Abstract
Background
The PI3K/AKT pathway is frequently altered in advanced triple-negative breast cancer (aTNBC), representing a promising target. Ipatasertib, a pan-AKT inhibitor, has shown activity with taxane-based chemotherapy and acceptable safety. This study evaluated the safety and efficacy of ipatasertib with non-taxane chemotherapy for aTNBC.
Methods
The PATHFINDER trial was a multicenter, open-label, non-comparative, phase IIa study with a safety run-in phase. Eligible patients had TNBC pretreated in the advanced setting with one or two chemotherapy regimens, including a taxane, and no prior exposure to PI3K/mTOR/AKT inhibitors. Patients received 21-day cycles of ipatasertib combined with capecitabine (arm A), eribulin (arm B), or carboplatin plus gemcitabine (arm C). The safety run-in phase determined feasibility and phase IIa doses. The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs). Key secondary endpoints included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). The analysis was exploratory without formal hypothesis testing.
Results
A total of 54 patients were assigned to arms A (N = 22), B (N = 25), and C (N = 7). Arm C was discontinued due to toxicity during the safety run-in phase. At data cut-off (November 2023), the overall median follow-up was 12.1 (range: 0.2–35.6) months. Common TEAEs in arm A were diarrhea (59.1%, 0.0% G ≥ 3), fatigue (36.4%, 0.0% G ≥ 3), and nausea (36.4%, 0.0% G ≥ 3); in arm B neutropenia (52.0%; 32.0% G ≥ 3), diarrhea (52.0%, 4.0% G3) and stomatitis (44.0%; 8.0% G3); and in arm C thrombocytopenia (85.7%, 85.7%G ≥ 3), anemia (85.7%, 57.1% G ≥ 3), neutropenia (71.4%, 71.4% G ≥ 3). No treatment-related deaths occurred. Median PFS was 2.7 (95%CI, 1.5–4.1) and 3.8 (95%CI, 1.5–9.6) months; median OS was 15.5 (95%CI, 11.8–19.3) and 11.5 (95%CI, 8.8–25.1) months; and ORR was 9.1% and 36.0% for arms A and B, respectively. No significant differences in efficacy were observed by PIK3CA mutational status.
Conclusions
Ipatasertib combined with capecitabine or eribulin showed acceptable safety but was not tolerable with carboplatin plus gemcitabine. The addition of ipatasertib to capecitabine or eribulin shows a potential efficacy signal in this patient population, compared to historical monotherapy data of these treatments. Identifying biomarkers to predict response to AKT inhibitors in TNBC is crucial.
Trial registration
www.clinicaltrials.gov, NCT04464174. Registered 09 July 2020.
Supplementary Information
The online version contains supplementary material available at 10.1186/s13058-025-02089-4.
Keywords: Ipatasertib, PI3K/AKT, Capecitabine, Eribulin, Gemcitabine plus carboplatin, Non-taxane, Advanced triple-negative breast cancer
Background
Triple-negative breast cancer (TNBC) accounts for approximately 10–15% of all diagnosed breast cancers [1]. These tumors are characterized by the lack of expression of hormone receptors (estrogen and progesterone receptors) and no overexpression or amplification of human epidermal growth factor receptor 2 (HER2). Therefore, chemotherapy remains the mainstay of treatment, with several approved regimens both in the (neo)adjuvant and metastatic settings, including taxanes, anthracyclines, and platinum-based regimens, among others [2, 3]. Despite its high degree of chemosensitivity, TNBC has a worse prognosis than other breast cancer subtypes [4, 5]. Patients with early-stage TNBC who experience recurrence typically do so within the first three years, with rapid progression from distant recurrence to death and a 5-year survival rate ranging from 10 to 15% [5].
Recent advances in the molecular biology of TNBC are expanding the therapeutic landscape for this complex disease. These include immunotherapy for programmed death ligand 1 (PD-L1)-positive tumors [6–8], antibody–drug conjugates targeting trophoblast cell surface antigen 2 (Trop-2) [9, 10], and trastuzumab deruxtecan in HER2-low TNBC [11]. However, the median overall survival (OS) for patients with advanced TNBC (aTNBC) remains poor, typically ranging from 18 to 24 months [12], underscoring the persistent unmet medical need for more effective therapeutic strategies, particularly in later lines of treatment.
The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/phosphatase and tensin homolog (PTEN) signaling pathway plays a crucial role in carcinogenesis, promoting cell survival, proliferation, metabolism, metastasis, and treatment resistance [13]. The PIK3CA gene encodes the p110alpha protein, which serves as the catalytic subunit of class I PI3K. Aberrations in the PIK3CA/AKT/PTEN pathway have been identified in numerous solid tumors [14]. In TNBC, approximately one-third of patients harbor these alterations [14–16], representing a promising therapeutic target.
Ipatasertib (GDC-0068) is a potent and selective pan-AKT inhibitor that has demonstrated, alone or combined, promise in the treatment of advanced solid tumors [17–19]. The phase II LOTUS trial was a randomized, double-blind, placebo-controlled study that enrolled 124 patients with previously untreated aTNBC to receive ipatasertib or placebo in combination with paclitaxel, irrespective of PIK3CA/AKT1/PTEN status. The addition of ipatasertib resulted in a statistically significant improvement in progression-free survival (PFS), especially in patients with PIK3CA/AKT/PTEN-altered tumors. These results led to the design of the IPATunity130 randomized phase III trial. In cohort A, 255 patients with previously untreated, PIK3CA/AKT1/PTEN-altered aTNBC were randomly assigned to receive ipatasertib or placebo in combination with paclitaxel. However, this study failed to demonstrate a PFS advantage for the ipatasertib arm over chemotherapy alone [22, 23]. Evidence on the combination of ipatasertib with non-taxane-based chemotherapy is very limited [24], but indicates a safe, well-tolerated regimen with clinical activity.
Here, we report the results of the PATHFINDER trial, an open-label, non-comparative, phase IIa study exploring the safety and efficacy of ipatasertib in combination with non-taxane chemotherapy (capecitabine, eribulin, or carboplatin plus gemcitabine) in taxane-pretreated aTNBC patients.
Methods
Study design and patients
The PATHFINDER study was a multicenter, three-arm design, open-label, non-comparative, phase IIa trial with a safety run-in phase conducted across 11 sites in Spain.
Eligible participants were adult women with locally confirmed aTNBC, defined according to the American Society of Clinical Oncology/College of American Pathologists guidelines [25]. Patients must have received at least one, but not more than two, prior chemotherapeutic regimens for advanced disease. Earlier (neo)adjuvant chemotherapy was considered as one of the required prior regimens if the development of advanced disease occurred within 12 months after completion of the (neo)adjuvant treatment. Prior therapy must also include a taxane in any indication, unless clinically contraindicated. Measurable or evaluable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version (v.) 1.1, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate bone marrow and organ function were also required. Key exclusion criteria were previous treatment with PI3K, AKT, and/or mammalian target of rapamycin (mTOR) inhibitors, and known active brain metastases and/or leptomeningeal disease. Full eligibility criteria are described in the Supplementary Material.
This study was conducted in compliance with the Declaration of Helsinki and was approved by the institutional review boards or independent ethics committees at each site. All patients provided written informed consent prior to participation in any study-related activities. This trial is registered at ClinicalTrials.gov, NCT04464174.
Procedures
Patients were assigned to each arm based on local investigator assessment and available slots. All study participants were aware of the treatment assignment.
Ipatasertib (400 mg) was administered orally once a day on Days 1–14 in 21-day cycles combined with standard doses of chemotherapeutic agents. Specifically, patients in arm A were treated with ipatasertib plus capecitabine (1000 mg/m2 administered orally twice a day on Days 1–14); those in arm B with ipatasertib plus eribulin (1.23 mg/m2 administered intravenously on Days 1 and 8); and those in arm C with ipatasertib plus carboplatin (area under the curve [AUC]5 administered intravenously on Day 1) and gemcitabine (1000 mg/m2 administered intravenously on Days 1 and 8). Prophylactic loperamide was mandatory for all patients during at least the first initial cycle of treatment and could be extended to the next cycle if necessary. Treatment continued until disease progression, unacceptable toxicity, death, or patient withdrawal, whichever occurred first. Dose interruption and dose reduction were allowed for ipatasertib and chemotherapy as defined by prespecified protocol guidelines. Patients were permitted to discontinue chemotherapy and continue with ipatasertib alone, and vice versa.
