Abstract P1-18-34: Solti-1507 IPATHER - A phase Ib study of ipatasertib (IPAT) and dual anti-HER2 therapy with pertuzumab and trastuzumab (HP) in patients with HER2-positive (HER2+) advanced breast cancer (ABC) and a PIK3CA mutation (mut): Results from the first safety cohort
Authors: Oliveira Mafalda , Ciruelos Eva , Morales Serafín , Gavilá Joaquín , Quiroga Vanesa , Vega Estela , Bofill Javier Salvador , Cortegoso Alexandra , Henao Fernando , Tolosa Pablo , Canes Jordi , Villagrasa Patricia , Farré Xavier Gonzalez , Pascual Tomás , Saura Cristina 
Published: March 2022

Abstract
Background The combination of HP and a taxane increases progression-free survival (PFS) and overall survival (OS) in patients with HER2+ ABC. PIK3CA mut can occur in 30-35% of HER2+ tumors, independently of hormone receptor (HR) status. In an exploratory analysis from CLEOPATRA, patients with a tumor harboring a PIK3CA mut had a shorter PFS. The AKT inhibitor IPAT blocks the PI3K/AKT pathway and has activity in PI3K/AKT-altered tumors. Patients and Methods IPATHER (NCT04253561) is an open-label, single-arm, phase Ib study to evaluate the safety and preliminary efficacy of IPAT plus HP in patients with HER2+ ABC with a PIK3CA-mut (detected in tissue or plasma ctDNA in a Central Laboratory) who are candidates to receive maintenance HP after taxane discontinuation in the first line setting for a reason different to progressive disease. The primary objective is to characterize the safety and tolerability of IPAT in combination with HP, and to identify a maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). The study has two phases: a dose safety phase and a dose expansion phase. MTD is defined as the highest dose level at which ≤1 of 6 subjects experience a dose-limiting toxicity (DLT) during the first 28 days of treatment. DLT during first 28 days of therapy is defined as grade ≥3 diarrhea lasting more than 72 hours, grade ≥2 diarrhea lasting more than 5 days, and other non-hematologic or hematologic toxicities that are ≥ grade 3 and probably or definitely related to study therapy. Given the low risk for overlapping toxicities, the first cohort of the dose safety phase tested IPAT at 400 mg orally once daily D1-21 q28d and standard dose HP. Dose level -1 and -2 of IPAT were 300 mg and 200 mg in case dose de-escalation was needed. Loperamide was given as prophylaxis for diarrhea. In HR-positive tumors, endocrine therapy could be started after the DLT period. Here, we present the results of the dose safety phase of IPATHER. Results A total of 6 female patients with PI3KCA-mut/HER2+ ABC were included in the first dose safety cohort. Median age was 52 (41-78), most patients had ECOG 0 (66.6%), and 50% were postmenopausal. Five out of six patients (83.3%) had HR-negative tumors and visceral metastases. Patients received a median of 6 treatment cycles (range 4-7) with taxane plus HP. At the time of the data cut-off (28/02/2021), all the patients remained on treatment. Median follow up is 4 months (range 2-12). Treatment was well tolerated with no DLTs or grade 3/4 adverse events (AEs) observed during the DLT period or the rest of treatment period (Table 1). The most common treatment-related AEs were diarrhea (N=5, [83.3%]) and nausea (N=2,[33.3%]), mostly grade 1. There was no dose reduction and diarrhea was controlled with prophylactic loperamide. A partial response (PR) was observed in one patient, and 5 had stable disease. Of note, the addition of IPAT to HP in the patient with a PR deepened the response achieved during the induction phase with chemotherapy plus HP.
Conclusion IPAT 400 mg orally once daily D1-21 q28d in combination with HP is well tolerated and has shown preliminary signs of efficacy. Given the favourable safety profile, the dose expansion phase testing IPAT 400 mg in combination with HP has started and will include 19 additional patients.
Table 1.Adverse Events during treatment period related with study treatment (IPAT and/or HP).Adverse EventN AEsN patientsGrade 1Grade 2% (N=6)Diarrhea55 (83%)5083%Nausea32 (33%)2033Vomiting21 (17%)1017Anemia11 (17%)1033Lymphopenia11 (17%)1033Gastroesophageal reflux11 (17%)0117Dyspepsia11 (17%)1017Hyporexia11 (17%)1017
Citation Format: Mafalda Oliveira, Eva Ciruelos, Serafín Morales, Joaquín Gavilá, Vanesa Quiroga, Estela Vega, Javier Salvador Bofill, Alexandra Cortegoso, Fernando Henao, Pablo Tolosa, Jordi Canes, Patricia Villagrasa, Xavier Gonzalez Farré, Tomás Pascual, Cristina Saura. Solti-1507 IPATHER - A phase Ib study of ipatasertib (IPAT) and dual anti-HER2 therapy with pertuzumab and trastuzumab (HP) in patients with HER2-positive (HER2+) advanced breast cancer (ABC) and a PIK3CA mutation (mut): Results from the first safety cohort [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 P1-18-34.