Chemotherapy-Free Regimen Shows Promise in HER2+/HR+ Metastatic Breast Cancer

DETECT V trial data suggest dual HER2-targeted and endocrine therapy might be an effective option in HER2+/HR+ breast cancer.

Findings from the phase 3 DETECT V trial (NCT02344472) showed that the use of dual HER2-targeted therapy plus endocrine therapy could serve as an acceptable option for patients with HER2-positive and hormone receptor–positive metastatic breast cancer.

Progression-free survival (PFS) and overall survival (OS) did not differ between those who received chemotherapy (CT)-free and -containing treatment. Data showed the hazard ratio (HR) for PFS for CT-free vs CT-containing treatment was 1.19 (95% CI, 0.84-1.69; P = .34). An adjusted multivariable analysis showed that the HR for PFS was 1.18 (95% CI, 0.81-1.72; P = .381). The HR for OS for chemotherapy-free vs -containing treatment was 1.03 (95% CI, 0.63-1.70; P = .907). Adjusted multivariable analysis showed an HR of 1.07 (95% CI, 0.62-1.82; P = .816).

OS and PFS were significantly improved in patients receiving ribociclib (Kisqali) in addition to chemotherapy or endocrine therapy–based treatment. The HR for PFS was 0.52 (95% CI, 0.37-0.75; P < .001). The HR for OS was 0.42 (95% CI, 0.24-0.74; P = .002). Adjusted multivariable analysis revealed an HR for PFS of 0.57 (95% CI, 0.39-0.85; P = .005) and an HR for OS of 0.47 (95% CI, 0.26-0.85; P = .013).

In a presentation at the 2024 ESMO Congress, lead study author Wolfgang Janni, MD, PhD, noted, “CT-free treatment with dual HER2-targeted therapy plus endocrine therapy might be an effective alternative treatment option for patients with HER2-positive and hormone receptor–positive metastatic breast cancer. The addition of ribociclib may further improve survival.” Janni is a professor and chair of the Department of Obstetrics and Gynecology at the University of Ulm, Germany.

Study Design

The study included patients with a primary hormone receptor–positive/HER2-positive tumor who had received 1 to 3 prior lines of treatment. Patients were required to have histologically confirmed metastatic breast cancer, be at least 18 years old, and have an ECOG performance status of 0 or 1.2

The trial consisted of two treatment arms.1 Patients in the CT-containing arm received chemotherapy in the form of capecitabine, docetaxel, paclitaxel, vinorelbine, eribulin, or nab-paclitaxel (Abraxane) in combination with trastuzumab (Herceptin) and pertuzumab (Perjeta), followed by maintenance therapy with endocrine therapy in the form of fulvestrant (Faslodex), exemestane (Aromasin), letrozole (Femara), anastrozole (Arimidex), or gonadotropin-releasing hormone analog (Lupron) plus trastuzumab/pertuzumab. Patients in the CT-free arm received endocrine therapy plus trastuzumab and pertuzumab. Following a study amendment after the enrollment of 124 patients, the CDK4/6 inhibitor ribociclib was added to the endocrine therapy in both arms.

The primary objective of the study was to compare the efficacy and tolerability of the CT-free and the -containing arms. Secondary objectives included evaluating the effect of adding ribociclib to both treatment arms.

As of the second interim efficacy analysis, with a data cutoff of April 3, 2024, 271 patients had been enrolled, and 54 were still on the follow-up period.

Baseline Patient Characteristics

The baseline characteristics of patients in the DETECT V trial were well balanced between the CT-free (n = 135) and CT-containing (n = 136) arms. The median age in both arms was 60 years (P = .473). The median body mass index was similar between the two groups, recorded as 26.2 kg/m² in the CT-free arm and 26.0 kg/m² in the CT-containing arm (P = .500). Regarding menopausal status, 72.6% of patients in the CT-free arm and 69.9% in the CT-containing arm were postmenopausal (P = .618). Tumor grading showed similar distributions, with grade 2 tumors being the most prevalent in both arms (CT-free, 51.1%; CT-containing, 59.6%; P = .468).

