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Purpose:To assess palbociclib in combination with trastuzumab with or without endocrine therapy in patients with HER2-positive advanced breast cancer.Patients and Methods:PATRICIA is a prospective, open-label, multicenter phase II trial. Patients had received 2–4 prior lines of anti-HER2–based regimens. Treatment consisted of palbociclib 200 mg daily for 2 weeks and 1 week off plus trastuzumab. The study was based on a Simon two-stage design comprising three cohorts: estrogen receptor (ER)-negative (cohort A), ER-positive (cohort B1), and ER-positive with letrozole (cohort B2). ER-positive patients were randomized to cohorts B1 or B2. Primary endpoint was progression-free survival rate at 6 months (PFS6). Secondary objectives included safety and evaluation of the PAM50 intrinsic subtypes.Results:Seventy-one patients were recruited (n = 15 in cohort A and 28 in each cohort B). The PFS6 rate in cohorts A, B1, and B2 was 33.3% (5/15), 42.8% (12/28), and 46.4% (13/28), respectively. Regarding safety, grade 1–2 and 3–4 toxicities occurred in 97.7% and 84.4% of patients, respectively. The most common grade 3–4 toxicities were neutropenia (66.4%) and thrombocytopenia (11.3%). Regarding PAM50, 59 (83.1%) tumors were profiled. Luminal disease defined by PAM50 was found independently associated with longer PFS compared with non-luminal disease (10.6 vs. 4.2 months median PFS; adjusted hazard ratio = 0.40; P = 0.003).Conclusions:Palbociclib in combination with trastuzumab is safe and exhibits promising survival outcomes in trastuzumab pretreated ER-positive/HER2-positive advanced breast cancer with a PAM50 Luminal A or B subtype. The enrollment was stopped prematurely, and a new randomized cohort was opened in this population.

Purpose:The activating mutation AKT1E17K occurs in approximately 7% of estrogen receptor–positive (ER+) metastatic breast cancer (MBC). We report, from a multipart, first-in-human, phase I study (NCT01226316), tolerability and activity of capivasertib, an oral AKT inhibitor, as monotherapy or combined with fulvestrant in expansion cohorts of patients with AKT1E17K-mutant ER+ MBC.Patients and Methods:Patients with an AKT1E17K mutation, detected by local (next-generation sequencing) or central (plasma-based BEAMing) testing, received capivasertib 480 mg twice daily, 4 days on, 3 days off, weekly or 400 mg twice daily combined with fulvestrant at the labeled dose. Study endpoints included safety, objective response rate (ORR; RECIST v1.1), progression-free survival (PFS), and clinical benefit rate at 24 weeks (CBR24). Biomarker analyses were conducted in the combination cohort.Results:From October 2013 to August 2018, 63 heavily pretreated patients received capivasertib (20 monotherapy, 43 combination). ORR was 20% with monotherapy, and within the combination cohort was 36% in fulvestrant-pretreated and 20% in fulvestrant-naïve patients, although the latter group may have had more aggressive disease at baseline. AKT1E17K mutations were detectable in plasma by BEAMing (95%, 41/43), droplet digital PCR (80%, 33/41), and next-generation sequencing (76%, 31/41). A ≥50% decrease in AKT1E17K at cycle 2 day 1 was associated with improved PFS. Combination therapy appeared more tolerable than monotherapy [most frequent grade ≥3 adverse events: rash (9% vs. 20%), hyperglycemia (5% vs. 30%), diarrhea (5% vs. 10%)].Conclusions:Capivasertib demonstrated clinically meaningful activity in heavily pretreated patients with AKT1E17K-mutant ER+ MBC, including those with prior disease progression on fulvestrant. Tolerability and activity appeared improved by the combination.

