy in HR+/HER2− advanced breast cancer after progression on a CDK4/6 inhibitor: Final efficacy, safety, and biomarker results from TRINITI-1
Authors: Hurvitz Sara A. , Clark Amy S. , Rugo Hope S. , Bardia Aditya , Zelnak Amelia , Yardley Denise A. , Karuturi Meghan , Sanft Tara , Blau Sibel , Hart Lowell , Ma Cynthia , Purkayastha Das , Eppig Colleen , DeMichele Angela 
Published: March 2022

Background: Combination cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and endocrine therapy (ET) is a standard-of-care treatment for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC). However, disease progression inevitably occurs during CDK4/6i + ET treatment, highlighting the need for effective subsequent regimens. TRINITI-1 (NCT02732119) assessed triplet therapy with CDK4/6i ribociclib (RIB), mTORi everolimus (EVE), and ET exemestane (EXE) in patients (pts) with HR+/HER2− ABC who experienced disease progression on CDK4/6i treatment. We previously reported pooled Phase I/II results from TRINITI-1 demonstrating promising efficacy (per investigator assessment) and tolerability with RIB + EVE + EXE triplet therapy (Bardia, et al. Clin Cancer Res. 2021). Here we present the final efficacy (central review and OS) and safety data from the phase 2 study, and the final biomarker data. Methods: TRINITI-1 was a phase 1/2, multicenter, open-label study that enrolled postmenopausal women with ET-refractory HR+/HER2− ABC with most recent disease progression after ≥ 4 months of CDK4/6i treatment. Pts received once-daily, oral EXE 25 mg with either RIB 300 mg + EVE 2.5 mg (group 1) or RIB 200 mg + EVE 5 mg (group 2); all pts were given a prophylactic steroid mouthwash. Group 1 was enrolled first, followed by group 2; both began enrollment in phase 1 and were expanded in phase 2. Endpoints included clinical benefit rate (CBR) by 24 weeks (primary endpoint), progression-free survival (PFS), overall survival (OS), tumor response, and safety/tolerability. Results: A total of 79 pts (n = 46, group 1; n = 33, group 2) were enrolled and treated. Median age was 58.0 years (range, 32.0-83.0 years) and median prior CDK4/6i duration was 12.1 months (range, 3.5-34.0 months). As of the cutoff date (June 15, 2020), 73 pts (92.4%) had discontinued study treatment; the primary reasons included progressive disease (67.1%) and physician decision (16.5%). The CBR by week 24 (central review) was 65.2% and 59.4% for groups 1 and 2, respectively; the objective response rate was 6.5% and 9.4%, respectively (Table). Median PFS by central review was 8.0 months in group 1 and 4.7 months in group 2. For pts with ≥ 12 months of prior CDK4/6i, median PFS was 12.8 months in group 1 and 5.5 months in group 2; for those with &lt; 12 months of prior CDK4/6i, median PFS was 5.3 months in group 1 and 3.6 months in group 2. Biomarker analysis showed numerically shorter median PFS when tumors expressed ESR1 or PIK3CA alterations. Median OS was 27.4 months in group 1 and not reached (NR) in group 2 at study end. For pts with ≥ 12 months of prior CDK4/6i, median OS was NR in both groups, and was 20.3 months (group 1) and 18.8 months (group 2) for pts with &lt; 12 months of prior CDK4/6i. The most common all-grade adverse events were stomatitis (54.3%), infections (50.0%), neutropenia (43.5%), and fatigue (43.5%) in group 1, and infections (48.5%), nausea (42.4%), stomatitis (36.4%), and thrombocytopenia (36.4%) in group 2. There was no grade &gt; 2 QTc prolongation. Conclusions: Results from TRINITI-1 demonstrate that triplet therapy with RIB + EVE + EXE is a relatively well tolerated and clinically active regimen directly following treatment with a CDK4/6i. There was a trend toward better outcomes in pts with longer durations of prior CDK4/6i treatment, wild-type ESR1, and wild-type PIK3CA.

Tumor response by central reviewGroup 1: RIB 300 mg,. EVE 2.5 mg, EXE 25 mg (n = 46)Group 2: RIB 200 mg,. EVE 5 mg, EXE 25 mg (n = 32)aCBR, n (%) by week 24b30 (65.2)c19 (59.4)dORR, n (%)e3 (6.5)3 (9.4)SurvivalMedian PFS by central review, months8.04.7HR (95% CI) = 0.740 (0.424-1.291)Median OS, months27.4NESurvival by duration of prior CDK4/6iGroup 1: RIB 300 mg,. EVE 2.5 mg, EXE 25 mg (n = 46)Group 2: RIB 200 mg,. EVE 5 mg, EXE 25 mg (n = 32)a&lt; 12 months. (n = 27)≥ 12 months. (n = 19)&lt; 12 months (n = 11)≥ 12 months (n = 21)Median PFS, months5.312.83.65.5Median OS, months20.3NR18.8NRMedian PFS by tumor mutation status, monthsWTAlteredHR (95% CI)ESR19.1 (n = 59)2.8 (n = 30)1.678 (0.995-2.828)PIK3CA 9.1 (n = 59)5.7 (n = 30)1.275 (0.756-2.150)BOR, best overall response; CBR, clinical benefit rate; CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; CI, confidence interval; CR, complete response; ESR1, estrogen receptor 1; EVE, everolimus; EXE, exemestane; HR, hazard ratio; NR, not reached; ORR, objective response rate; OS, overall survival; PD, progressive disease; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PFS, progression-free survival; PR, partial response; pt, patient; RIB, ribociclib; SD, stable disease; WT, wild type. aOne pt did not progress on prior CDK4/6i and thus was not evaluable for efficacy. bBOR of CR, PR, SD, or non-CR/non-PD. cn = 10 required to show a clinical benefit. dn = 8 required to show a clinical benefit. eBOR of CR or PR.

Citation Format: Sara A. Hurvitz, Amy S. Clark, Hope S. Rugo, Aditya Bardia, Amelia Zelnak, Denise A. Yardley, Meghan Karuturi, Tara Sanft, Sibel Blau, Lowell Hart, Cynthia Ma, Das Purkayastha, Colleen Eppig, Angela DeMichele. Ribociclib, everolimus, exemestane triplet therapy in HR+/HER2− advanced breast cancer after progression on a CDK4/6 inhibitor: Final efficacy, safety, and biomarker results from TRINITI-1 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD13-03.