LBA3 - SOLTI-1507 IPATHER: Primary results of the phase Ib study of ipatasertib (IPAT) and dual anti-HER2 therapy with trastuzumab and pertuzumab (HP) in patients (pts) with PIK3CA mutant (mut) HER2+ advanced breast cancer (ABC)

Background

In the CLEOPATRA trial, pts with HER2+ PIK3CAmut ABC had a shorter progression-free survival (PFS) than those with PIK3CAwt. We hypothesized that IPAT, an AKT inhibitor with activity in PI3K/AKT-altered tumors, combined with HP was both safe and effective in PIK3CAmut HER2+ ABC.

Methods

IPATHER is an open-label, single-arm, phase Ib trial that evaluates the safety and efficacy of IPAT + HP in pts with PIK3CAmut HER2+ ABC candidates to maintenance HP following discontinuation of first-line chemotherapy (CT) for reasons other than progressive disease. The primary aim was to determine the maximum tolerated dose (MTD) of IPAT + HP, defined as the highest dose at which ≤1 of the first 6 pts enrolled experienced a dose-limiting toxicity (DLT: grade [G] ≥3 diarrhea >72 hours, G ≥2 diarrhea >5 days [d], other treatment related adverse events [TRAEs] G ≥ 3) during the first 28d of treatment. Initial IPAT dose was 400mg d1-21 in 28d cycles with standard dose HP (de-escalation doses are 300mg and 200mg). Secondary aims included safety, overall response rate (ORR), clinical benefit rate (CBR), and PFS.

Results

PIK3CAmut was detected in 24/108 HER2+ tumors (22%). From Feb/2020 to Nov/2023, 17 pts were enrolled, median age 54 (41-78). Most had HR- tumors, visceral metastases, and stage IV disease at diagnosis (59% each). At data cut-off (April 2024), 6 pts (35%) remained on treatment. No DLTs were observed in the first 6 pts and IPAT 400mg + HP was defined as MTD. In the remaining 11 pts, 3 had a DLT (G3 diarrhea, G3 vomiting, and G3 rash). The most common TRAEs were diarrhea (82%), nausea (47%), decreased appetite (35%), and fatigue, rash, and vomiting (29% each). G3/4 TRAEs occurred in 35%; most common were diarrhea and nausea (12% each). With a median follow-up of 19.9 months (m), confirmed ORR was 31%, CBR 69%, and median PFS 15.4m (9.4-NR), with 48% pts progression-free after 18m from enrollment.

Conclusions

Maintenance treatment with IPAT 400mg + HP following CT had an acceptable safety profile and showed promising efficacy in pts with PIK3CAmut HER2+ ABC. Combining a PI3K/AKT pathway inhibitor with anti-HER2 treatment in this setting merits further evaluation.

Clinical trial identification

NCT04253561.

Legal entity responsible for the study

SOLTI Cancer Research Group.

