Triplet Shows Modest Benefit in Nonmutated Tumors in HR+/HER2– Breast Cancer

A coclinical trial determined that the triplet combination therapy of fulvestrant (Faslodex), palbociclib (Ibrance), and rogaratinib (BAY 1163877) is effective only in patients with nonmutated tumors for both the PIK3CA and ESR1 genes, in advanced hormone receptor–positive (HR+), HER2-negative breast cancer that has become resistant to standard endocrine therapy combined with CDK4/6 inhibitors (CDK4/6i).¹

The study also established the feasibility and manageable toxicity of the triple-drug regimen. Despite the trial's premature termination due to sponsor-driven decisions, the concordant results from the patient-derived organoid (PDO) models and the clinical cohort provide a strong rationale for designing future biomarker-enriched trials. This approach has the potential to refine patient selection and significantly improve outcomes for a difficult-to-treat subgroup of breast cancer patients.

Although the overall efficacy was modest, the results stratified by the PDO-derived biomarker signature were striking. The median progression-free survival (PFS) for the entire cohort of 9 patients was 3.5 months. The median PFS for patients with nonmutant PIK3CA and ESR1 genes (n = 4) was 9.1 months (P =.0005) vs 1.9 months for patients with mutant PIK3CA and ESR1 genes (n = 5). No objective responses were observed, but 66.7% of patients achieved stable disease.

The triple combination was found to be feasible with a manageable toxicity profile. No new emergent toxicities from drug-drug interactions were observed. The most frequent adverse events were grade 3 neutropenia (66.7%), grade 1/2 hyperphosphatemia (77.7%), and grade 1 to 3 diarrhea (44.4%).

The trial was closed prematurely after 9 patients were enrolled because the sponsor, Bayer, discontinued the development of rogaratinib.

The central challenge in this clinical setting is the significant mutational heterogeneity of tumors, which limits the efficacy of current second-line treatments to a PFS of only 4 to 6 months.

The study hypothesized that simultaneously targeting the estrogen receptor, CDK4/6, and the FGFR pathway could overcome this resistance, particularly in patients with FGFR alterations. Using a coclinical design that combined a clinical trial (ROGABREAST, NCT04483505) with preclinical analysis of PDOs, the research yielded a critical biomarker-driven insight.

In the preclinical arm, PDOs were established from tumor biopsies of 4 patients with HR+ breast cancer who had progressed on CDK4/6i and endocrine therapy.

In the clinical arm, patients were required to have FGFR1 and/or FGFR2 amplification or messenger RNA overexpression and were treated with the triplet combination of rogaratinib, palbociclib, and fulvestrant.

All PDOs were resistant to fulvestrant or palbociclib monotherapy. Rogaratinib monotherapy also showed no meaningful activity. In the FGFR-amplified, nonmutant PIK3CA/ESR1 PDO, significant sensitivity to the triplet combination was identified. In the ESR1-mutant PDO, substituting fulvestrant with camizestrant sensitized the organoid to the combination therapy. In the PIK3CA-mutant PDO, substituting palbociclib with alpelisib (Piqray) achieved a similar sensitizing effect.

The median age of patients was 56.9 years (range, 46-72 years). Patients had an ECOG score of 0 (88.9%) or 1 (11.1%). The median time from metastatic diagnosis to trial was 14.9 months.

FGFR1/2 amplification or overexpression is observed in a significant portion of HR+ breast cancer cases. In this study's screening, over 40% of patients exhibited FGFR alterations.

Preclinical research indicates that FGFR1 amplification is directly linked to resistance to endocrine therapy, CDK4/6i, and their combination.

“FGFR1 amplification has been associated with tumor progression features in breast cancer and other malignancies,” said Martinez-Janez et al, authors of the study. “Multiple studies, including our own, have demonstrated its link to increased metastatic relapse in early [HR+] breast cancer, irrespective of treatment type (endocrine therapy alone or combined with chemotherapy) or other prognostic factors (grade, Ki67, nodal status). The identification of FGFR1 as an amplified kinase, coupled with the efficacy of FGFR inhibitors in FGFR-mutated or rearranged bladder and cholangiocarcinomas, initially raised expectations for a new targetable oncogene addiction driver in breast cancer. However, despite promising preclinical data, clinical results have been modest at best.”

The primary limitations are the small sample size (n = 9) and the premature termination of the trial, which prevented further enrollment and validation.

REFERENCE

1. Martinez-Janez N, Garcia-Saenz J, Pernas S, et al. Co-clinical trial targeting ER, FGFR and CDK4/6 in resistant hormone-positive breast cancer with FGFR alterations. NPJ Precis Oncol. 2025;9(1):343. doi:10.1038/s41698-025-01106-1