A safety and tolerability run-in phase for ipatasertib combinations was conducted as an initial step of the phase IIa study (Supplementary Fig. 1). This initial phase involved up to three patients initially receiving 400 mg/day of ipatasertib in combination with each of the three regimens of chemotherapy. If one significant toxicity was observed in one patient during the first two cycles, three additional patients were enrolled. If two or more significant toxicities occurred in these six patients, the dose of ipatasertib was reduced to 300 mg/day or the chemotherapy treatment was adjusted (if toxicity was attributed to chemotherapy). Further reductions to 200 mg/day or treatment arm interruption were considered if two or more toxicities persisted. Patients were evaluated if they completed at least 70% of the protocol-specified doses for each individual drug during Cycle 1. Definitions of significant toxicities are detailed in Supplementary Table 1. Phase IIa included all evaluable patients from the safety run-in phase and additional patients receiving the established dose of ipatasertib and chemotherapy.
Tumor assessments were conducted via computed tomography or magnetic resonance imaging according to RECIST v.1.1 at baseline and every 6 weeks for the first 6 months following the initiation of study treatment. Thereafter, disease assessments were performed every 9 weeks until the end of treatment. Bone scans were mandatory at baseline for all patients and subsequently repeated every 24 weeks for those patients whose bone lesions were identified at baseline, unless bone progression was clinically or biochemically suspected.
Safety was evaluated in all patients who received at least one dose of the study treatment by assessment of significant toxicities, treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) as per the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.5.0.
Outcomes
The primary endpoint of the study was to evaluate the safety and tolerability of ipatasertib in combination with capecitabine, eribulin, or carboplatin plus gemcitabine in the intention-to-treat (ITT) population defined as the incidence of TEAEs as assessed by the investigator, with severity determined by NCI-CTCAE v.5.0.
Secondary endpoints included PFS, overall response rate (ORR), duration of response, time to response, clinical benefit rate (CBR), best percentage of change from baseline in the size of target tumor lesions, and OS. Definitions of secondary endpoints are described in Supplementary Table 2.
Exploratory endpoints included the analysis of potential molecular markers of sensitivity and/or resistance for the combination of ipatasertib and non-taxane chemotherapy specifically focused on alterations in the PI3K/AKT/PTEN signaling pathway.
Analysis of PIK3CA mutational status
Blood samples were collected during the screening period, after two cycles of study treatment, and upon disease progression or study termination for molecular analysis.
The mutational analysis of PIK3CA (exon 1: R88Q; exon 7: E453K; exon 9: L540V, E542K, E545Q, and E545K; and exon 20: H1047L and H1047R) in cell-free DNA (cfDNA) was conducted via next-generation sequencing with unique molecular identifiers (UMIs) (Eurofins, Spain). Briefly, extracted cfDNA was tagged with UMIs and enriched via hybridization capture via region-specific probes. Libraries were subsequently constructed and sequenced on an Illumina NextSeq platform. Data analysis was performed via CLC Genomics Workbench software, where detected variants were rigorously filtered to remove low-quality reads, sequencing artifacts, and germline variants. The remaining variants were annotated, and only those with clinical significance (classified as pathogenic or likely pathogenic) and an allele frequency exceeding 0.5% were reported.
Statistical methods
During the safety run-in phase, toxicity was assessed in all patients who either completed the first two cycles of treatment or discontinued treatment due to significant toxicities. Safety and efficacy during phase IIa were evaluated in the safety set and full analysis set (considered the ITT population), which included all patients that accomplished selection criteria and received at least one dose of study treatment.
Statistical analysis was exploratory with no hypothesis testing. However, based on a previous study [20], the incidence of TEAEs for ipatasertib was estimated to be 100% for all grades and 50% for grade(G) ≥ 3. Therefore, the justification of the sample size was based on the level of precision deemed acceptable in finding such incidences. For an observed incidence of any grade TEAEs of 100%, a sample size of 18 patients per treatment arm provided a 95% Clopper-Pearson confidence interval (CI) ranging from 81.5% to 100%, with a margin of error (half-width of the CI) of 9.25%. On the other hand, for an observed incidence of G ≥ 3 TEAEs of 50%, a sample size of 18 patients per treatment arm provided a 95% Clopper-Pearson CI ranging from 26 to 74%, with a margin of error (half-width of the CI) of 24%. Treatment arms could be discontinued due to feasibility or safety concerns. In that case, patients could have been assigned to an alternative active treatment arm. At the end of the study, a total of 54 participants had to be recruited, unless all arms were discontinued.
Results
Recruitment and patient disposition
From 30th July 2020 through 11th November 2022, a total of 54 patients were enrolled in the PATHFINDER study, which included a safety run-in phase and a subsequent phase IIa. The safety run-in phase involved 13 patients: three in arm A (ipatasertib + capecitabine), three in arm B (ipatasertib + eribulin), and seven in arm C (ipatasertib + carboplatin + gemcitabine). Phase IIa stage included all patients from previous phase and 41 additional patients, 19 on arm A and 22 on arm B. No additional patients were included in arm C. In total, phase IIa consisted of 22 patients in arm A, 25 patients in arm B, and seven patients in arm C (Fig. 1). In the overall patient population, the median treatment duration was 3.2 (range: 0.7–35.7) months. At the final analysis cut-off (11th November 2023), the median follow-up was 12.1 (range: 0.2–35.6) months and all patients discontinued the study treatment, primarily due to disease progression (36/54 patients, 66.7%) (Supplementary Table 3).
Fig. 1.
PATHFINDER study. *DL1: 400 mg/day ipatasertib administered orally once a day on Days 1–14 in 21-day cycles + chemotherapy at standard doses: Capecitabine at 1000 mg/m2 administered orally twice a day on Days 1–14 (arm A); Eribulin at 1.23 mg/m2 administered intravenously on Days 1 and 8 (arm B); Carboplatin at AUC 5 administered intravenously on Day 1 + gemcitabine at 1000 mg/m2 administered intravenously on Days 1 and 8. (arm C) #DL2: 300 mg/day ipatasertib + chemotherapy at standard doses. ‡Phase IIa included all evaluable patients from the safety run-in phase (N = 13) and additional patients (N = 41) receiving the established dose of ipatasertib and chemotherapy. Abbreviations: AUC: area under de curve; DL: dose level; N: number of patients
Baseline characteristics (ITT population)
The median age was 55 (range: 34–79) years. A total of 38 (70.4%) patients had an ECOG performance status of 0. Visceral disease was present in 37 (85.2%) patients, 14 (25.9%) of whom had liver metastases. Fifteen (27.8%) patients had three or more metastatic sites (Table 1).
Table 1.