Funding

F. Hoffmann-La Roche Ltd.

Disclosure

M. Oliveira: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Daiichi Sankyo / AstraZeneca; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Advisory Board: Gilead; Financial Interests, Personal, Invited Speaker: Gilead; Financial Interests, Personal, Other, Educational activity: Libbs; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: Relay Therapeutics; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Invited Speaker: Seagen; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Cureo Science; Financial Interests, Personal, Advisory Board: iOne; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Invited Speaker: Medscape; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker: GSK; Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Invited Speaker: Roche; Financial Interests, Institutional, Invited Speaker: Seattle Genetics; Financial Interests, Institutional, Invited Speaker: Zenith Epigenetics; Financial Interests, Institutional, Invited Speaker: Gilead; Financial Interests, Institutional, Invited Speaker: Ayala Pharmaceuticals; Financial Interests, Institutional, Invited Speaker: Pfizer; Non-Financial Interests, Member of Board of Directors, Head: SOLTI Breast Cancer Research; Other, Travel Grant: Pierre Fabre; Other, Travel Grant: Eisai; Other, Travel Grant: Gilead; Other, Travel Grant: AstraZeneca. E.M. Ciruelos: Financial Interests, Personal, Other, Speakers Bureau. Educational activities: Roche; Financial Interests, Personal, Invited Speaker, Symposia and Educational activities: Roche; Financial Interests, Personal, Advisory Board, Non-permanent advisor: Roche; Financial Interests, Personal, Invited Speaker, Symposia and Education: Lilly; Financial Interests, Personal, Advisory Board, Non-permanent advisor: Lilly; Financial Interests, Personal, Advisory Board, Non-permanent advisor: Novartis; Financial Interests, Personal, Invited Speaker, Educational activities: Pfizer; Financial Interests, Personal, Advisory Board, Non-permanent advisor: Pfizer; Financial Interests, Personal, Advisory Board, Non-permanent advisor, Travel accommodation: AstraZeneca; Financial Interests, Personal, Advisory Board, Non-permanent advisor: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Non-permanent advisor: MSD; Financial Interests, Personal, Other, Advisory Board: Gilead; Financial Interests, Personal, Other, Advisory Board, Invited speaker: Seagen; Financial Interests, Institutional, Funding, PI for Patricia 2 trial (sponsor: SOLTI Group): Pfizer; Financial Interests, Institutional, Funding, PI for Prometeo 2 trial (sponsor: SOLTI Group): Pfizer; Financial Interests, Institutional, Funding, PI for TATEN trial (sponsor: SOLTI Group): MSD; Financial Interests, Institutional, Funding, PI for ATREZZO trial (sponsor: SOLTI Group): Roche; Non-Financial Interests, Member of Board of Directors, Non-profit organization dedicated to breast cancer research: SOLTI Cooperative Group; Non-Financial Interests, Advisory Role, Scientific Evaluator at ISCIII (Spanish Government Academic Research Platform): Instituto de Salud Carlos III. F.J. Salvador Bofill: Non-Financial Interests, Personal, Invited Speaker: Lilly; Non-Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Pfizer; Non-Financial Interests, Personal, Invited Speaker: AstraZeneca; Non-Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Non-Financial Interests, Personal, Advisory Board: Lilly; Non-Financial Interests, Personal, Advisory Board: Novartis; Non-Financial Interests, Personal, Advisory Board: Pfizer; Non-Financial Interests, Personal, Advisory Board: AstraZeneca; Non-Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Non-Financial Interests, Personal, Speaker’s Bureau: Lilly; Non-Financial Interests, Personal, Speaker’s Bureau: Novartis; Non-Financial Interests, Personal, Speaker’s Bureau: Pfizer; Non-Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Non-Financial Interests, Personal, Speaker’s Bureau: Daiichi Sankyo. J. Gavilá-Gregori: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Astra-Zeneca; Financial Interests, Personal, Invited Speaker: Daichii-Sankyo; Financial Interests, Personal, Invited Speaker: Seagen ; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Astra-Zeneca; Financial Interests, Personal, Advisory Board: Daichii-Sankyo; Financial Interests, Personal, Advisory Board: Seagen. A.S. Cortegoso Mosquera: Financial Interests, Personal, Invited Speaker, Participation as speaker in a scientist meeting in 2023 (talking about: GSK; Financial Interests, Personal, Invited Speaker, participation as speaker in a scientist meeting in 2023 (presenting a clinical case in a metastatic breast cancer board): Daiichi Sankyo ǀ AstraZeneca; Financial Interests, Personal, Advisory Board, Advisory meeting in Gynecological cancer in 2022: GSK; Financial Interests, Personal, Other, Video recording for public display in 2022 (summirizing the Alpelisib results abstract presented in ASCO 2022 ): Novartis; Financial Interests, Personal, Invited Speaker, participation in a scientist