Patients with breast cancer that harbors 

 fusions achieved deep and durable responses following treatment with entrectinib (Rozlytrek), according to updated data from the phase 2 STARTRK-2 trial (NCT02568267) presented at the ESMO Breast Cancer Congress 2022.

At a median duration of survival follow-up of 35.3 months in patients with 

 fusion–positive disease (n = 7), entrectinib elicited a 71% (95% CI, 29.0%–96.3%) overall response rate (ORR); 2 patients achieved a complete response (CR) and 3 patients had a partial response (PR). Response data were missing on the other 2 patients. Both patients who achieved a CR had secretory disease, and among the 3 patients to have a PR, 2 had secretory disease and 1 had non-secretory disease. Among the 5 responders, the median duration of response (DOR) was 12.9 months (95% CI, 4.2-not evaluable [NE]).

 gene fusions are drivers in many solid tumors, including breast cancer.

 Though less than 1% of all breast cancer cases harbor 

 fusions, they are present in more than 90% of secretory breast carcinomas.

Prior data from the ALKA-372-001 trial (EudraCT 2012-000148-88), the phase 1 STARTRK-1 trial (NCT02097810), and STARTRK-2 showed entrectinib demonstrated deep and durable responses in patients with 

 Prior data from STARTRK-2 showed patients with 

 fusion–positive breast cancer achieved an ORR of 83% (n = 5 of 6), a median DOR of 12.9 months (95% CI, 4.2-NE), a median progression-free survival (PFS) of 10.1 months (95% CI, 5.1-NE), and a median overall survival (OS) of 23.9 months (95% CI, 5.1-23.9).

STARTRK-2 enrolled patients with locally advanced or metastatic solid tumors that harbored an 

 fusion–positive breast cancer. Moreover, patients were eligible regardless of central nervous system (CNS) metastases, and patients were required to be naïve to TRK inhibitors.

Enrolled patients received 600 mg of entrectinib once daily. Tumor burden was assessed following the first cycle of therapy, followed by every 8 weeks after by blinded independent central review per RECIST v1.1 criteria. Notably, regular brain scans were required for patients with baseline CNS metastases.

The primary end points were ORR and DOR per blinded independent central review. Secondary end points included PFS, OS, intracranial efficacy, CNS progression, and safety.

 fusion–positive breast cancer, all were female with a median age of 61 years (range, 36-67), and 5 patients were White. Patients had an ECOG performance status of 0 (n = 3), 1 (n = 2), or 2 (n = 2). All patients had received prior chemotherapy, radiotherapy, and hormonal therapy, and 5 patients were administered prior targeted therapy. One patient had previous radiotherapy of the brain.

Prior lines of therapy for metastatic disease included 0 (n = 3), 1 (n = 1), 3 (n = 1), and 4 or more (n = 2). Two patients presented with CNS metastases at baseline, and the median time since diagnosis for all patients was 130.1 months (range, 32.6-309.1). Histology included non-secretory (n = 2), secretory (n = 4), and not specified (n = 1).

Additional data showed the median PFS was 10.1 months (95% CI, 5.1-NE), and the median OS was 19.2 months (95% CI, 5.1–NE).

In the 2 patients with CNS metastases at baseline, the first had HER2-positive, estrogen receptor (ER)–positive, PGR-negative disease and received whole brain radiation 2-6 months prior to beginning entrectinib. This patient received no prior lines of systemic therapy for metastatic disease, and she achieved a PR and an intracranial non-CR and non–progressive disease. The second patient had HER2-negative, ER-positive, PGR-positive disease and received 6 prior lines of systemic therapy for metastatic disease. This patient did not have response data after dying 1.7 months following the first dose of entrectinib, though her death was not considered related to treatment.

Notably, no patients experienced a CNS progression event, regardless of baseline status.

Among 12 patients who received at least 1 dose of entrectinib and were evaluable for safety, 4 patients experienced a grade 3 or higher treatment-related adverse effect (TRAE). These included anemia (n = 2), fatigue (n = 1), and increased alanine aminotransferase (n = 1). There were no grade 5 TRAEs recorded. Only 1 patient had a series TRAE.