Baseline patient characteristics
| Baseline characteristics (n%) | Arm A (N = 22) | Arm B (N = 25) | Arm C (N = 7) |
Overall (N = 54) |
|---|---|---|---|---|
| Age, median (range) years |
54.5 (34.0; 79.0) |
55.0 (35.0; 79.0) |
59.0 (38.0; 68.0) |
55.0 (34.0; 79.0) |
| Menopausal status | ||||
| Postmenopausal | 13 (59.1%) | 14 (56.0%) | 5 (71.4%) | 32 (59.3%) |
| Premenopausal | 9 (40.9%) | 11 (44.0%) | 2 (28.6%) | 22 (40.7%) |
| ECOG performance status | ||||
| 0 | 18 (81.8%) | 17 (68.0%) | 3 (42.9%) | 38 (70.4%) |
| 1 | 4 (18.2%) | 8 (32.0%) | 4 (57.1%) | 16 (29.6%) |
| TNBC at initial advanced disease diagnosis | 20 (90.9%) | 20 (80.0%) | 7 (100.0%) | 47 (87.0%) |
| Prior chemotherapy in the (neo)adjuvant setting | ||||
| Yes | 15 (68.2%) | 19 (76.0%) | 6 (85.7%) | 40 (74.1%) |
| No | 7 (31.8%) | 6 (24.0%) | 1 (14.3%) | 14 (25.9%) |
| Prior chemotherapy regimens for advanced disease | ||||
| 0* | 5 (22.7%) | 8 (32.0%) | 3 (42.9%) | 16 (29.6%) |
| 1 | 15 (68.2%) | 9 (36.0%) | 2 (28.6%) | 26 (48.2%) |
| 2 | 2 (9.1%) | 8 (32.0%) | 2 (28.6%) | 12 (22.2%) |
| Number of metastatic sites | ||||
| < 3 | 14 (63.6%) | 19 (76.0%) | 6 (85.7%) | 39 (72.2%) |
| ≥ 3 | 8 (36.4%) | 6 (24.0%) | 1 (14.3%) | 15 (27.8%) |
| Metastatic sites | ||||
| Lymph node | 11 (50.0%) | 11 (44.0%) | 2 (28.6%) | 24 (44.4%) |
| Lung | 11 (50.0%) | 7 (28.0%) | 5 (71.4%) | 23 (42.6%) |
| Bone | 9 (40.9%) | 15 (60.0%) | 5 (71.4%) | 29 (53.7%) |
| Liver | 7 (31.8%) | 7 (28.0%) | 0 (0.0%) | 14 (25.9%) |
| Others | 10 (45.5%) | 12 (48.0%) | 3 (42.9%) | 25 (46.3%) |
| Visceral involvement | ||||
| Yes | 17 (77.3%) | 14 (56.0%) | 6 (85.7%) | 37 (68.5%) |
| No | 5 (22.7%) | 11 (44.0%) | 1 (14.3%) | 17 (31.5%) |
*Earlier systemic treatment in the curative setting was considered as one line of therapy if the development of unresectable locally advanced or metastatic disease occurred within a 12-month period after completion of treatment
n (%): number of participants (percentage based on N)
N: Number of participants in the population
Abbreviations: Arm A, ipatasertib plus capecitabine, Arm B, ipatasertib plus eribulin, Arm C, ipatasertib plus carboplatin plus gemcitabine, ECOG, Eastern Cooperative Oncology Group, TNBC, triple-negative breast cancer
A total of 40 (74.1%) patients had previously received (neo)adjuvant chemotherapy for early-stage disease. For advanced disease, 38 (70.4%) patients had received prior chemotherapy-based treatment —26 (48.2%) received one regimen— and nine (16.7%) patients had received prior immunotherapy with atezolizumab or pembrolizumab. Notably, 16 (29.6%) patients received the study treatment as first-line therapy for advanced disease due to early progression after completing (neo)adjuvant treatment for early-stage breast cancer. Additional demographic and baseline characteristics for all patients and each specific treatment arm are shown in Table 1.
Primary endpoint: safety
All patients received at least one dose of each study drug. Median relative dose intensity for ipatasertib was 88.2% (interquartile range [IQR]: 71.8–96.2), 90.2% (IQR: 82.0–98.4) in arm A, 83.3% (IQR: 71.8–96.1) in arm B, and 65.3% (IQR: 64.1–90.9) in arm C. Median relative dose intensity for chemotherapy was 88.4% (IQR: 51.8–101.6) for capecitabine (arm A), 91.2% (IQR: 48.3–108.3) for eribulin (arm B), and 64.2% (IQR: 44.1–100.0) and 50.0% (IQR: 37.4–70.3) for carboplatin and gemcitabine (arm C), respectively.
During the safety run-in phase, significant toxicities related to the study treatment were initially observed in two out of three patients in arm C (cohort 1). As per protocol, a second cohort of three additional patients receiving 300 mg/day of ipatasertib was recruited, with all three also experiencing significant toxicities. Although protocol plans included the recruitment of three further patients as part of this phase, recruitment challenges and observed toxicities allowed for the inclusion of only one additional patient receiving 300 mg/day of ipatasertib. In total, five out of seven (71.4%) patients experienced significant toxicities, leading to the premature, permanent discontinuation of arm C. Patients in arms A and B did not present any significant toxicities (Table 2).
Table 2.
Overview of safety profile in the ITT population
| n(%) | Arm A | Arm B | Arm C | Overall |
|---|---|---|---|---|
| Safety run-in phase | N = 3 | N = 3 | N = 7 | N = 13 |
| Significant toxicities | 0 (0.0) | 0 (0.0) | 5 (71.4) | 5 (71.4) |
| Unrelated | 0 (0.0) | 0 (0.0) | 1 (14.3) | 1 (14.3) |
| Related | 0 (0.0) | 0 (0.0) | 5 (71.4) | 5 (71.4) |
| Related to both medications | 0 (0.0) | 0 (0.0) | 4 (57.1) | 4 (57.1) |
| Related to chemotherapy | 0 (0.0) | 0 (0.0) | 2 (28.6) | 2 (28.6) |
| Related to Ipatasertib | 0 (0.0) | 0 (0.0) | 1 (14.3) | 1 (14.3) |
| Phase IIa | (N = 22) | (N = 25) | (N = 7) | (N = 54) |
| TEAEs | 21 (95.5) | 24 (96.0) | 7 (100.0) | 52 (96.3) |
| Unrelated | 20 (90.9) | 20 (80.0) | 6 (85.7) | 46 (85.2) |
| Related | 18 (81.8) | 22 (88.0) | 7 (100.0) | 47 (87.0) |
| Related to chemotherapy | 10 (45.5) | 15 (60.0) | 6 (85.7) | 31 (57.4) |
| Related to both medications | 12 (54.5) | 11 (44.0) | 7 (100.0) | 30 (55.6) |
| Related to Ipatasertib | 7 (31.8) | 18 (72.0) | 4 (57.1) | 29 (53.7) |
| Missing | 0 (0.0) | 1 (4.0) | 0 (0.0) | 1 (1.9) |
| Severity grade 3–5 TEAEs | 6 (27.3) | 18 (72.0) | 7 (100.0) | 31 (57.4) |
| Unrelated | 4 (18.2) | 10 (40.0) | 1 (14.3) | 15 (27.8) |
| Related | 2 (9.1) | 14 (56.0) | 7 (100.0) | 23 (42.6) |
| Related to chemotherapy | 0 (0.0) | 7 (28.0) | 4 (57.1) | 11 (20.4) |
| Related to Ipatasertib | 1 (4.5) | 6 (24.0) | 2 (28.6) | 9 (16.7) |
| Related to both medications | 1 (4.5) | 2 (8.0) | 6 (85.7) | 9 (16.7) |
| Missing | 0 (0.0) | 1 (4.0) | 0 (0.0) | 1 (1.9) |
| SAEs | 2 (9.1) | 9 (36.0) | 4 (57.1) | 15 (27.8) |
| Unrelated | 1 (4.5) | 6 (24.0) | 1 (14.3) | 8 (14.8) |
| Related | 1 (4.5) | 5 (20.0) | 4 (57.1) | 10 (18.5) |
| Related to both medications | 1 (4.5) | 1 (4.0) | 3 (42.9) | 5 (9.3) |
| Related to chemotherapy | 0 (0.0) | 2 (8.0) | 1 (14.3) | 3 (5.6) |
| Related to Ipatasertib | 0 (0.0) | 1 (4.0) | 0 (0.0) | 1 (1.9) |
| Missing | 0 (0.0) | 1 (4.0) | 0 (0.0) | 1 (1.9) |
| AESIs | 1 (4.5) | 6 (24.0) | 2 (28.6) | 9 (16.7) |
| Unrelated | 0 (0.0) | 1 (4.0) | 1 (14.3) | 2 (3.7) |
| Related | 1 (4.5) | 5 (20.0) | 2 (28.6) | 8 (14.8) |
| Related to Ipatasertib | 0 (0.0) | 5 (20.0) | 0 (0.0) | 5 (9.3) |
| Related to both medications | 1 (4.5) | 0 (0.0) | 2 (28.6) | 3 (5.6) |
| TEAEs leading to any of the study treatment permanent discontinuation | 1 (4.5) | 2 (8.0) | 3 (42.9) | 6 (11.1) |
| Unrelated | 1 (4.5) | 0 (0.0) | 0 (0.0) | 1 (1.9) |
| Related | 0 (0.0) | 2 (8.0) | 3 (42.9) | 5 (9.3) |
| Related to both medications | 0 (0.0) | 0 (0.0) | 2 (28.6) | 2 (3.7) |
| Related to chemotherapy | 0 (0.0) | 1 (4.0) | 1 (14.3) | 2 (3.7) |
| Related to Ipatasertib | 0 (0.0) | 1 (4.0) | 0 (0.0) | 1 (1.9) |
| Death due to TEAEs | 0 (0.0) | 2 (8.0) | 0 (0.0) | 2 (3.7) |
| Unrelated | 0 (0.0) | 2* (8.0) | 0 (0.0) | 2 (3.7) |
*Unrelated COVID-19 pneumonia and hyperacute ischemic stroke
n (%): number of participants (percentage based on N)
N: Number of participants in the population
Abbreviations: Arm A ipatasertib plus capecitabine, Arm B ipatasertib plus eribulin, Arm C ipatasertib plus carboplatin plus gemcitabine, AESI adverse events of special interest, ITT intention-to-treat, SAE serious adverse event, TEAE treatment-emergent adverse event
Overall, ipatasertib dosing was reduced to 300 mg/day due to toxicities related to the study treatment in five (20.0%) patients in arm B and one (14.3%) patient from cohort 1 in arm C and for other adverse events unrelated to the study treatment in two (9.1%) patients in arm A. Additionally, a dose reduction of ipatasertib to 200 mg/day was required for one (14.3%) patient from cohort 2 in arm C. Temporary interruption of ipatasertib due to toxicity was observed in 6 (27.3%) patients in arm A, 11 (44.0%) patients in arm B, and 6 (85.7%) patients in arm C. Permanent discontinuations of ipatasertib due to treatment-related toxicities occurred in one (4.5%) patient in arm A and one (4.0%) patient in arm B (Supplementary Table 4).
