Oral metronomic vinorelbine combined with endocrine therapy in hormone receptor-positive HER2-negative breast cancer: SOLTI-1501 VENTANA window of opportunity trial.

BACKGROUND: The biological effect of oral metronomic vinorelbine (mVNB) alone or in combination with endocrine therapy in patients with hormone receptor-positive (HR+)/HER2-negative breast cancer has been scarcely addressed. METHODS: Postmenopausal women with untreated stage I-III HR+/HER2-negative breast cancer were randomized (1:1:1) to receive 3 weeks of letrozole (LTZ) 2.5 mg/day, oral mVNB 50 mg 3 days/week, or the combination. The primary objective was to evaluate, within PAM50 Luminal A/B disease, if the anti-proliferative effect of LTZ+mVNB was superior to monotherapy. An anti-proliferative effect was defined as the mean relative decrease of the PAM50 11-gene proliferation score in combination arm vs. both monotherapy arms. Secondary objectives included the evaluation of a comprehensive panel of breast cancer-related genes and safety. An unplanned analysis of stromal tumor-infiltrating lymphocytes (sTILs) was also performed. PAM50 analyses were performed using the nCounter®-based Breast Cancer 360™ gene panel, which includes 752 genes and 32 signatures. RESULTS: Sixty-one patients were randomized, and 54 paired samples (89%) were analyzed. The main patient characteristics were mean age of 67, mean tumor size of 1.7 cm, mean Ki67 of 14.3%, stage I (55.7%), and grades 1-2 (90%). Most baseline samples were PAM50 Luminal A (74.1%) or B (22.2%). The anti-proliferative effect of 3 weeks of LTZ+mVNB (- 73.2%) was superior to both monotherapy arms combined (- 49.9%; p = 0.001) and mVNB (- 19.1%; p < 0.001). The anti-proliferative effect of LTZ+mVNB (- 73.2%) was numerically higher compared to LTZ (- 65.7%) but did not reach statistical significance (p = 0.328). LTZ+mVNB induced high expression of immune-related genes and gene signatures, including CD8 T cell signature and PDL1 gene and low expression of ER-regulated genes (e.g., progesterone receptor) and cell cycle-related and DNA repair genes. In tumors with ≤ 10% sTILs at baseline, a statistically significant increase in sTILs was observed following LTZ (paired analysis p = 0.049) and LTZ+mVNB (p = 0.012). Grade 3 adverse events occurred in 3.4% of the cases. CONCLUSIONS: Short-term mVNB is well-tolerated and presents anti-proliferative activity alone and in combination with LTZ. The high expression of immune-related biological processes and sTILs observed with the combination opens the possibility of studying this combination with immunotherapy. Further investigation comparing these biological results with other metronomic schedules or drug combinations is warranted. TRIAL REGISTRATION: NCT02802748 , registered 16 June 2016.

The DEBBRAH trial: Trastuzumab deruxtecan in HER2-positive and HER2-low breast cancer patients with leptomeningeal carcinomatosis.

