Ipatasertib/Anti-HER2 Therapy Is Safe and Active in PIK3CA-Mutant, HER2+ Advanced Breast Cancer


Key Takeaways

  • Ipatasertib combined with trastuzumab and pertuzumab showed efficacy and acceptable safety in HER2-positive advanced breast cancer with PIK3CA mutations.
  • The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ipatasertib were established at 400 mg.
Mafalda Oliveira, MD, PhD

Mafalda Oliveira, MD, PhD

Ipatasertib with trastuzumab (Herceptin) plus pertuzumab (Perjeta) as maintenance therapy following first-line chemotherapy plus trastuzumab and pertuzumab was effective and associated with an acceptable safety profile in patients with HER2-positive advanced breast cancer harboring PIK3CA mutations, according to primary findings from the phase 1b IPATHER trial (NCT04253561), which were presented during the 2024 ESMO Breast Cancer Congress.1

In the dose-safety phase of the trial (n = 6), no dose-limiting toxicities (DLTs) were observed among the patients who received ipatasertib at 400 mg plus the maximum tolerated dose (MTD) of trastuzumab and pertuzumab. In the dose-expansion phase, the safety profile and preliminary efficacy of the regimen were evaluated in an additional 11 patients. The MTD and recommended phase 2 dose (RP2D) was determined to be 400 mg of ipatasertib on days 1 through 21 of each 28-day cycle plus the standard dose of trastuzumab at 600 mg plus pertuzumab at 420 mg.

PIK3CA mutations occur in 30% to 35% of HER2-positive breast tumors, regardless of hormone receptor (HR) status. An exploratory analysis of the phase 3 CLEOPATRA trial (NCT00567190), which evaluated frontline pertuzumab plus trastuzumab and docetaxel in patients with HER2-positive metastatic breast cancer, demonstrated that PIK3CA-mutated disease was associated with a shorter median progression-free survival (PFS) vs PIK3CA wild-type disease, at 12.5 months vs 21.8 months, respectively.2

“Ipatasertib, which is an AKT inhibitor, has activity in [PI3K]/AKT pathway–altered tumors, so we hypothesized that the combination of ipatasertib with trastuzumab and pertuzumab as maintenance after first-line chemotherapy plus [trastuzumab and pertuzumab would be] safe and could improve outcomes of patients with PIK3CA-mutant, HER2-positive advanced breast cancer,” lead study author Mafalda Oliveira, MD, PhD, said in the presentation.1

Oliveira is an attending phyisician in the Medical Oncology Department of the Breast Cancer Group at the Vall d”Hebron University Hospital and Vall d’Hebron Institute of Oncology in Barcelona, Spain.

This open-label, single-arm trial enrolled both men in addition to women who were pre- or post-menopausal with HER2-positive advanced breast cancer and PIK3CA mutations in tissue or plasma. Patients must have received prior frontline treatment with chemotherapy plus trastuzumab and pertuzumab and have no evidence of progressive disease following this regimen. Upon screening for PIK3CA mutational status, patients received study treatment. The DLT period lasted for one 28-day cycle. Oral ipatasertib plus loperamide prophylaxis was administered in 28-day cycles for 21 days on followed by 7 days off. Subcutaneous trastuzumab and intravenous pertuzumab were administered continuously in 21-day cycles. Beginning at cycle 2, patients with HR-positive disease were permitted to receive endocrine therapy. Circulating tumor DNA testing was conducted on day 1 of cycle 1, day 1 of cycle 2, and at the end of treatment.

The coprimary end points of this trial were the determination of the MTD and the RP2D. Secondary end points included safety and tolerability, overall response rate (ORR), clinical benefit rate (CBR), and PFS.

IPATHER employed a de-escalation design. Patients at all dose levels received pertuzumab at 420 mg plus trastuzumab at 600 mg. Patients at dose levels 1, 2, and 3 received ipatasertib at 400 mg, 300 mg, and 200 mg, respectively.

“Stringent de-escalation criteria were implemented if [the 400-mg dose of ipatasertib] proved intolerable,” Oliveira noted.

The MTD was defined as the highest dose level at which 1 or fewer of the first 6 patients dosed experienced a DLT during the first treatment cycle. DLTs were defined as grade 3 or higher diarrhea lasting over 72 hours; grade 2 or higher diarrhea lasting over 5 days; or other grade 3 or higher nonhematologic or hematologic toxicities determined to be probably or definitely related to the study therapy.