Dose reductions and interruptions of chemotherapy were implemented as per protocol: capecitabine dose was reduced in seven (31.8%) patients; eribulin dose was reduced in six (24.0%) and interrupted in 11 (44.0%) patients; carboplatin dose was reduced in four (57.1%) and interrupted in five (71.4%) patients, and gemcitabine dose was reduced and interrupted in five (71.4%) patients. Permanent discontinuations of chemotherapy due to treatment-related toxicities occurred in six (24.0%) patients in arm B and three (42.8%) patients in arm C (Supplementary Tables 5–7).
In the phase IIa, overall incidence of treatment-related TEAEs was 87.0% (42.6% G ≥ 3), treatment-related SAEs was 18.5%, and AESIs was 14.8% (Table 2). In arm A, 18 (81.8%) patients experienced TEAEs related to the study treatment, with two (9.1%) of them presenting G ≥ 3 TEAEs. Treatment-related SAEs and AESIs were reported in one (4.5%) patient for each category. In arm B, 22 (88.0%) patients experienced TEAEs related to the study treatment, with 14 (56.0%) of them presenting G ≥ 3 TEAEs. Treatment-related SAEs and AESIs occurred in five (20.0%) patients for each category (Table 2). In arm C, all patients experienced TEAEs related to the study treatment, all of whom presented G ≥ 3 TEAEs. Treatment-related SAEs and AESIs occurred in four (57.1%) and two (28.6%) patients, respectively (Table 2).
Incidence of the most common TEAEs of any grade in arm A were 59.1% diarrhea (0.0% G ≥ 3), 36.4% fatigue (0.0% G ≥ 3), 36.4% nausea (0.0% G ≥ 3), 27.3% vomiting (0.0% G ≥ 3), and 27.3% neutropenia (4.5% G ≥ 3) (Table 3).
Table 3.
Most common (≥ 15% of patients) TEAEs in arm A
| N = 22 | Any grade | Grade 3 | Grade 4 |
|---|---|---|---|
| TEAEs, (n%) | 21 (95.5%) | 4 (18.2%) | 2 (9.1%) |
| Hematologic | 7 (31.8%) | 0 (0.0%) | 1 (4.5%) |
| Blood and lymphatic system disorders | 7 (31.8%) | 0 (0.0%) | 1 (4.5%) |
| Neutropenia | 6 (27.3%) | 0 (0.0%) | 1 (4.5%) |
| Non-hematologic | 21 (95.5%) | 4 (18.2%) | 1 (4.5%) |
| Gastrointestinal disorders | 18 (81.8%) | 1 (4.5%) | 0 (0.0%) |
| Diarrhea | 13 (59.1%) | 0 (0.0%) | 0 (0.0%) |
| Nausea | 8 (36.4%) | 0 (0.0%) | 0 (0.0%) |
| Vomiting | 6 (27.3%) | 0 (0.0%) | 0 (0.0%) |
| Constipation | 5 (22.7%) | 0 (0.0%) | 0 (0.0%) |
| Nervous system disorders | 12 (54.5%) | 1 (4.5%) | 0 (0.0%) |
| Headache | 3 (13.6%) | 0 (0.0%) | 0 (0.0%) |
| General disorders and administration site conditions | 9 (40.9%) | 0 (0.0%) | 0 (0.0%) |
| Fatigue | 8 (36.4%) | 0 (0.0%) | 0 (0.0%) |
| Investigations | 7 (31.8%) | 1 (4.5%) | 0 (0.0%) |
| Gamma-glutamyltransferase increased | 4 (18.2%) | 1 (4.5%) | 0 (0.0%) |
n (%): number of participants (percentage based on N)
N: Number of participants in the population
Abbreviations: TEAE treatment-emergent adverse event
Incidence of the most common TEAEs of any grade in arm B was 52.0% neutropenia (32.0% G ≥ 3), 52.0% diarrhea (4.0% G ≥ 3), 44.0% stomatitis (8.0% G ≥ 3), 40.0% fatigue (0.0% G ≥ 3), 40.0% rash (16.0% G ≥ 3), 32.0% nausea (0.0% G ≥ 3), and 28.0% vomiting (0.0% G ≥ 3) (Table 4).
Table 4.
Most common (≥ 15% of patients) or grade 5 TEAEs in arm B
| N = 25 | Any grade | Grade 3 | Grade 4 | Grade 5 |
|---|---|---|---|---|
| TEAEs, (n%) | 24 (96.0%) | 10 (40.0%) | 5 (20.0%) | 2 (8.0%) |
| Hematologic | 15 (60.0%) | 5 (20.0%) | 5 (20.0%) | 0 (0.0%) |
| Blood and lymphatic system disorders | 15 (60.0%) | 5 (20.0%) | 5 (20.0%) | 0 (0.0%) |
| Neutropenia | 13 (52.0%) | 4 (16.0%) | 4 (16.0%) | 0 (0.0%) |
| Anemia | 4 (16.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Non-hematologic | 24 (96.0%) | 9 (36.0%) | 0 (0.0%) | 2 (8.0%) |
| Gastrointestinal disorders | 20 (80.0%) | 3 (12.0%) | 0 (0.0%) | 0 (0.0%) |
| Diarrhea | 13 (52.0%) | 1 (4.0%) | 0 (0.0%) | 0 (0.0%) |
| Stomatitis | 11 (44.0%) | 2 (8.0%) | 0 (0.0%) | 0 (0.0%) |
| Nausea | 8 (32.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Constipation | 7 (28.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Vomiting | 7 (28.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| General disorders and administration site conditions | 15 (60.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Fatigue | 10 (40.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Pyrexia | 5 (20.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Investigations | 12 (48.0%) | 3 (12.0%) | 1 (4.0%) | 0 (0.0%) |
| Alanine aminotransferase increased | 5 (20.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Gamma-glutamyltransferase increased | 4 (16.0%) | 2 (8.0%) | 0 (0.0%) | 0 (0.0%) |
| Blood alkaline phosphatase increased | 4 (16.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Protein total decreased | 4 (16.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Skin and subcutaneous tissue disorders | 12 (48.0%) | 4 (16.0%) | 0 (0.0%) | 0 (0.0%) |
| Rash | 10 (40.0%) | 4 (16.0%) | 0 (0.0%) | 0 (0.0%) |
| Nervous system disorders | 10 (40.0%) | 1 (4.0%) | 0 (0.0%) | 1 (4.0%) |
| Ischemic stroke | 1 (4.0%) | 0 (0.0%) | 0 (0.0%) | 1 (4.0%) |
| Metabolism and nutrition disorders | 9 (36.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Hyperglycemia | 6 (24.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Infections and infestations | 7 (28.0%) | 3 (12.0%) | 0 (0.0%) | 1 (4.0%) |
| COVID-19 | 3 (12.0%) | 0 (0.0%) | 0 (0.0%) | 1 (4.0%) |
n (%): number of participants (percentage based on N)
N: Number of participants in the population
Abbreviations: TEAE treatment-emergent adverse event
Incidence of the most common TEAEs of any grade in arm C was 85.7% thrombocytopenia (85.7% G ≥ 3), 85.7% anemia (57.1% G ≥ 3), 71.4% neutropenia (71.4% G ≥ 3), 71.4% fatigue (14.3% G ≥ 3), 57.1% diarrhea (0.0% G ≥ 3), 57.1% nausea (28.6% G ≥ 3), 42.9% stomatitis (14.3% G ≥ 3), 42.9% vomiting (0.0% G ≥ 3), 42.9% constipation (0.0% G ≥ 3), 28.6% febrile neutropenia (28.6% G ≥ 3), 28.6% alanine aminotransferase increased (14.3% G ≥ 3), and 28.6% hyperglycemia (0.0% G ≥ 3) (Table 5). n (%): number of participants (percentage based on N) N: Number of participants in the population
Table 5.