BACKGROUND: Leptomeningeal disease (LMD) is associated with poor survival and diminished quality of life. Trastuzumab deruxtecan (T-DXd) has shown remarkable intracranial and extracranial activity in human epidermal growth factor receptor 2 (HER2)-positive and HER2-low advanced breast cancer (ABC). The DEBBRAH trial was designed to evaluate its efficacy and safety in patients with HER2-positive and HER2-low ABC with a history of brain metastases (BMs) and/or LMD. Here, we report results from cohort 5, which specifically included patients with pathologically confirmed LMD. METHODS: This single-arm, open-label, five-cohort, phase 2 trial enrolled seven patients in cohort 5 who received 5.4 mg/kg T-DXd intravenously every 21 days until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS). Key secondary endpoints included progression-free survival (PFS) and safety profile. FINDINGS: At data cutoff (April 4, 2023), the median duration of follow-up was 12.0 months (range, 2.5-18.6). The median OS was 13.3 months (95% confidence interval [CI], 5.7-NA, p < 0.001), meeting the primary endpoint. The median PFS was 8.9 months (95% CI, 2.1-NA). Two (28.6%) of seven patients remained on treatment after 18.6 and 11.9 months, respectively. Of the five patients who progressed and died, none had intracranial progression or clinical worsening of leptomeningeal symptoms. Notably, 71.4% (95% CI, 29.0-96.3) achieved prolonged stabilization (≥24 weeks) by response evaluation criteria in solid tumors (RECIST) v.1.1. No unexpected safety signals and no treatment-related deaths were observed. CONCLUSIONS: T-DXd showed promising antitumor activity in patients with HER2-positive and HER2-low ABC with previously untreated, pathologically confirmed LMD. These encouraging data warrant further investigation to address the unmet need in this difficult-to-treat condition. FUNDING: This work was funded by Daiichi Sankyo/AstraZeneca. This trial is registered with ClinicalTrials.gov: NCT04420598.

Preventing alpelisib-related hyperglycaemia in HR+/HER2-/PIK3CA-mutated advanced breast cancer using metformin (METALLICA): a multicentre, open-label, single-arm, phase 2 trial.

Background: Hyperglycaemia is an early and frequent adverse event during alpelisib treatment. METALLICA aimed to evaluate prophylactic metformin to prevent or reduce hyperglycaemia occurrence in patients with HR+/HER2-/PIK3CA-mutated advanced breast cancer (ABC). Methods: Between August 13th, 2020 and March 23rd, 2022, this 2-cohort, phase 2, multicentre, single-arm trial (NCT04300790) enrolled patients with HR+/HER2-/PIK3CA-mutated ABC: cohort A, normal glycaemia (fasting plasma glucose <100 mg/dL [<5.6 mmol/L] and HbA1c <5.7%), and cohort B, prediabetes (fasting plasma glucose 100-140 mg/dL [5.6-7.8 mmol/L] and/or haemoglobin A1C [HbA1c] 5.7-6.4%). Participants were at least 18 years old, with Eastern Cooperative Oncology Group performance status of 0-1, and up to two prior lines of endocrine therapy (ET) for ABC. Alpelisib plus ET were administered in 28-day cycles after initiation of prophylactic metformin plus ET. Primary endpoint was the incidence of grade 3-4 hyperglycaemia over the first 8 weeks. Secondary endpoints included safety, progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). The primary objective for cohort A and B is met with ≤7 (14.6%) and ≤4 (20%) patients with grade 3-4 hyperglycaemia over the first 8 weeks, respectively. Findings: 233 patients were screened, and 68 (20.2%) patients were enrolled in cohorts A (n = 48) and B (n = 20). Median follow-up was 7.8 months (IQR 1.4-19.6). Over the first 8 weeks, one (2.1%) of 48 patients in cohort A (95% CI: 0.5-11.1; P < 0.0001), and three (15.0%) of 20 patients in cohort B (95% CI: 5.6-37.8; P = 0.016) had grade 3-4 hyperglycaemia. Serious treatment-related adverse events occurred in seven patients (10.3%). The most common were rash (two [2.9%]), vomiting (two [2.9%]), and diarrhoea (two [2.9%]). Discontinuation of alpelisib caused by AEs was reported in nine patients (13.2%), none caused by hyperglycaemia. At data cutoff (15 June, 2022), no treatment-related deaths were observed. In the full analysis set, median PFS was 7.3 months (95% CI: 5.9-not reached), ORR was 20.6% (95% CI: 11.7-32.1%), and CBR was 52.9% (95% CI: 40.4-65.2). Interpretation: In HR+/HER2-/PIK3CA-mutated ABC, prophylactic metformin before alpelisib plus endocrine treatment has low incidence and severity of alpelicib-induced hyperglycaemia. Funding: Novartis Pharmaceuticals.

