Receptor 2-negative Metastatic Breast Cancer Research Articles

Sacituzumab Govitecan in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer.

Hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) endocrine-resistant metastatic breast cancer is treated with sequential single-agent chemotherapy with poor outcomes. Sacituzumab govitecan (SG) is a first-in-class antibody-drug conjugate with an SN-38 payload targeting trophoblast cell-surface antigen 2, an epithelial antigen expressed in breast cancer. In this global, randomized, phase III study, SG was compared with physician's choice chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine) in endocrine-resistant, chemotherapy-treated HR+/HER2- locally recurrent inoperable or metastatic breast cancer. The primary end point was progression-free survival (PFS) by blinded independent central review. Patients were randomly assigned to receive SG (n = 272) or chemotherapy (n = 271). The median age was 56 years, 95% had visceral metastases, and 99% had a prior cyclin-dependent kinase 4/6 inhibitor, with three median lines of chemotherapy for advanced disease. Primary end point was met with a 34% reduction in risk of progression or death (hazard ratio, 0.66 [95% CI, 0.53 to 0.83; P = .0003]). The median PFS was 5.5 months (95% CI, 4.2 to 7.0) with SG and 4.0 months (95% CI, 3.1 to 4.4) with chemotherapy; the PFS at 6 and 12 months was 46% (95% CI, 39 to 53) v 30% (95% CI, 24 to 37) and 21% (95% CI, 15 to 28) v 7% (95% CI, 3 to 14), respectively. Median overall survival (first planned interim analysis) was not yet mature (hazard ratio, 0.84; P = .14). Key grade ≥ 3 treatment-related adverse events (SG v chemotherapy) were neutropenia (51% v 38%) and diarrhea (9% v 1%). SG demonstrated statistically significant PFS benefit over chemotherapy, with a manageable safety profile in patients with heavily pretreated, endocrine-resistant HR+/HER2- advanced breast cancer and limited treatment options.

Prospective Cohort Study of Combination Therapy With Abemaciclib and Hormonal Therapy for Chemotherapy-Treated Patients With Hormone Receptor-Positive Metastatic Breast Cancer.

BackgroundCombination therapy with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors and hormonal therapy as the first-line and second-line treatments has already been shown to be effective in patients with hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) in clinical trials. On the other hand, in clinical practice, CDK4/6 inhibitors are used not only as first-/second-line but also as later-line hormonal therapies, or for patients receiving prior chemotherapy in metastatic setting. However, the efficacy and safety of combination therapy in these patients remain unclear. In this study, we evaluate the clinical efficacy and safety of combination therapy with abemaciclib and hormonal therapy for chemotherapy-treated patients with HR+ HER2- MBC.MethodsThis multi-institutional prospective cohort study will involve a total of 300 chemotherapy-treated patients with HR+ HER2- MBC. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival, time to treatment failure, response rate, clinical benefit rate, and adverse events. The preplanned subpopulation analysis is the number of chemotherapy regimens for HR+ HER2- MBC (two or less vs. three or more), prior treatment history with CDK4/6 inhibitors other than abemaciclib (presence vs. absence) and menopausal status (pre vs. post). We also planned to determine PFS of the subpopulation treated with abemaciclib as maintenance therapy after chemotherapy.DiscussionIn this multi-institutional prospective cohort study, we evaluate the clinical efficacy and safety of combination therapy with abemaciclib and hormonal therapy for chemotherapy-treated patients with HR+ HER2- MBC. We also evaluate this combination therapy as maintenance therapy in patients who respond to early-line chemotherapy.

Prospective Cohort Study of Palbociclib Treatment in Postmenopausal Patients With Unresectable and Metastatic Hormone Receptor-Positive Breast Cancer: Study Protocol for a CSPOR-BC Palbociclib Cohort Trial.