meeting in 2022 (talking about luminal metastatic breast cancer to GPs): Pfizer; Financial Interests, Personal, Invited Speaker, participating in a scientist meeting in 2022 (multidisciplinary meeting about advanced gynecological cancer): AstraZeneca; Financial Interests, Institutional, Invited Speaker, Local PI and steering committee member of IPATHER phase 1 clinical trial: SOLTI / ROCHE; Financial Interests, Institutional, Invited Speaker, Local PI of the TropionBreast04 phase 3 clinical trial: AstraZeneca / Daiichi Sankyo. P. Tolosa Ortega: Financial Interests, Personal, Invited Speaker: Novartis, Pfizer, Lilly, Seagen, AstraZeneca, Daiichi Sankyo and MSD; Financial Interests, Personal, Advisory Board: Novartis, Adamed, Seagen and Daiichi Sankyo; Financial Interests, Personal, Full or part-time Employment, Medical Advisor and Madical Monitor: SOLTI; Financial Interests, Institutional, Funding: Novartis. G. Villacampa Javierre: Financial Interests, Personal, Invited Speaker, Invited speaker in a course: MSD; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Invited speaker in an internal training: Pierre Fabre; Financial Interests, Personal, Invited Speaker, Invited speaker in an internal training: GSK; Financial Interests, Personal, Invited Speaker, Internal discussion about the interpretation of some published results: Pfizer; Financial Interests, Personal, Other, Collaborations with specific projects: Reveal Genomics. X. González Farre: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Gilead; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Other, Travel & congress: AstraZeneca; Financial Interests, Personal, Other, Travel & congress: Eli Lilly. T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer/ AstraZeneca / Veracyte / Novartis; Financial Interests, Personal, Advisory Board: Roche/Genentech; Financial Interests, Personal, Advisory Board: Novartis. C. Saura Manich: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Expert Testimony: Boehringer Ingelheim; Financial Interests, Personal, Expert Testimony: Bristol Meyers Squibb; Financial Interests, Personal, Other, SC: Byondis B.V.; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Exact Sciences; Financial Interests, Personal, Advisory Board: Exeter Pharma; Financial Interests, Personal, Advisory Board: F. Hoffmann - La Roche Ltd; Financial Interests, Personal, Advisory Board: Gilead; Financial Interests, Personal, Other, SC: Glaxo; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Other, SC: Macrogenics; Financial Interests, Personal, Other, SC: Menarini; Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme; Financial Interests, Personal, Other, SC: Merus; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Philips; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board: PintPharma; Financial Interests, Personal, Advisory Board: Puma; Financial Interests, Personal, Advisory Board: Roche Farma; Financial Interests, Personal, Advisory Board: Sanofi.-Aventis; Financial Interests, Personal, Advisory Board: SeaGen; Financial Interests, Personal, Other, SC: Synthon Biopharpaceuticals; Financial Interests, Personal, Advisory Board: Zymeworks; Financial Interests, Personal, Expert Testimony: Genentech; Financial Interests, Personal, Expert Testimony: Innoup; Financial Interests, Personal, Expert Testimony: Millenium; Financial Interests, Personal, Advisory Board: Pharmalex Spain SLU; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Bayer Pharma; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb (BMS); Financial Interests, Institutional, Invited Speaker: Byondis B.V.; Financial Interests, Institutional, Research Grant: Cytomx Therapeutics; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Eli Lilly and Company; Financial Interests, Institutional, Research Grant: F. Hoffmann-La RocheLtd; Financial Interests, Institutional, Research Grant: Genentech; Financial Interests, Institutional, Research Grant: GSK; Financial Interests, Institutional, Research Grant: Immunomedics; Financial Interests, Institutional, Research Grant: Innoup Farma; Financial Interests, Institutional, Research Grant: Macrogenics; Financial Interests, Institutional, Research Grant: Menarini Ricerche; Financial Interests, Institutional, Research Grant: Merus; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Puma; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Sanofi-Aventis; Financial Interests, Institutional, Research Grant: Seattle Genetics; Non-Financial Interests, Member: Spanish Society of Medical Oncology (SEOM); Non-Financial Interests, Member: American Society for Clinical Oncology (ASCO); Non-Financial Interests, Member, Junta Directiva y Comité Científico: SOLTI group (Academic research group in breast cancer); Non-Financial Interests, Member: Geicam (Spanish Breast Cancer Research Group); Non-Financial Interests, Member: European Society for Medical Oncology (ESMO); Non-Financial Interests, Member: Sinology Society of the Official College of Physicians of Barcelona (COMB). All other authors have declared no conflicts of interest.