Observational study of HR+/HER2- metastatic breast cancer patients treated with abemaciclib in Spain in the Named Patient Use Program (AbemusS).

INTRODUCTION/OBJECTIVES: To describe abemaciclib use in patients with hormone receptor-positive, human epidermal growth factor receptor-negative (HR+/HER2-) metastatic breast cancer (mBC) who participated in the Named Patient Use program (NPU) in Spain. MATERIAL AND METHODS: This retrospective study was based on medical record review of patients across 20 centers during 2018/2019. Patients were followed up until death, enrolment in a clinical trial, loss of follow-up or study end. Clinical and demographic characteristics, treatment patterns and abemaciclib effectiveness were analyzed; time-to-event and median times were estimated using the Kaplan-Meier (KM) method. RESULTS: The study included 69 female patients with mBC (mean age 60.4 ± 12.4 years), 86% of whom had an initial diagnosis of early BC and 20% had an ECOG ≥ 2. Median follow-up was 23 months (range 16-28). Metastases were frequently observed in bone (79%) and visceral tissue (65%), with 47% having metastases in > 2 sites. Median number of treatment lines before abemaciclib was 6 (range 1-10). Abemaciclib monotherapy was received by 72% of patients and combination therapy with endocrine therapy by 28% of patients; 54% of patients required dose adjustments, with a median time to first adjustment of 1.8 months. Abemaciclib was discontinued in 86% of patients after a median of 7.7 months (13.2 months for combination therapy and 7.0 months for monotherapy) mainly due to disease progression (69%). CONCLUSION: These results suggest that abemaciclib is effective, as monotherapy and in combination, for patients with heavily pretreated mBC, consistent with clinical trial results.

Trastuzumab deruxtecan in patients with central nervous system involvement from HER2-positive breast cancer: The DEBBRAH trial.

BACKGROUND: Trastuzumab deruxtecan (T-DXd) has shown durable antitumor activity in pretreated patients with HER2-positive advanced breast cancer (ABC), but its efficacy has not yet been evaluated in patients with active brain metastases (BMs). DEBBRAH aims to assess T-DXd in patients with HER2-positive or HER2-low ABC and central nervous system involvement. METHODS: This ongoing, five-cohort, phase II study (NCT04420598) enrolled patients with pretreated HER2-positive or HER2-low ABC with stable, untreated, or progressing BMs, and/or leptomeningeal carcinomatosis. Here, we report findings from HER2-positive ABC patients with non-progressing BMs after local therapy (n = 8; cohort 1), asymptomatic untreated BMs (n = 4; cohort 2), or progressing BMs after local therapy (n = 9; cohort 3). Patients received 5.4 mg/kg T-DXd intravenously once every 21 days. The primary endpoint was 16-week progression-free survival (PFS) for cohort 1 and intracranial objective response rate (ORR-IC) for cohorts 2 and 3. RESULTS: As of October 20, 2021, 21 patients received T-DXd. In cohort 1, 16-week PFS rate was 87.5% (95%CI, 47.3-99.7; P < .001). ORR-IC was 50.0% (95%CI, 6.7-93.2) in cohort 2 and 44.4% (95%CI, 13.7-78.8; P < .001) in cohort 3. Overall, the ORR-IC in patients with active BMs was 46.2% (95%CI, 19.2-74.9). Among patients with measurable intracranial or extracranial lesions at baseline, the ORR was 66.7% (12 out of 18 patients; 95%CI, 41.0-86.7), 80.0% (95%CI, 28.4-99.5) in cohort 1, 50.0% (95%CI, 6.7-93.2) in cohort 2, and 66.7% (95%CI, 29.9-92.5) in cohort 3. All responders had partial responses. The most common adverse events included fatigue (52.4%; 4.8% grade ≥3), nausea (42.9%; 0% grade ≥3), neutropenia (28.6%; 19% grade ≥3), and constipation (28.6%; 0% grade ≥3). Two (9.5%) patients suffered grade 1 interstitial lung disease/pneumonitis. CONCLUSIONS: T-DXd showed intracranial activity with manageable toxicity and maintained the quality of life in pretreated HER2-positive ABC patients with stable, untreated, or progressing BMs. Further studies are needed to validate these results in larger cohorts.