BackgroundCombining palbociclib with letrozole or fulvestrant improved progression-free survival in hormone receptor (HR)-positive and human epidermal growth factor receptor-negative metastatic breast cancer. However, combining palbociclib to endocrine treatment increases toxicity and cost compared with the endocrine treatment alone. Moreover, palbociclib treatment may affect the outcome of the subsequent treatment because its benefit in terms of overall survival has not been observed yet. Therefore, it is crucial to examine whether palbociclib can improve clinical outcomes and quality of life (QoL) of patients in the real world.MethodsA prospective observational study with palbociclib is planned in 3 cohorts (A, B, and C) as per the line of endocrine treatment (i.e., first-line, second-line, or third-line or later-line treatment) for postmenopausal metastatic or unresectable breast cancer. The primary endpoint is progression-free survival in each treatment line, the most commonly used endpoint for global phase 3 studies. As per the results of these studies, the planned sample size is 700 cases: cohort A, 340 cases; cohort B, 200 cases; and cohort C, 130 cases. The secondary endpoints are overall survival, clinical benefit rate, time to chemotherapy, adverse events (AEs), patient-reported outcomes (PROs), and health-related QoL (HRQoL). These endpoints are evaluated again during the subsequent treatment. This study will examine whether the efficacy, safety, and QoL effects of palbociclib treatment in daily clinical practice are not inferior compared to those in clinical trials and whether palbociclib treatment affects the efficacy and safety of the subsequent treatment. Moreover, this study would provide information on the most effective time of adding palbociclib to endocrine treatment.DiscussionThe reproducibility of randomized clinical trials (RCTs) using real-world data must be confirmed to evaluate whether real-world treatment benefits are similar to those observed in RCTs. Although the efficacy of palbociclib has been confirmed in RCTs, Aes of this drug, including its toxicities and cost, are not comparable to those of mono-hormone therapies. Thus, PROs/HRQoL is an important element of this study because several patients with HR-positive metastatic breast cancer have diseases for which sequential hormone therapy is preferential.

NextMONARCH Phase 2 randomized clinical trial: overall survival analysis of abemaciclib monotherapy or in combination with tamoxifen in patients with endocrine-refractory HR + , HER2– metastatic breast cancer

PurposeResistance to endocrine therapy poses a major clinical challenge for patients with hormone receptor-positive (HR +), human epidermal growth factor receptor 2-negative (HER2–) metastatic breast cancer (MBC). We present the preplanned 24-month final overall survival (OS) results, alongside updated progression-free survival (PFS), and objective response rate (ORR) results.MethodsnextMONARCH is an open-label, controlled, randomized, Phase 2 study of abemaciclib alone or in combination with tamoxifen in women with endocrine-refractory HR + , HER2– MBC previously treated with chemotherapy. Patients were randomized 1:1:1 to: abemaciclib 150 mg and tamoxifen 20 mg (A + T), abemaciclib 150 mg (A-150), or abemaciclib 200 mg and prophylactic loperamide (A-200). OS was the main prespecified secondary endpoint. PFS, ORR, and safety at 24 months were compared to previously reported primary analysis results.ResultsOf the 234 patients enrolled, 12 were receiving study treatment at data cutoff (28Jun2019). Median follow-up was 27.2 months. Median OS was 24.2 months in the A + T arm, 20.8 months in A-150, and 17.0 months in A-200 (A + T versus A-200: HR 0.62; 95%CI [0.40, 0.97], P = 0.03 and A-150 versus A-200: HR 0.96; 95%CI [0.64, 1.44], P = 0.83). PFS and ORR results at 24 months were consistent with the primary analysis. The safety profile corresponded with previous reports.ConclusionThe addition of tamoxifen to abemaciclib demonstrated greater OS benefit than monotherapy. This study confirmed the single-agent activity of abemaciclib in heavily pretreated women with endocrine-refractory HR + , HER2– MBC, as well as the previously reported primary PFS and ORR results, with no new safety signals observed.Trial Registration ClinicalTrials.gov Identifier: NCT02747004.

Safety and efficacy of nivolumab plus bevacizumab, paclitaxel for HER2-negative metastatic breast cancer: Primary results and biomarker data from a phase 2 trial (WJOG9917B)