Histological subtypes of the primary tumor were also comparable, with ductal carcinoma being the predominant subtype (CT-free, 64.4%; CT-containing, 68.4%; P = .666). First metastatic site distribution was balanced, with visceral metastases observed in 55.6% and 55.1% of patients, respectively (P = .946). Metastasis-free intervals of 12 months or more were noted in 48.9% and 53.7% of patients, respectively (P = .547). For first-line treatment in the metastatic setting, 75.6% and 78.7% of patients had received prior treatment (P = .781).

The baseline characteristics of patients enrolled before or following the addition of ribociclib to study treatment for all patients, irrespective of the randomization arm, were mostly well balanced. The median patient age in the with-ribociclib arm (n = 147) and without-ribociclib arm (n = 124) was 60 years (P = .175). The median body mass index in the respective arms was 26.0 kg/m2 and 26.4 kg/m2 (P = .107). Most patients were postmenopausal (70.7% vs 71.8%; P = .853). About half of patients had grade 2 primary tumor (54.4% vs 56.5%; grading of the primary tumor, P = .955). Most patients ductal histology (61.9% vs 71.8%; P = .021); notably, this was a comparison of subsequent study cohorts, not a randomized comparison. About half of patients had a visceral first metastatic site (51.7%; 59.7%; first metastatic site, P = .188). The metastasis-free interval was 12 months or longer for 49.0% vs 54.0% of patients or under 12 months for 48.3% vs 45.2% of patients; this information was missing for 2.7% vs 0.8% of patients (P = .502). Most patients had received frontline treatment in the metastatic setting (80.3% vs 73.4%), 17.0% vs 25.8% did not, and this information was missing for 2.7% vs 0.8% of patients (P = .091).

Safety For CT-Free Vs CT-Containing Treatment

In the CT-free arm, at least 1 serious adverse effect (SAE) was experienced in 38.5% of patients; this percentage was 33.8% in the CT-containing arm (P = .421). At least 1 grade 3 or higher AE occurred in 54.8% and 61.0% of patients, respectively (P = .300). The most common all-grade AEs observed in patients included diarrhea (CT-free arm, n = 100; CT-containing arm, n = 146), neutrophil count decrease (64; 53), nausea (49; 59), fatigue (43; 66), decreased white blood cell count (34; 51), anemia (34; 37), peripheral sensory neuropathy (14; 50), increased alanine aminotransferase (ALT; 21; 35), oral mucositis (14; 40), alopecia (15; 37), vomiting (22; 19); increased aspartate aminotransferase (17; 22), dyspnea (21; 17), hypertension (18; 19), headache (20; 13), epistaxis (17; 16), dry skin (16; 14), hot flashes (19; 11), GGT increase (14; 11), left ventricular systolic dysfunction (4; 4).

Safety for Treatment With/Without Ribociclib

At least 1 SAE was reported in 37.4% of those who received ribociclib vs 34.7% of those who did not (P = .640). At least 1 grade 3, 4, or 5 AE was experienced by 64.6% of those who received ribociclib vs 50.0% of those who did not (P = .015). The most common all-grade AEs experienced by those who received ribociclib vs those who did not included diarrhea (131; 115), decreased neutrophil count (100; 17), fatigue (67; 41), nausea (54; 54), decreased white blood cell count (66; 19), anemia (43; 28), peripheral sensory neuropathy (37; 27), increased ALT (50; 6), oral mucositis (19; 35), alopecia (32; 20), vomiting (23; 18), increased AST (35; 4), dyspnea (14; 24), hypertension (24; 13), headache (15; 18), epistaxis (19; 14), dry skin (17; 13), hot flashes (14; 16), GGT increase (21; 4), and left ventricular systolic dysfunction (4; 4).

Limitations

Investigators noted that the study was powered for tolerability comparison between the arms, not for PFS or OS. The study was also not randomized for the addition of ribociclib, and the ribociclib cohort has shorter follow-up. They concluded by saying that final results for the interim analysis are pending.

References

  1. Janni W, Fehm TN, Mueller V, et al. Omission of chemotherapy and addition of the CDK4/6 inhibitor ribociclib in HER2-positive and hormone-receptor positive metastatic breast cancer – Second interim efficacy analysis of the randomized phase III DETECT V trial. Ann Oncol. 2024;35(suppl 2):S362. doi:10.1016/j.annonc.2024.08.298
  2. Detect V /​ CHEVENDO (chemo vs. endo). ClinicalTrials.gov. Updated June 4, 2024. Accessed December 5, 2024. https://clinicaltrials.gov/study/NCT02344472