The most common TRAEs of any grade included dizziness (n = 5), nausea (n = 5), anemia (n = 4), constipation (n = 4), vomiting (n = 4), dysgeusia (n = 3), diarrhea (n = 3), increased alanine aminotransferase (n = 3), increased aspartate aminotransferase (n = 3), increased blood creatinine (n = 3), paresthesia (n = 3), and increased weight (n = 3).

Treatment-related adverse events resulted in the dose interruptions in 6 patients, dose reductions in 5 patients, and treatment discontinuations in 1 patient.

“In line with previous reports, entrectinib was associated with a manageable safety profile in patients with 

 fusion-positive breast cancer,” lead study author Min Janice Lu, MD, of USC Norris Comprehensive Cancer Center, wrote in the poster.

Lu J, Blakely CM, Barve M, et al. Entrectinib in NTRK fusion-positive (NTRK-fp) breast cancer: updated data from STARTRK-2. Presented at: 2022 ESMO Breast Cancer Congress; May 3-5, 2022; Berlin, Germany. Poster 173P.

Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. 

. 2015;5(1):25-34. doi:10.1158/2159-8290.CD-14-0765

Wu S, Shi X, Ren X, Li K, Pang J, Liang Z. Evaluation of NTRK gene fusion by five different platforms in triple-negative breast carcinoma. 

. 2021;8:654387. doi:10.3389/fmolb.2021.654387

Demetri GD, Braud FD, Drilon A, et al. Updated integrated analysis of the efficacy and safety of entrectinib in patients with NTRK fusion-positive solid tumors. 

. 2022;28(7):1302-1312. doi:10.1158/1078-0432.CCR-21-3597

Lu J, Blakely CM, Le Tourneau C, et al. Efficacy and safety of entrectinib in NTRK fusion-positive (NTRK-fp) breast cancer. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Abstract PS11-28.

Basket study of entrectinib (RXDX-101) for the treatment of patients with solid tumors harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK gene rearrangements (fusions) (STARTRK-2). ClinicalTrials.gov. Updated May 3, 2022. Accessed May 11, 2022. 

https://clinicaltrials.gov/ct2/show/NCT02568267

This article was originally published on OncLive as “Entrectinib Continues to Yield Promising Data in NTRK Fusion–Positive Breast Cancer”

Articles

Entrectinib elicited encouraging responses in patients with breast cancer that harbors NTRK fusions, according to updates from the phase 2 STARTRK-2 trial.

Entrectinib Generates Favorable Outcomes in NTRK Fusion+ Breast Cancer

HER2-positive breast cancer who also harbor brain metastases and were enrolled in the phase 2 TUXEDO-1 trial (NCT04752059) derived clinical benefit from treatment with fam-trastuzumab deruxtecan-nxki (Enhertu), according to data presented at the European Society for Medical Oncology Breast Cancer Congress 2022.

Among the 15 patients in the intention-to-treat (ITT) population, the objective response rate (ORR) via response assessment in neuro-oncology criteria was 73.3% (95% CI, 48.1%-89.1%). Bartsch noted that in the analysis 1 patient was found to have dural brain metastases only resulting in 14 patients meeting protocol requirements. The ORR among these patients was 78.6%. The clinical benefit rate in the ITT population was 86.7% and 92.9% in the per-protocol population.

“Brain metastases are a common and devastating complication of HER2-postitive breast cancer,” Rupert Bartsch, MD, associate professor, codirector of the Brain Metastases Program, and a consultant for hematology and medical oncology in the Department of the Medicine I, Clinical Division of Oncology at the Medical University of Vienna in Austria, said. “Local therapy has long been the main stay of treatment, but recent years have seen growing interest in systemic treatments as well.”

Data from combination regimens of HER2 tyrosine kinase inhibitors (TKIs), such as lapatinib (Tykerb) or neratinib (Nerlynx) plus capecitabine, have yielded clinically relevant activity for patients with HER2-positive breast cancer and brain metastases who progress after local therapy.