Background: On January 30th, 2020, the World Health Organization (WHO) declared public health emergencies of international concern (PHEIC) because of the outbreak of SARS-CoV2 and coronavirus disease 2019 (COVID-19). It has rapidly expanded all around the world, highlighting Madrid as one of the cities with a highest incidence. Oncologists have had to adapt treatments in order to reduce the pandemic impact. CDK4/6 inhibitors (CDK4/6i) in combination with hormone therapy are the standard of care in hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer (mBC) patients (P). Asymptomatic neutrophil count decrease is the most frequent toxicity of these agents and may negatively impact on incidence and severity of COVID-19 disease. Methods: Hospitalized P increased exponentially from 10 to 16 March 2020 in our hospital. 78 P diagnosed with ER+/HER2- mBC were on CDK4/6i treatment at that time. At the physicians’ discretion CDK4/6i withdrawal or dose adjustment was performed (considering age, comorbidities, and presence of previous neutropenia). The presence of risk factors such as advanced age or previous neutropenia were key issues when deciding to withdraw or adjust CDK4/6i. We conducted a retrospective analysis to evaluate this decision. All P were selected, and data were collected on May 15th, 2020. The main end point was to evaluate the impact of CDK4/6i withdrawal or dose adjustment (non-exposed) on the incidence of COVID-19 defined as high clinical suspicion (including anosmia) or positive PCR; we estimate the odds ratio (OR) through logistic regression. As secondary objectives P characteristics were evaluated to identify and control potential confounding factors, we also calculate adjusted OR by multivariate analysis. Results: A total of 78 P were evaluated, 44 P treated with palbociclib, 21 with ribociclib, and 13 with abemaciclib in combination with hormonal therapies. Incidence of COVID-19 was 7.7% (6/78 P), 12.8% (5/39) in exposed P, and 2.7% (1/39) in non-exposed P. The OR for exposed patients was 5.8 IC 95% (0.62 to 50.25) p 0,077. Age over 65 years and bone-only disease were associated with a lower COVID 19 relative risk, while diabetes mellitus was associated with a higher incidence. None of the 25 patients over age 70 were infected. In multivariate analysis the adjusted OR for exposed P was 7.68 (p 0.24). Incidence of COVID-19 was numerically higher in patients treated with ribociclib (14.29%) compared to palbociclib (4.55%) or abemaciclib (7.69%). No risk of progression disease was observed in P who had CDK 4/6i withdrawn or dose reduction (p 0.98). Conclusions: Despite the lack of statistical significance, CDK4/6i withdrawn or dose reduction may reduce the incidence of COVID-19. Greater collection of data during COVID-19 pandemic is needed and will provide us with strong evidence to make decisions in case of new outbreaks. Citation Format: Pablo Tolosa, Ana Sanchez-Torre, Helena Bote de Cabo, Rodrigo Sánchez-Bayona, Mercedes Herrera, Ramón Yarza, Laura Lema, Luis Manso, Eva Ciruelos. Impact of CDK 4/6i withdrawal or dose adjustment on COVID-19 incidence in HR+/HER2- mBC patients during the pandemic [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr PO-020.

Purpose: Brain metastases develop in one third of patients with advanced HER2+ breast cancer. Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clinical challenge. Lapatinib, an epidermal growth factor receptor/HER2 inhibitor, was associated with regressions of CNS lesions in a small phase 2 trial. The current study was done to further evaluate the CNS activity of lapatinib. The study was later amended to allow patients who progressed on lapatinib the option of receiving lapatinib plus capecitabine. Experimental Design: Eligible patients had HER2+ breast cancer, progressive brain metastases, prior trastuzumab, and cranial radiotherapy. The primary end point was CNS objective response, defined as ≥50% volumetric reduction of CNS lesion(s) in the absence of increasing steroid use, progressive neurologic signs and symptoms, or progressive extra-CNS disease. Results: Two-hundred and forty-two patients entered the study. CNS objective responses to lapatinib were observed in 6% of patients. In an exploratory analysis, 21% of patients experienced a ≥20% volumetric reduction in their CNS lesions. An association was observed between volumetric reduction and improvement in progression-free survival and neurologic signs and symptoms. Of the 50 evaluable patients who entered the lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40% experienced a ≥20% volumetric reduction in their CNS lesions. Conclusions: This study confirms the modest CNS antitumor activity of lapatinib. Additional responses were observed with the combination of lapatinib and capecitabine. Further studies of lapatinib-based regimens for CNS metastases from HER2+ breast cancer are warranted.

Purpose: Predicting prognosis in HR+/HER2− metastatic breast cancer (MBC) might be clinically useful; however, no validated prognostic biomarkers exist in this setting to date. Patients and Methods: In phase III, EGF30008 trial, 484 patients with HER2− MBC who received letrozole and placebo or lapatinib were selected. PAM50 data, ECOG performance status, visceral disease, number of metastasis, biopsy type, and age were evaluated. A progression-free survival (PFS) Cox model was evaluated. The final model (PAM50MET) with a prespecified cutoff was validated in patients (n = 261) with HR+/HER2− advanced breast cancer (aBC) from BOLERO-2 (phase III trial that evaluated exemestane and placebo or everolimus). Results: In EGF30008, prognostic models with PAM50 plus clinical variables yielded higher C-index values versus models with only PAM50 or clinical variables. The PAM50MET model combined 21 variables: 2 PAM50 subtypes, basal signature, 14 genes, and 4 clinical variables. In EGF30008, the optimized cutoff was associated with PFS [HR = 0.37; 95% confidence interval (CI), 0.29–0.47; P < 0.0001] and overall survival (OS; HR = 0.37; 95% CI, 0.27–0.51; P < 0.0001). The median (months; 95% CI) PFS and OS were 22.24 (19.0–24.9) and not reached in PAM50MET-low versus 9.13 (8.15–11.0) and 33.0 (28.0–40.0) in PAM50MET-high groups, respectively. In BOLERO-2, the PAM50MET-low was associated with better PFS (HR = 0.72; 95% CI, 0.53–0.96; P = 0.028) and OS (HR = 0.51; 95% CI, 0.35–0.69; P < 0.0001). The median (months) (95% CI) PFS and OS were 6.93 (5.57–11.0) and 36.9 (33.4–NA) in PAM50MET-low versus 5.23 (4.2–6.8) and 23.5 (20.2–28.3) in PAM50MET-high groups, respectively. Conclusions: PAM50MET is prognostic in HR+/HER2− MBC, and further evaluation might help identify candidates for endocrine therapy only or novel therapies.