BackgroundPreclinical models revealed potential synergistic effects of programmed cell death-1 inhibitors and anti-vascular endothelial growth factor (VEGF) antibodies. Therefore, we investigated the use of nivolumab, bevacizumab, and paclitaxel triple therapy for metastatic breast cancer. MethodsThis phase 2, multicentre, single-arm study (NEWBEAT) investigated the safety and efficacy of first-line nivolumab, paclitaxel, and bevacizumab in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer, regardless of programmed cell death-ligand 1 expression. The primary end-point was objective response rate. Key secondary end-points included progression-free survival, overall survival, and toxicities. A biomarker study evaluated tumour programmed cell death-ligand 1 expression and serum VEGF-A levels. ResultsBetween February 2018 and October 2018, 57 patients were enrolled. An objective response rate was seen in 39/56 patients (70%, 95% confidence interval [CI]: 55.9–81.2%), meeting the primary end-point. The objective response rate was 74% in patients with hormone receptor-positive breast cancer versus 59% in patients with triple-negative breast cancer. The median progression-free survival and overall survival were 14.0 (95% CI 11.0–16.3) and 32.5 (95% CI 26.0–not evaluable) months, respectively (median follow-up: 29.5 months). Grade 3/4 adverse drug reactions occurred in 33 of 57 patients (58%). There were no grade 5 adverse events. Immune-related adverse events occurred in 43 of 57 patients (75%), with grade 3/4 events in eight patients (14%). Biomarker analysis showed that tumour programmed cell death-ligand 1 expression was not correlated with the efficacy of triple therapy. Efficacy outcomes were similar between the serum VEGF-high and VEGF-low groups. ConclusionsFirst-line nivolumab, bevacizumab, and paclitaxel therapy showed promising efficacy and manageable toxicity in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer.

Abstract 4089: Time to treatment discontinuation and time to next treatment as proxies of real-world progression-free survival in breast cancer patients

Abstract Background: There is no standardized real-world proxy for progression-free survival (PFS), although it is a key treatment response metric in clinical trials. Real-world PFS (rwPFS) has been curated from clinician-documented progression in unstructured electronic health records (EHRs), a time and resource intensive approach, that is not readily accessible in claims or structured EHRs. Alternatively, time to treatment discontinuation (rwTTD) and time to next treatment (rwTTNT) are used as treatment-based scalable proxies of disease progression. We compared clinician-documented rwPFS to rwTTD and rwTTNT. Methods: The study included patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer (A/MBC) who initiated first line treatment with palbociclib plus an aromatase inhibitor (1L) between 2015 and 2019 in US community health systems. Demographics, clinical characteristics, and outcomes were extracted from EHRs. rwPFS was captured through EHR-documented confirmation by two clinicians of disease progression based on imaging and/or pathology results. rwPFS, rwTTD and rwTTNT were defined as the time from 1L initiation until the date of clinician-confirmed progression, 1L discontinuation, or 2L initiation, respectively. Patients were censored at the first of: (1) death, (2) date of last contact, (3) study end date, (4) or at 2L for rwPFS. Results: The study included 241 patients with median age 66 at A/MBC diagnosis, among whom 85% were postmenopausal and 57% were de novo A/MBC. During study follow-up (median 22.4 months), 86 (36%) patients had a clinician-confirmed progression (rwPFS events); 130 (54%) discontinued 1L (rwTTD events), and 96 (40%) initiated 2L (rwTTNT events). With clinician-confirmed progression as the “gold standard”, rwTTD had higher sensitivity (90% vs 71%) but lower specificity (66% vs 77%) than rwTTNT. Patient’s choice, hospice referral, and toxicity were common reasons for treatment discontinuation apart from disease progression. The 12, 24, and 48-month survival estimates were closer between rwPFS (0.78, 0.64, 0.51) and rwTTNT (0.80, 0.63, 0.47), than rwTTD (0.69, 0.51, 0.37). Median rwPFS (39 months, 95% confidence interval [95% CI]: 30-NA) and rwTTNT (32 months, 95% CI: 29-46) were also more alike (log-rank p = 0.90) than median rwPFS and rwTTD (24 months, 95% CI: 18-30; log-rank p=0.02). The correlation between rwPFS and rwTTNT was 0.72 (95% CI: 0.56-0.83), compared to 0.73 (95% CI: 0.57-0.84) between rwPFS and rwTTD. Results were similar in sensitivity analyses where death was part of rwPFS, rwTTNT, and rwTTD events rather than a censoring event. Conclusions: Our results suggest that rwTTNT may be a more adequate at-scale proxy for rwPFS than rwTTD. Studies should assess the generalizability of these findings to other tumor types and treatment settings. Citation Format: Monika A. Izano, Mahder Teka, Colden Johanson, Jeanna Wallenta Law, Ronda Broome, Daniele Morgan, Amy Stone, Mary Tran, Thomas D. Brown, Chenan Zhang. Time to treatment discontinuation and time to next treatment as proxies of real-world progression-free survival in breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4089.

