Results from the phase 2 ROSALINE trial (NCT04551495) presented at the 2025 ESMO Breast Congress revealed that the combination of entrectinib (Rozlytrek) with letrozole demonstrated limited efficacy in the neoadjuvant setting for patients with invasive lobular breast cancer (ILBC).
The trial failed to meet its primary endpoint, with none of the 41 efficacy-evaluable patients achieving a residual cancer burden (RCB) of 0 or 1 following treatment. Among these patients, 61% had RCB II and 39% had RCB III outcomes.
"Endocrine therapy plus entrectinib demonstrated limited efficacy in the neoadjuvant setting of lobular breast cancer," stated Dr. Soraia Lobo-Martins, medical oncologist and research fellow at Institut Jules Bordet in Brussels, Belgium, who presented the findings.
Trial Design and Patient Population
ROSALINE is the first neoadjuvant endocrine therapy trial dedicated exclusively to invasive lobular breast cancer, a subtype that accounts for approximately 15% of all breast cancers but is often underrepresented in clinical trials.
The single-arm phase 2 trial enrolled female patients at least 18 years of age with previously untreated stage IIA to IIIA invasive lobular breast cancer. Eligible patients had tumor sizes greater than 20 mm, N0 or N1 disease, and an ECOG performance status of 0 or 1.
Treatment consisted of 4 28-day cycles of entrectinib at 600 mg plus letrozole at 2.5 mg with or without goserelin at 3.6 mg (for premenopausal patients), followed by surgery. Entrectinib treatment was interrupted at least 7 days before surgery, while letrozole could be continued until the day of surgery.
Of the 56 patients who began treatment, 41 were deemed evaluable after completing at least 80% of the planned entrectinib doses. The median age of evaluable patients was 56 years, with 44% being premenopausal and 85% having an ECOG performance status of 0. Clinical stage distribution included 37% stage IIA, 46% stage IIB, and 17% stage IIIA disease.
Scientific Rationale
The trial was based on preclinical evidence suggesting synthetic lethality between E-cadherin deficiency and ROS1 inhibition. Approximately 90% of invasive lobular breast tumors lack E-cadherin due to CDH1 alterations, making ROS1 inhibition a potentially targeted approach.
Entrectinib, a potent small-molecule tyrosine kinase inhibitor that targets TRK, ROS1, and ALK, was selected based on its established activity in tumors harboring NTRK, ROS1, and ALK gene fusion mutations, particularly in lung cancer.
Efficacy Outcomes
Despite not meeting the primary endpoint, the trial showed some activity through secondary measures. The MRI-assessed confirmed objective response rate (cORR) was 49%, including complete responses in 10% of patients, partial responses in 39%, and stable disease in 51%.
In the intention-to-treat (ITT) population (n=52), which included patients who received fewer than 80% of the planned doses of entrectinib, one patient achieved an RCB of 0 or I. The rates of RCB II and III were 50% and 48%, respectively.
No patients in the efficacy population achieved a pathological complete response (pCR). Pathological staging after surgery showed 11% with stage I, 30% with stage IIA, 20% with stage IIB, 30% with stage IIIA, and 10% with stage IIIC disease.
Safety Profile
Adverse effects (AEs) occurred in all patients in the efficacy population, with 22% experiencing grade 3 or higher events. The most common AEs included constipation (71%), dysgeusia (61%), vertigo (48%), fatigue (43%), and arthralgia (38%).
Dose reductions were required in 61% of patients in the efficacy population, though no patients discontinued treatment. In the broader safety-evaluable ITT population (n=56), dose reductions occurred in 55% of patients, and 18% discontinued treatment.
No grade 5 AEs were reported. Adverse events of special interest included cognitive disorders, memory impairment, and congestive heart failure (one case each).
Future Directions
Although the results did not meet expectations, Dr. Lobo-Martins emphasized that "translational analyses to identify mechanisms of resistance and identify biomarkers are ongoing and will be presented at a later meeting."
The trial demonstrates the feasibility of conducting subtype-specific trials in invasive lobular breast cancer. Researchers are now looking to ongoing and future studies, such as the REPLOT trial using the next-generation ROS1 inhibitor repotrectinib, to build on these findings.
Dr. Guilherme Nader Marta from Dana-Farber Cancer Institute commented, "Although the primary endpoint was not met, ORR by MRI was 49%. Biomarker analyses are underway. Another example that ILC-focused trials are feasible!"
Dr. Jason A. Mouabbi from MD Anderson Cancer Center added, "The ROSALINE trial results are here! Did not meet primary endpoint but ROS1i entrectinib has shown activity in early stage ILC. Our study REPLOT using the next-gen ROS1i repotrectinib is currently enrolling metastatic ILC in the US."
While the ROSALINE trial's primary results were disappointing, the study represents an important step in developing targeted approaches for invasive lobular breast cancer, with ongoing molecular profiling potentially offering insights for future therapeutic strategies.