Most common (≥ 15% of patients) TEAEs in arm C
| N = 7 | Any grade | Grade 3 | Grade 4 |
|---|---|---|---|
| TEAEs, (n%) | 7 (100.0%) | 2 (28.6%) | 5 (71.4%) |
| Hematologic | 7 (100.0%) | 1 (14.3%) | 5 (71.4%) |
| Blood and lymphatic system disorders | 7 (100.0%) | 1 (14.3%) | 5 (71.4%) |
| Thrombocytopenia | 6 (85.7%) | 2 (28.6%) | 4 (57.1%) |
| Anemia | 6 (85.7%) | 3 (42.9%)* | 1 (14.3%)* |
| Neutropenia | 5 (71.4%) | 2 (28.6%)* | 3 (42.9%)* |
| Febrile neutropenia | 2 (28.6%) | 0 (0.0%) | 2 (28.6%) |
| Non-hematologic | 7 (100.0%) | 5 (71.4%) | 0 (0.0%) |
| Gastrointestinal disorders | 6 (85.7%) | 3 (42.9%) | 0 (0.0%) |
| Nausea | 4 (57.1%) | 2 (28.6%) | 0 (0.0%) |
| Diarrhea | 4 (57.1%) | 0 (0.0%) | 0 (0.0%) |
| Stomatitis | 3 (42.9%) | 1 (14.3%) | 0 (0.0%) |
| Vomiting | 3 (42.9%) | 0 (0.0%) | 0 (0.0%) |
| Constipation | 3 (42.9%) | 0 (0.0%) | 0 (0.0%) |
| General disorders and administration site conditions | 5 (71.4%) | 1 (14.3%) | 0 (0.0%) |
| Fatigue | 5 (71.4%) | 1 (14.3%) | 0 (0.0%) |
| Infections and infestations | 3 (42.9%) | 1 (14.3%) | 0 (0.0%) |
| Investigations | 2 (28.6%) | 1 (14.3%) | 0 (0.0%) |
| Alanine aminotransferase increased | 2 (28.6%) | 1 (14.3%) | 0 (0.0%) |
| Metabolism and nutrition disorders | 2 (28.6%) | 0 (0.0%) | 0 (0.0%) |
| Hyperglycemia | 2 (28.6%) | 0 (0.0%) | 0 (0.0%) |
*Due to rounding effects, percentages may not sum precisely
n (%): number of participants (percentage based on N)
N: Number of participants in the population
Abbreviations: TEAE treatment-emergent adverse event
No treatment-related deaths were reported in arms A and C. Two deaths resulting from TEAEs but unrelated to the study treatment were reported in arm B: one attributed to an hyperacute ischemic stroke and one to COVID-19 pneumonia.
Secondary endpoints: efficacy
Median investigator-assessed PFS was 2.7 (95% CI, 1.5–4.1) and 3.8 (95% CI, 1.5–9.6) months in arms A and B, respectively (Fig. 2A). The estimated proportion of patients with PFS at 6 months was 19.2% (95%CI, 6.0–37.9) for arm A and 36.4% (95%CI, 17.4–55.7) for arm B. Median OS was 15.5 (95%CI, 11.8–19.3) and 11.5 (95%CI, 8.8–25.1) months in arms A and B, respectively (Fig. 2B).
Fig. 2.
Kaplan–Meier analysis for PFS (A) and OS (B) in the ITT population, by arm. Abbreviations: Arm A: ipatasertib plus capecitabine; Arm B: ipatasertib plus eribulin; Arm C: ipatasertib plus carboplatin plus gemcitabine; CI: confidence interval; ITT: intention-to-treat; KM Est: Kaplan–Meier estimates; PFS: progression-free survival; OS: overall survival
Locally assessed ORR was 9.1% (95%CI, 1.1–29.2) and 36.0% (95%CI, 18.0–57.5) in arms A and B, respectively. In Arm A, one (4.5%) patient had a complete response, one (4.5%) patient had a partial response, and three (13.6%) patients had a disease stabilization ≥ 24 weeks. CBR was achieved in 22.7% (95%CI, 7.8–45.4) of patients. In Arm B, nine (36.0%) patients had a partial response, and four (16.0%) patients had disease stabilization ≥ 24 weeks. CBRs were achieved in 52.0% (95%CI, 31.3–72.2) of patients (Supplementary Table 8).
Efficacy results of patients included in arm C are detailed in Fig. 2 and Supplementary Table 8.
Exploratory endpoints: efficacy according to PIK3CA status
PIK3CA mutational status was analyzed in 40 out of the 47 (85.0%) patients included in arms A and B. Hotspot mutations were found in eight out of 40 (20.0%) patients, six in arm A and two in arm B (Supplementary Table 9).
While no statistically significant differences in median PFS or OS were observed based on PIK3CA mutational status, numerically better outcomes were noted in patients with PIK3CA-altered tumors. Patients with PIK3CA-mutated tumors had a median PFS of 3.3 months (95%CI, 1.5-not evaluable [NE]), whereas patients with wild-type PIK3CA status had a median PFS of 2.8 (95%CI, 2.0–5.5) months Supplementary Fig. 2). Median OS times were 17.9 (95%CI, 2.4-NE) and 11.8 (95%CI, 10.0–15.6) months in patients with and without PIK3CA mutations, respectively (Supplementary Fig. 3). Interestingly, both patients with PIK3CA-mutated tumors in arm B (ipatasertib plus eribulin) were progression-free at 12 months and completed the study treatment as per protocol (Supplementary Table 9).
Discussion
Here, we describe the final results of the phase IIa PATHFINDER study, which demonstrated a manageable safety profile for the combination of ipatasertib with capecitabine or eribulin. However, the addition of ipatasertib to carboplatin plus gemcitabine was not tolerable even after the doses of ipatasertib and chemotherapy were reduced. To our knowledge, PATHFINDER represents the first phase II clinical trial exclusively evaluating the safety, tolerability, and preliminary efficacy of ipatasertib in combination with non-taxane-containing regimens in patients with taxane-pretreated aTNBC.
In breast cancer, the PI3K/AKT/PTEN pathway is one of the most frequently activated signaling pathways. Extensive large-scale genomic analyses have confirmed the heterogeneous nature of TNBC, including a subgroup with a PI3K/AKT/PTEN pathway activation signature characterized by PIK3CA or AKT1 activating mutations and PTEN alterations [16, 26, 27]. Indeed, one third of TNBC cases exhibit PIK3CA/AKT1/PTEN aberrations, underscoring AKT as a promising therapeutic target in this tumor type. To date, the effectiveness of ipatasertib in aTNBC has been evaluated mainly with paclitaxel [20, 22], but also to a lesser extent with platinum-based [24] chemotherapy, as well as in triplet regimens with atezolizumab and capecitabine [24] or atezolizumab and a taxane [28].
