Abstract PD13-02: Phase Ib expansion study of gedatolisib in combination with palbociclib and endocrine therapy in women with ER+ metastatic breast cancer
Authors: Layman Rachel , Wesolowski Robert , Han Hyo , Specht Jennifer M , Stringer-Reasor Erica M , Dees E. Claire , Kabos Peter , Mayer Ingrid A , Vaishampayan Ulka , Lu Janice , Gogineni Keerthi , Bardia Aditya , Schott Anne F , Abu-Khalaf Maysa , Howkins Doug , Sullivan Brian , Gorbatchevsky Igor , Rugo Hope 
Published: March 2022

Background: The addition of CDK4/6, PI3K-α, or mTOR inhibitors to endocrine therapy (ET) improves progression free survival (PFS) in first and later lines of therapy for estrogen receptor positive (ER+), HER2-negative metastatic breast cancer (MBC). We hypothesized that simultaneous inhibition of these pathways would improve treatment efficacy. We conducted a phase Ib study of triplet therapy with gedatolisib (G), a dual inhibitor of PI3K/mTOR, palbociclib (P) a CDK4/6 inhibitor, and ET with letrozole (L) or fulvestrant (F) in women with ER+/HER2-negative MBC. Manageable toxicity and preliminary antitumor activity were observed in 35 patients enrolled on the dose escalation portion of the study (ASCO 2018). We now report results from the dose expansion study arms. Methods: Patients with ER+/HER2- MBC were treated in four-arms: A) G+P+L as first-line treatment, B) G+P+F as 2-line treatment in patients without prior CDK4/6 inhibitor therapy; C) G+P+F in patients with prior CDK4/6 inhibitor therapy; D) G+P+F in patients whose most recent regimen included a CDK4/6 inhibitor. Palbociclib, letrozole and fulvestrant were administered at standard doses. Gedatolisib 180 mg was intravenously administered weekly in Arms A, B, and C and three weeks on/one week off in Arm D. Pre-/peri-menopausal women received ovarian suppression. The primary endpoint was objective response assessed by the investigator. Secondary endpoints included safety, duration of response (DOR), and PFS.Results: A total of 103 patients were enrolled: Arm A (n=31); Arm B (n=13); Arm C (n=32); Arm D (n=27). Median age was 54, 62, 59.5, and 59 years in each arm respectively. Progressed on last line of endocrine therapy in &lt; 6 months (refractory): Arms B: 4/13 (31%), Arm C: 15/32 (47%), Arm D: 7/27 (26%). ORR in evaluable patients, including unconfirmed responses: 84%; 75%, 33% and 64%. Median PFS (months) was not reached in Arm A, and for arms B, C and D was 11.9, 5.1, 12.9 respectively. Most common (≥50%), treatment emergent adverse events (TEAE) across all arms were: nausea 81.6% (all Gr1-2, no ≥Gr3), stomatitis 80.6% (27.2% Gr3), fatigue 79.6% (10.7% Gr3), vomiting 51.5 % (1% Gr3), neutropenia/neutrophil count decrease 79.6% (66.7% ≥Gr3). Most common (≥2%) treatment emergent SAEs were febrile neutropenia 4.9%, acute kidney injury and pyrexia 2.9% each. Hyperglycemia was reported in 26.2% (6.8% ≥Gr3) of patients regardless of relation to treatment. Most common reason for treatment discontinuation was disease progression.; 8.7% (9 out of 103) patients discontinued therapy due to a related AE across all arms. No treatment discontinuation due to TEAE and no SAE of stomatitis were observed in Arm D. Seventeen patients are continuing therapy at the time of data cut of May 10, 2021.Conclusions: The addition of Gedatolisib to palbociclib and endocrine therapy demonstrated promising antitumor activity in both first and later line settings for ER+ MBC that compared favorably to historical controls. Responses were also observed in patients refractory to the last treatment. Therapy was well tolerated with manageable toxicity and low number of treatment discontinuation due to related AE. The favorable safety profile and antitumor activity observed in patients treated with the three weeks on/one week off gedatolisib regimen supports use of this dosing schedule in future studies. A phase 3 study evaluating gedatolisib in patients with ER+/HER2- MBC is planned.

Table 1.Arm A, n=31Arm B, n=13Arm C, n=32Arm D, n=27EfficacyEvaluable for response25122725ORR in evaluable patients84% (21/25)75% (9/12)33% (9/27)64% (16/25)DCR (CR, PR, SD)92%92%48%85%Treatment DiscontinuationAll64.5% (20/31)76.9% (10/13)100% (32/32)85.2% (23/27)PD/general deterioration38.7% (12/31)61.5% (8/13)75% (24/32)70.4% (19/27)TEAE (related)9.7% (3/31)7.7% (1/13)12.5% (4/32)3.7% (1/27)Stomatitis3.2% (1/31)7.7% (1/13)9.4% (3/32)0TEAE (not related)07.7% (1/13)00Withdrew9.7% (3/31)012.5% (4/32)0Other6.5% (2/31)0011.1% (3/27)Treatment Emergent SAEAll22.6% (7/31)30.8% (4/13)21.9% (7/32)14.8% (4/27)Stomatitis3.2% (1/31)000

Citation Format: Rachel Layman, Robert Wesolowski, Hyo Han, Jennifer M Specht, Erica M Stringer-Reasor, E. Claire Dees, Peter Kabos, Ingrid A Mayer, Ulka Vaishampayan, Janice Lu, Keerthi Gogineni, Aditya Bardia, Anne F Schott, Maysa Abu-Khalaf, Doug Howkins, Brian Sullivan, Igor Gorbatchevsky, Hope Rugo. Phase Ib expansion study of gedatolisib in combination with palbociclib and endocrine therapy in women with ER+ metastatic breast cancer [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 PD13-02.