Palbociclib combined with endocrine therapy in heavily pretreated HR+/HER2- advanced breast cancer patients: Results from the compassionate use program in Spain (PALBOCOMP).

BACKGROUND: This study evaluated efficacy and safety of palbociclib, a CDK4/6 inhibitor, in heavily-pretreated hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) patients during the compassionate use program in Spain from February 2015 to November 2017. PATIENTS AND METHODS: Patient data were collected retrospectively from 35 hospitals in Spain. Patients with HR+/HER2- mBC who had progressed on ≥4 treatments for advanced disease were eligible. RESULTS: A total of 219 patients received palbociclib in combination with aromatase inhibitors (110; 50.2%), fulvestrant (87; 39.7%), tamoxifen (8; 3.6%) or as single agent (10; 4.6%). Mean age of the patients was 58 years; 31 patients (16.1%) were premenopausal and 162 (83.9%) were postmenopausal at the beginning of treatment with palbociclib. Patients had received a median of 3 previous lines of endocrine therapy (ET) for advanced disease. Real-world tumor response (rwTR) and clinical benefit rate were 5.9% (n = 13) and 46.2% (n = 101), respectively. The median real world progression-free survival (rwPFS) was 6.0 months (95% CI 5.7-7.0) and the median overall survival was 19.0 months (95% CI 16.4-21.7). Subgroup analysis revealed a significant difference in median rwPFS in patients treated with palbociclib plus fulvestrant depending on the duration of prior treatment with fulvestrant monotherapy (>6 versus ≤6 months; HR 1.93, 95% CI 1.37-2.73, p < 0.001). The most frequently reported toxicities were neutropenia, asthenia, thrombopenia and anemia. CONCLUSIONS: Palbociclib can be an effective and safe treatment option in patients with heavily pretreated endocrine-sensitive mBC, especially in those with longer PFS to previous ET.

Observational study of HR+/HER2− metastatic breast cancer patients treated with abemaciclib in Spain in the Named Patient Use Program (AbemusS)

Introduction/objectives To describe abemaciclib use in patients with hormone receptor-positive, human epidermal growth factor receptor-negative (HR+/HER2−) metastatic breast cancer (mBC) who participated in the Named Patient Use program (NPU) in Spain.Material and methods This retrospective study was based on medical record review of patients across 20 centers during 2018/2019. Patients were followed up until death, enrolment in a clinical trial, loss of follow-up or study end. Clinical and demographic characteristics, treatment patterns and abemaciclib effectiveness were analyzed; time-to-event and median times were estimated using the Kaplan–Meier (KM) method. Results The study included 69 female patients with mBC (mean age 60.4 ± 12.4 years), 86% of whom had an initial diagnosis of early BC and 20% had an ECOG ≥ 2. Median follow-up was 23 months (range 16–28). Metastases were frequently observed in bone (79%) and visceral tissue (65%), with 47% having metastases in > 2 sites. Median number of treatment lines before abemaciclib was 6 (range 1–10). Abemaciclib monotherapy was received by 72% of patients and combination therapy with endocrine therapy by 28% of patients; 54% of patients required dose adjustments, with a median time to first adjustment of 1.8 months. Abemaciclib was discontinued in 86% of patients after a median of 7.7 months (13.2 months for combination therapy and 7.0 months for monotherapy) mainly due to disease progression (69%). Conclusion These results suggest that abemaciclib is effective, as monotherapy and in combination, for patients with heavily pretreated mBC, consistent with clinical trial results (AU)