The toxicity profile of the ipatasertib combinations observed in PATHFINDER was manageable in both arm A (ipatasertib + capecitabine) and arm B (ipatasertib + eribulin), with G3/4 TEAEs related to the study treatment occurring in 9.1% and 56.0% of patients in arm A and B, respectively. Diarrhea (59.1% in arm A; 52.0% in arm B), fatigue (36.4% in arm A; 40.0% in arm B), neutropenia (27.3% in arm A; 52.0% in arm B), and nausea (36.4% in arm A; 32.0% in arm B) were the most common TEAEs observed. The addition of ipatasertib did not seem to exacerbate known adverse effects of these chemotherapeutic agents, including eribulin-associated hematological toxicity [29, 30] and capecitabine-associated hematological and cutaneous toxicities [31, 32]. In contrast, the addition of ipatasertib to carboplatin plus gemcitabine resulted in high rates of both hematological and non-hematological TEAEs, leading to the premature discontinuation of this arm during the safety-run in phase due to excess toxicity.
The main safety concern of ipatasertib therapy are gastrointestinal disorders, particularly diarrhea The safety profiles in arms A and B were consistent with prior studies of ipatasertib combined with chemotherapy [20, 23, 24], although the incidence of diarrhea was lower. In the phase II LOTUS trial, 93.0% of patients experienced diarrhea, 23.0% at G ≥ 3 [20]. In cohort A of the phase III IPATunity130 trial, diarrhea remained frequent (85.0%), but G ≥ 3 cases decreased to 9.0% with the use of loperamide prophylaxis in most of the patients [23]. In PATHFINDER, diarrhea was reported in 59.1% of patients in arm A and 52.0% in arm B, higher than with capecitabine or eribulin monotherapy. However, mandatory loperamide administration for all patients during at least the first initial cycle of treatment remarkably reduced both incidence and severity, with no cases of G ≥ 3 diarrhea in arm A and only 4.0% in arm B. This prophylactic strategy has been successfully used to prevent diarrhea with other anticancer drugs, such as neratinib [33] and sacituzumab govitecan [34].
In the LOTUS trial, the addition of ipatasertib to first-line paclitaxel significantly prolonged median PFS in the ITT population (6.2 vs. 4.9 months, hazard ratio [HR] 0.60, 95%CI, 0.37–0.98; p = 0.037), specially in patients with PIK3CA/AKT/PTEN-altered tumors (9.0 vs. 4.9 months, HR 0.44, 95%CI, 0.22–0.87; p = 0.037) [20, 21]. However, the confirmatory IPATunity130 study failed to confirm this benefit in patients with PI3K pathway alterations [23]. Similarly, the randomized phase III CAPItello-290 trial evaluating the AKT inhibitor capivasertib plus paclitaxel as a first-line treatment for patients with aTNBC did not improve survival outcomes, either in the overall population or in the subset of patients with PIK3CA/AKT/PTEN-altered tumors [35]. However, a numerical improvement in PFS and ORR was observed in the capivasertib-treated group.
In PATHFINDER, median PFS and OS were 2.7 and 15.5 months, respectively, for the combination of ipatasertib and capecitabine, and 3.8 and 11.5 months, respectively, for the combination of ipatasertib and eribulin. Compared with historical controls of capecitabine and eribulin use in monotherapy [29–31], the addition of ipatasertib appears to improve outcomes in this patient population. However, no significant differences in median PFS or OS were observed based on PIK3CA mutational status, although the number of patients with PIK3CA-mutated tumors was limited to make definitive conclusions. Notably, two out of the three patients in arm B with PIK3CA-mutated tumors were progression-free at 12 months. Inhibition of the PI3K/AKT/PTEN pathway has shown a synergistic effect with eribulin in preclinical models [36–38], where the addition of PI3K inhibitors was able to reverse primary and acquired resistance to eribulin, regardless of the genetic alterations in the PI3K/AKT pathway.
Although findings from this study, along with data from the LOTUS, IPATunity130, and CAPItello-290 trials, suggest limited overall efficacy of AKT inhibitors combined with chemotherapy as first-line treatment for aTNBC, signals of clinical activity remain noteworthy. Given the distinct mechanisms of AKT inhibitors and cytotoxic agents, patients with specific molecular alterations in the PIK3CA/AKT/PTEN axis may still benefit from certain combinations, such as ipatasertib and eribulin. Our exploratory study raises the hypothesis that a subset of patients with PI3K pathway activation may respond favorably to this regimen. A more comprehensive genomic profiling, such as next-generation sequencing covering the broader PI3K/AKT/mTOR pathway, might provide additional predictive biomarkers, including co-occurring mutations, activation signatures, or biomarkers of resistance to other therapies.
Limitations of our study include its small sample size and non-randomized design. Moreover, the exploratory analysis of efficacy according to PIK3CA mutational status is constrained by the exclusive focus on PIK3CA hotspot mutations. Consequently, the low number of patients identified with PIK3CA-mutated tumors precludes the ability to draw robust conclusions. Additionally, the ipatasertib regimen differed from those used in the LOTUS and IPATunity130 trials owing to variations in the chemotherapy regimens schedule administered in PATHFINDER. Moreover, the treatment landscape for aTNBC has rapidly evolved from the design to the completion of this study –especially with the advent of immunotherapy and antibody–drug conjugates– limiting the clinical impact of ipatasertib-based combinations in this scenario.
Conclusions
Combining ipatasertib with capecitabine or eribulin demonstrated acceptable safety. However, adding ipatasertib to carboplatin plus gemcitabine induced intolerable side effects. Compared with historical controls, the addition of ipatasertib to capecitabine or eribulin seems to improve efficacy outcomes in this patient population. Further studies to identify novel biomarkers that predict the response to AKT inhibitors in patients with aTNBC are critical to better define the clinical utility of this approach.
Supplementary Information
Acknowledgements
This study was sponsored by Medica Scientia Innovation Research (MEDSIR) and funded by Hoffmann-La Roche, who did not participate in data collection, data analysis, data interpretation, or writing of this report. We thank the patients and their caregivers for participating in this study, as well as the trial teams at the participating sites and the trial unit at MEDSIR.
Role of the study sponsor
PATHFINDER was conceived and designed by Medica Scientia Innovation Research (MEDSIR) in collaboration with Hoffmann-La Roche, which funded the study and provided ipatasertib. All the chemotherapy regimens and loperamide were supplied by each investigational site. As legal Sponsor of the study, MEDSIR was responsible for ensuring compliance with clinical and regulatory procedures and adherence to study protocol. MEDSIR also oversaw the collection, management, analysis, and interpretation of the data, as well as the preparation of this report.
Abbreviations
- AESIs
Adverse Events of Special Interest
- AKT
Serine/threonine Kinase B
- aTNBC
Advanced Triple-Negative Breast Cancer
- AUC
Area Under the Curve
- CBR
Clinical Benefit Rate
- CI
Confidence Interval
- DL
Dose Level
- DoR
Duration of Response
- ECOG
Eastern European Cooperative Oncology Group
- G
Grade
- HER2
Human Epidermal Growth Factor Receptor 2
- IQR
Interquartile Range
- ITT
Intention-To-Treat
- mTOR
Mammalian Target of Rapamycin
- NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for Adverse Events
- NE
Not Evaluable
- ORR
Objective Response Rate
- OS
Overall Survival
- PD-L1
Programmed Death Ligand 1
- PFS
Progression-Free Survival
- PI3K
Phosphoinositide 3-Kinase
- PIK3CA
P110α catalytic subunit of PI3K
- PTEN
Phosphatase and tensin homolog
- RECIST
Response Evaluation Criteria In Solid Tumors
- SAEs
Serious Adverse Events
- TEAEs
Treatment Emergent Adverse Events
- TROP-2
Trophoblast cell surface antigen 2
- TTR
Time to Response
- UMI
Unique Molecular Identifier
Authors’ contributions
Concept and design: E.L.M., J.M.P.G., A.L.C., and J.C.; Administrative support: O.B. and M.F.P.; Provision of study material or patients: all authors; Data analysis and visualization: D.A.L.; Supervision: J.M.P.G., E.L.M., A.L.C. and J.C.; Data interpretation: all authors; Data validation: all authors; Writing Original Draft: O.B., E.L.M., J.M.P.G., A.L.C. and J.C.; Writing, Review & Editing: all authors; Final approval of manuscript: all authors; Project administration: MEDSIR as the study sponsor.