The standard of care for these patients was defined in results of the HER2CLIMB trial (NCT02614794), in which tucatinib (Tukysa) plus trastuzumab (Herceptin) and capecitabine reduced the risk of intracranial progression with a median central nervous system (CNS) progression-free survival (PFS) of 9.9 months (95% CI, 8.0-13.9) vs 4.2 months (95% CI, 3.6-5.7) with trastuzumab and capecitabine alone (HR, 0.32; 95% CI, 0.22-0.48; 

 < .00001).4 A 42% reduction in the risk of death was also observed among the 198 patients with brain metastases who received the investigational approach vs the 98 patients who received placebo (HR, 0.58; 95% CI, 0.40-0.85; 

Data from trials such as the DEBBRAH trial (NCT04420598) have suggested a role for antibody-drug conjugates in patients with brain metastases, Bartsch said.

TUXEDO-1 is a single-center, single-arm trial for patients with histologically confirmed HER2-positive breast cancer with newly diagnosed brain metastases or brain metastases progressing after local therapy for whom there is no indication for immediate local therapy available. Prior exposure to trastuzumab and pertuzumab (Perjeta) were required and prior exposure to ado-trastuzumab emtansine (T-DM1; Kadcyla) was permitted.

Patients received trastuzumab deruxtecan at the recommended dose of 5.4 mg/kg intravenously once every 3 weeks until progression or unacceptable toxicity.

At baseline, patients had a median age of 69 years (range, 30-76) with 80% of patients having the presence of visceral metastases and 80% of patients having HER2-positive/Luminal B disease. Prior treatment with T-DM1 was reported among 60% of patients and prior laptatinib was reported among 26.7%. In terms of prior treatment for brain metastases, 60% of patients had progressive brain metastases after local therapy at baseline. The median number of prior lines of therapy was 2 (range, 1-5).

Investigators also reported other secondary outcome measures. The median overall survival was not reached and the median PFS was 14 months (95% CI, 11–not reached) at a median follow-up of 11 months (range, 3-17). The extracranial response rate among 13 patients with extracranial metastases was 27.8% and was 62.5% among 8 patients who had measurable extracranial disease at baseline.

In terms of safety, most adverse effects (AEs) were grade 1/2 the most common of which were fatigue (66.7%), nausea (46.7%), anemia (46.6%) neutropenia (46.6%), and constipation (40%). Grade 3 AEs included fatigue (15.3%), anemia (6.7%), diarrhea (6.7%), dyspnea (6.7%), and urinary tract infection (6.7%).

AEs of special interest included 1 instance of ejection fraction decrease which was grade 3 and 1 instance interstitial lung disease which was grade 2 and was resolved after 6 weeks of corticosteroid treatment, according to Bartsch. Further, 6 serious AEs were reported in a total of 4 patients and 1 patient experienced grade 5 urosepsis which was not related to treatment.

“Global health status, physical function, and emotional function were maintained over the entire treatment period with an initial drop seen in the first weeks of therapy,” Bartsch said. “Importantly, in a trial conducted in patients with active brain metastases, cognitive function was maintained over the entire treatment period.”

Bartsch R, Berghoff AS, Furtner J, et al. Trastuzumab-deruxtecan (T-DXd) in HER2-positive breast cancer patients with active brain metastases: primary outcome analysis from the TUXEDO-1 trial. Presented at: European Society for Medical Oncology Breast Cancer Congress 2022. May 3-5, 2022; Berlin, Germany.

Lin NU, Diéras V, Paul D, et al. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. 

. 2009;15(4):1452-1459. doi:10.1158/1078-0432.CCR-08-1080

Freedman RA, Gelman RS, Anders CK, et al; Translational Breast Cancer Research Consortium. A phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. 

. 2019;37(13):1081-1089. doi:10.1200/JCO.18.01511

Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. 

. 2020;38(23):2610-2619. doi:10.1200/JCO.20.00775

This article was originally published on OncLive as “Evidence Grows to Support Trastuzumab Deruxtecan in Patients With HER2+ Breast Cancer and Active Brain Metastases”

Patients with HER2-positive breast cancer who also have brain metastases experienced clinical benefit with fam-trastuzumab deruxtecan-nxki in the phase 2 TUEXEDO-trial.

ESMO Breast Cancer Congress

Entrectinib Generates Favorable Outcomes in NTRK Fusion+ Breast Cancer

Trastuzumab Deruxtecan Continues to Elicit Responses in HER2+ Breast Cancer With Active Brain Metastases