Between February 2020 and November 2023, 116 patients were assessed for eligibility, of whom 92 were not eligible because of PIK3CA wild-type disease (n = 84), HER2-negative disease (n = 4), or other reasons (n = 4). Among the 24 patients who had PIK3CA-mutated and HER2-positive disease, 7 were not included because the selection criteria were not met (n = 5) or withdrawal of consent (n = 2). In total, 17 patients were enrolled in the trial, all of whom comprised the safety population; the efficacy population consisted of 16 patients. Of these patients, 6 remained on treatment at data cutoff.

Patients had a median age of 54 years (range, 41-78 years). Seventy-six percent of patients had an ECOG performance status of 0, and all patients were Caucasian and female. Most patients (52%) were postmenopausal, had estrogen receptor–negative disease (59%), had visceral metastases (59%), and had stage IV disease at diagnosis (59%). The median duration of prior chemotherapy plus trastuzumab and pertuzumab was 3.8 months (95% CI, 2.1-5.6). The best responses to prior chemotherapy plus trastuzumab and pertuzumab were partial response (PR; 53%) and stable disease (SD; 47%).

Any-grade treatment-related adverse effects (TRAEs) occurred in 94.1% of patients, and 35.3% of patients experienced grade 3 TRAEs. The most common TRAEs, occurring in over 10% of patients, included diarrhea (any-grade, 82.4%; grade 3, 11.8%), nausea (47.1%; 11.8%), decreased appetite (35.3%; 0%), fatigue (29.4%; 5.9%), rash (29.4%; 5.9%), vomiting (29.4%; 5.9%), anemia (17.6%, 0%), stomatitis (17.6%; 0%), dysgeusia (11.8%; 0%), lymphopenia (11.8%; 0%), and increased alanine transaminase/aspartate aminotransferase (11.8%; 0%).

Dose reductions, interruptions, and discontinuations of ipatasertib occurred in 29.4%, 23.5%, and 17.6% of patients, respectively. Dose interruptions and discontinuations of trastuzumab plus pertuzumab occurred in 11.8% and 17.6% of patients, respectively.

Investigators observed 3 toxicities fulfilling the trial’s definition of DLTs in the dose-expansion cohort: diarrhea, vomiting, and rash, all of which were grade 3. No grade 4/5 AEs were noted, and 29.4% of patients experienced serious AEs.

At a median follow-up of 19.9 months (95% CI, 9.3-not reached [NR]), the confirmed ORR was 31.3% (95% CI, 12.1%-58.5%), including best overall responses of complete response (12.5%), PR (18.7%), SD for at least 24 weeks (37.5%), and SD for less than 24 weeks (31.3%). The CBR was 84.6% (95% CI, 53.7%-97.3%), and the median duration of response was NR (12.1 months-NR).

The median PFS (from enrollment) was 15.4 months (95% CI, 9.4-NR). The 12- and 18-month PFS rates were 67.3% (95% CI, 45.3%-100%) and 48.1% (95% CI, 26.0%-88.8%), respectively.

“These results suggest and support that combining a PI3K/AKT pathway inhibitor with anti-HER2 treatment in this setting merits further evaluation,” Oliveira concluded.

Disclosures: Dr Oliveira reports institutional grant/research support from AstraZeneca, Ayala Pharmaceuticals, Boehringer-Ingelheim, Genentech, Gilead, Immutep, Roche, Seagen, and Zenith Epigenetics; consultant positions with AstraZeneca, Cureos Science, Daiichi-Sankyo/AstraZeneca, Gilead, iTEOS, Lilly, MSD, Relay Therapeutics, Roche, and Seagen; honoraria from AstraZeneca, Eisai, Gilead, Libbs, Lilly, MSD, Novartis, Pfizer, Roche, and Seagen; travel grants from AstraZeneca, Eisai, Gilead, and Pierre-Fabre. Dr Oliveira also reports her presidency of the SOLTI Breast Cancer Group.


  1. Oliveira M, Ciruelos E, Morales S, et al. 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). Presented at: 2024 ESMO Breast Cancer Annual Congress; May 15-17, 2024; Berlin, Germany. Abstract LBA3.
  2. Baselga J, Cortés J, Im SA, et al. Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-line metastatic breast cancer. J Clin Oncol. 2014;32(33):3753-61. doi:10.1200/JCO.2013.54.5384
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