Funding
This work was supported by Hoffmann-La Roche, which had no role in data collection, data analysis, data interpretation, or writing of this report.
Data availability
Data collected within this study will be made available to researchers after contacting the corresponding author and upon revision and approval based on scientific merit by the trial management group (which includes a qualified statistician) of a detailed proposal for their use. The data required for the approved, specified purposes and the trial protocol will be provided after the completion of a data-sharing agreement that will be set up by the study sponsor, beginning 1 month and ending 5 years after article publication. All data provided are anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. Estimate timeframe for response will be within 30 days. Please, address requests for data to the corresponding author (Dr. Javier Cortés; email address: javier.cortes@maj3.health).
Declarations
Ethics approval and consent to participate
This study was conducted in compliance with the Declaration of Helsinki and was approved by the institutional review boards or independent ethics committees at each site. All patients provided written informed consent prior to participation in any study-related activities.
Competing interests
E.L.M. reports having received personal honoraria from AstraZeneca, Seagen, Lilly and Daichii Sankyo; having received personal honoraria for advisory board participation from AstraZeneca, Daichii Sankyo and Seagen; having received personal speakers’ bureaus from Lilly and AstraZeneca; having personal support for attending meetings and/or travel from Gilead and Roche. J.M.P.G. reports having received personal honoraria for advisory board participation from Lilly, Roche, Eisai, Daichii Sankyo, AstraZeneca, Seattle Genetics, MSD, and Gilead; having personal support for attending meetings and/or travel from Roche; being an employee at MEDSIR. M.G. reports having received honoraria from Novartis, Gilead, Astra Zeneca, Pfizer; having personal support for attending meetings and/or travel from Roche, Pfizer, Astra Zeneca, Gilead; having received honoraria for advisory board participation from Gilead, Novartis, AstraZeneca, Pfizer. N.R. reports having received personal speakers’ bureaus from Novartis, Pfizer, Daichii-AstraZeneca, Lilly and Gilead; having received institutional financial support from Pfizer. M.M.G. reports having received personal honoraria for consulting, advisory or speaker fees from Gilead, Novocure, Seagen, Boehringer Ingelheim, Roche, Celgene, Lilly Astra Zeneca-Daiichi sankyo, Reddy Pharma Iberia; having personal support for attending meetings and/or travel from Pfizer, Gilead and Roche; having received institutional financial support from Pfizer and Roche. S.G.S reports having received personal honoraria for advisory board participation from AstraZeneca; having received personal speakers’ bureaus from Novartis; having personal support for attending meetings and/or travel from Pfizer. B.B. reports having received personal honoraria for medical edication as consulting or advisory board from MSD, Roche, Pierre Fabre, Novartis, AstraZeneca and Seagen; having received personal speakers’ bureaus from Pfizer, Roche, MSD, Palex, Eisai, Daichii Sankyo/AstraZeneca and Seagen. S.M. having personal support for attending meetings and/or travel from AstraZeneca, Daiichi Sankyo, Gilead, Lilly, Novartis, MSD,and Pfizer; having received institutional financial support from Lilly. L.G. reports having received personal speakers’ bureaus from Novartis and Daichii Sankyo. M.F.P. is a full-time employee at MEDSIR; S.G.V. is a full-time employee at MEDSIR; A.G.S is a full-time employee at MEDSIR; A.M.M.is a full-time employee at MEDSIR; O.B.S. is a full-time employee at MEDSIR; D.A.L. is a full-time employee at MEDSIR. A.L.C reports having received institutional financial support from Roche, Agendia, Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Gilead, and Daichii-Sanyo; having received personal honoraria for consulting/advisory from Lilly, Roche, Pfizer, and Novartis; having received personal speakers’ bureaus from Lilly, AstraZeneca, MSD, Pfizer and Novartis; having personal support for attending meetings and/or travel from Roche, Pfizer, AstraZeneca, Steamline therapeutics and MSD; stock or other ownership of MEDSIR and MAJ3 Capital & Initia-Research; and patents: Her2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy. Aleix Prat, Antonio Llombart, Javier Cortés.US 2019/0338368 A1. LICENSED. J.C reports having received personal honoraria for consulting/advisory from AstraZeneca, Seattle Genetics, Daiichi Sankyo, Lilly, Merck Sharp&Dohme, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, Scorpion Therapeutics, Expres2ion Biotechnologies, Jazz Pharmaceuticals, Abbvie, BridgeBio, Biontech, Biocon, Circle Pharma, Delcath Systems, Inc., Hexagon Bio; having received honoraria from Roche, Novartis, Eisai, Pfizer, Lilly, Merck Sharp&Dohme, Daiichi Sankyo, Astrazeneca, Gilead, Steamline Therapeutics; having received institutional research funding from Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics,Iqvia, Queen Mary University of London; stock of MedSIR, MAJ3 Capital, Leuko (relative); having personal support for attending meetings and/or travel from Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo, Astrazeneca, Gilead, Merck Sharp&Dhome, Steamline Therapeutics; and patents: Pharmaceutical Combinations of A Pi3k Inhibitor And A Microtubule Destabilizing Agent. Javier Cortés Castán, Alejandro Piris Giménez, Violeta Serra Elizalde. WO 2014/199294 A. ISSUED; Her2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy. Aleix Prat, Antonio Llombart, Javier Cortés.US 2019/0338368 A1. LICENSED. The remaining authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Contributor Information
Antonio Llombart-Cussac, Email: antoniollombart@medsir.org.
Javier Cortés, Email: javier.cortes@maj3.health.
References
- 1.Garrido-Castro AC, Lin NU, Polyak K. Insights into molecular classifications of triple-negative breast cancer: improving patient selection for treatment. Cancer Discov. 2019;9(2):176–98. 10.1158/2159-8290.CD-18-1177. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Gennari A, André F, Barrios CH, et al. Esmo clinical practice guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021. 10.1016/j.annonc.2021.09.019. [DOI] [PubMed] [Google Scholar]
- 3.Loibl S, André F, Bachelot T, et al. Early breast cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. 2024;35(2):159–82. 10.1016/j.annonc.2023.11.016. [DOI] [PubMed] [Google Scholar]
- 4.Courtney D, Davey MG, Moloney BM, et al. Breast cancer recurrence: factors impacting occurrence and survival. Ir J Med Sci. 2022;191(6):2501–10. 10.1007/s11845-022-02926-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Dent R, Trudeau M, Pritchard KI, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res. 2007;13(15):4429–34. 10.1158/1078-0432.CCR-06-3045. [DOI] [PubMed] [Google Scholar]
- 6.Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396(10265):1817–28. 10.1016/S0140-6736(20)32531-9. [DOI] [PubMed] [Google Scholar]
- 7.Schmid P, Rugo HS, Adams S, et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21(1):44–59. 10.1016/S1470-2045(19)30689-8. [DOI] [PubMed] [Google Scholar]
- 8.Miles D, Gligorov J, André F, et al. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol. 2021;32(8):994–1004. 10.1016/j.annonc.2021.05.801. [DOI] [PubMed] [Google Scholar]
- 9.Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384(16):1529–41. 10.1056/NEJMoa2028485. [DOI] [PubMed] [Google Scholar]
- 10.Bardia A, Rugo HS, Tolaney SM, et al. Final results from the randomized phase III ASCENT clinical trial in metastatic triple-negative breast cancer and association of outcomes by human epidermal growth factor receptor 2 and trophoblast cell surface antigen 2 expression. JCO. 2024;42(15):1738–44. 10.1200/JCO.23.01409. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9–20. 10.1056/NEJMoa2203690. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.American Cancer Society. American Cancer Society: Breast cancer facts and figures 2019–2020. July 16, 2021. Published online July 16, 2021. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2019-2020.pdf. Accessed 02 Aug 2025.
- 13.Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129(7):1261–74. 10.1016/j.cell.2007.06.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.LoRusso PM. Inhibition of the PI3K/AKT/mTOR pathway in solid tumors. JCO. 2016;34(31):3803–15. 10.1200/JCO.2014.59.0018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Millis SZ, Gatalica Z, Winkler J, et al. Predictive Biomarker Profiling of > 6000 Breast Cancer Patients Shows Heterogeneity in TNBC. With Treatment Implications Clin Breast Cancer. 2015;15(6):473-481.e3. 10.1016/j.clbc.2015.04.008. [DOI] [PubMed] [Google Scholar]
- 16.Pascual J, Turner NC. Targeting the PI3-kinase pathway in triple-negative breast cancer. Ann Oncol. 2019;30(7):1051–60. 10.1093/annonc/mdz133. [DOI] [PubMed] [Google Scholar]
- 17.Isakoff SJ, Tabernero J, Molife LR, et al. Antitumor activity of ipatasertib combined with chemotherapy: results from a phase Ib study in solid tumors. Ann Oncol. 2020;31(5):626–33. 10.1016/j.annonc.2020.02.007. [DOI] [PubMed] [Google Scholar]
- 18.Lin J, Sampath D, Nannini MA, et al. Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models. Clin Cancer Res. 2013;19(7):1760–72. 10.1158/1078-0432.CCR-12-3072. [DOI] [PubMed] [Google Scholar]
- 19.Doi T, Fujiwara Y, Matsubara N, et al. Phase I study of ipatasertib as a single agent and in combination with abiraterone plus prednisolone in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. 2019;84(2):393–404. 10.1007/s00280-019-03882-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Kim SB, Dent R, Im SA, et al. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2017;18(10):1360–72. 10.1016/S1470-2045(17)30450-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Dent R, Oliveira M, Isakoff SJ, et al. Final results of the double-blind placebo-controlled randomized phase 2 LOTUS trial of first-line ipatasertib plus paclitaxel for inoperable locally advanced/metastatic triple-negative breast cancer. Breast Cancer Res Treat. 2021;189(2):377–86. 10.1007/s10549-021-06143-5. [DOI] [PubMed] [Google Scholar]
- 22.Dent R, Kim SB, Oliveira M, et al. IPATunity130: A pivotal randomized phase III trial evaluating ipatasertib (IPAT) + paclitaxel (PAC) for PIK3CA/AKT1/PTEN -altered advanced triple-negative (TN) or hormone receptor-positive HER2-negative (HR+/HER2–) breast cancer (BC). JCO. 2018;36(15_suppl):TPS1117–TPS1117. 10.1200/JCO.2018.36.15_suppl.TPS1117. [Google Scholar]
- 23.Dent RA, Kim SB, Oliveira M, et al. Ipatasertib plus paclitaxel for patients with PIK3CA / AKT1 / PTEN -altered locally advanced unresectable or metastatic triple-negative breast cancer in the IPATunity130 phase III trial. Clin Cancer Res. 2024;30(19):4329–38. 10.1158/1078-0432.CCR-24-0465. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Yuan Y, Yost SE, Cui Y, et al. Phase I Trial of Ipatasertib Plus Carboplatin, Carboplatin/Paclitaxel, or Capecitabine and Atezolizumab in Metastatic Triple-Negative Breast Cancer. Oncologist. 2023;28(7):e498–507. 10.1093/oncolo/oyad026. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Wolff AC, Somerfield MR, Dowsett M, et al. Human epidermal growth factor receptor 2 testing in breast cancer: ASCO–college of American pathologists guideline update. JCO. 2023;41(22):3867–72. 10.1200/JCO.22.02864. [DOI] [PubMed] [Google Scholar]
- 26.Costa RLB, Han HS, Gradishar WJ. Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: a review. Breast Cancer Res Treat. 2018;169(3):397–406. 10.1007/s10549-018-4697-y. [DOI] [PubMed] [Google Scholar]
- 27.Network CGA. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70. 10.1038/nature11412. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Schmid P, Savas P, Espinosa E, et al. Abstract PS12–28: phase 1b study evaluating a triplet combination of ipatasertib (IPAT), atezolizumab, and a taxane as first-line therapy for locally advanced/metastatic triple-negative breast cancer (TNBC). Cancer Res. 2021;81(4_Supplement):PS12-28-PS12-28. 10.1158/1538-7445.SABCS20-PS12-28. [Google Scholar]
- 29.Twelves C, Cortes J, Vahdat L, et al. Efficacy of eribulin in women with metastatic breast cancer: a pooled analysis of two phase 3 studies. Breast Cancer Res Treat. 2014;148(3):553–61. 10.1007/s10549-014-3144-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Pivot X, Marmé F, Koenigsberg R, Guo M, Berrak E, Wolfer A. Pooled analyses of eribulin in metastatic breast cancer patients with at least one prior chemotherapy. Ann Oncol. 2016;27(8):1525–31. 10.1093/annonc/mdw203. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Rugo HS, Roche H, Thomas E, et al. Efficacy and safety of ixabepilone and capecitabine in patients with advanced triple-negative breast cancer: a pooled analysis from two large phase III. randomized clinical trials. Clin Breast Cancer. 2018;18(6):489–97. 10.1016/j.clbc.2018.07.024. [DOI] [PubMed] [Google Scholar]
- 32.Bonnefoi H, Lerebours F, Pulido M, et al. Darolutamide or capecitabine in triple-negative, androgen receptor-positive, advanced breast cancer (UCBG 3–06 START): a multicentre, non-comparative, randomised, phase 2 trial. Lancet Oncol. 2025;26(3):355–66. 10.1016/S1470-2045(24)00737-X. [DOI] [PubMed] [Google Scholar]
- 33.Jacobs SA, Robidoux A, Abraham J, et al. NSABP FB-7: a phase II randomized neoadjuvant trial with paclitaxel + trastuzumab and/or neratinib followed by chemotherapy and postoperative trastuzumab in HER2+ breast cancer. Breast Cancer Res. 2019;21(1):133. 10.1186/s13058-019-1196-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Pérez García JM, Gión M, Ruiz-Borrego M, et al. Prevention of sacituzumab govitecan (SG)-related neutropenia and diarrhea in patients (pts) with triple-negative or HR+/HER2- advanced breast cancer (ABC; PRIMED): a phase 2 trial. JCO. 2024;42(16_suppl):1101–1101. 10.1200/JCO.2024.42.16_suppl.1101. [Google Scholar]
- 35.Schmid P, McArthur HL, Cortés J. LBA19 - Capivasertib (C) + paclitaxel (P) as first-line treatment of metastatic triple-negative breast cancer (mTNBC): The CAPItello-290 phase III trial. Ann Oncol. 2024;35(suppl_2):1–72. 10.1016/annonc/annonc1623 [DOI] [PubMed]
- 36.Morgillo F, Della Corte CM, Diana A, et al. Phosphatidylinositol 3-kinase (PI3Kα)/AKT axis blockade with taselisib or ipatasertib enhances the efficacy of anti-microtubule drugs in human breast cancer cells. Oncotarget. 2017;8(44):76479–91. 10.18632/oncotarget.20385. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Rajput S, Guo Z, Li S, Ma CX. PI3K inhibition enhances the anti-tumor effect of eribulin in triple negative breast cancer. Oncotarget. 2019;10(38):3667–80. [PMC free article] [PubMed] [Google Scholar]
- 38.Jeong YG, Katuwal NB, Kang MS, et al. Combined PI3K inhibitor and eribulin enhances anti-tumor activity in preclinical models of paclitaxel-resistant, PIK3CA-mutated endometrial cancer. Cancers. 2023;15(19):4887. 10.3390/cancers15194887. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data collected within this study will be made available to researchers after contacting the corresponding author and upon revision and approval based on scientific merit by the trial management group (which includes a qualified statistician) of a detailed proposal for their use. The data required for the approved, specified purposes and the trial protocol will be provided after the completion of a data-sharing agreement that will be set up by the study sponsor, beginning 1 month and ending 5 years after article publication. All data provided are anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. Estimate timeframe for response will be within 30 days. Please, address requests for data to the corresponding author (Dr. Javier Cortés; email address: javier.cortes@maj3.health).