Adjuvant study of amcenestrant (SAR439859) versus tamoxifen for patients with hormone receptor-positive (HR+) early breast cancer (EBC), who have discontinued adjuvant aromatase inhibitor therapy due to treatment-related toxicity (AMEERA-6).

TPS607 Background: There are currently limited treatment options for patients with HR+ EBC who have discontinued adjuvant treatment with aromatase inhibitors (AIs) due to treatment-related toxicity. Amcenestrant is an optimized oral selective estrogen receptor degrader (SERD) with potent dual activity which antagonizes and degrades the ER resulting in inhibition of the ER signalling pathway. Preliminary clinical evidence from the phase 1/2 AMEERA-1 trial has demonstrated meaningful antitumour activity and a favourable safety profile of amcenestrant in the treatment of HR+ advanced breast cancer (Linden HM, Campone M, Bardia A, et al: Abstract PD8-08: A phase 1/2 study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), as monotherapy and in combination with other anti-cancer therapies in postmenopausal women with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC): AMEERA-1. SABCS 2020 PD8-08). Methods: AMEERA-6 is a prospective, randomized, international, double-blind, double-dummy, phase 3 study. 3738 patients will be randomized 1:1 to receive either amcenestrant 200 mg daily or tamoxifen 20 mg daily. Eligible patients are pre-or postmenopausal women or men with HR+ EBC (stage IIB-III) who have received at least 6 months of adjuvant AIs (at least 3 months in the adjuvant setting if they have received prior neoadjuvant AI therapy) and discontinued them within 30 months of initiation due to treatment-related toxicity. Participants will be centrally assessed to have ER+ and/or PgR+ (≥10% positive stained cells) status by immunohistochemistry assay. Prior use of adjuvant CDK4/6 inhibitors are allowed. Patients are eligible irrespective of HER2 status; for patients with HER2-positive disease adjuvant anti-HER2 treatment and chemotherapy must be completed prior to randomization. Stratification factors include: duration of AI therapy, HER2 status, prior chemotherapy, prior CDK4/6 inhibitors, geographic region, and menopausal status. Planned treatment duration is 5 years. Patients will be followed-up for 10 years from randomization. The primary endpoint is invasive breast cancer-free survival (IBCFS). Invasive disease-free survival is a key secondary endpoint, while other secondary endpoints include distant relapse-free survival (RFS), locoregional RFS, overall survival, breast-cancer specific survival, safety, patient reported outcomes and pharmacokinetics. Adherence to treatment is an exploratory endpoint. AMEERA-6 opened for recruitment in January 2022. Clinical trial information: NCT05128773.

Phase Ib/II study of BCL-2 inhibitor lisaftoclax (APG-2575) safety and tolerability when administered alone or combined with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor in patients with estrogen receptor-positive (ER+) breast cancer or advanced solid tumors.

TPS1122 Background: Various cancers evade apoptosis by overexpressing BCL-2 proteins. Investigational agent lisaftoclax (APG-2575) is a novel, potent, selective BCL-2 inhibitor, while palbociclib inhibits cyclin-dependent kinases (CDK) 4 and 6. In preclinical studies, palbociclib decreased proliferation of ER+ breast cancer cell lines by arresting them in the G1 cycle phase. Preclinical data demonstrate favorable, complementary effects of palbociclib when combined with a BCL-2 inhibitor and support this combination in patients with ER+/ human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer. Methods: This global multicenter open-label dose escalation and dose expansion study is assessing the safety of lisaftoclax monotherapy in patients with histologically or cytologically confirmed advanced solid tumors that have progressed on standard therapy or when combined with CDK4/6 inhibitor palbociclib in physiologically postmenopausal women with ER+/ HER2- metastatic breast cancer that has progressed or relapsed after treatment with a CDK4/6 inhibitor. This trial consists of 2 parts: a phase Ib dose escalation phase using a standard 3+3 design to determine the maximum tolerated dose (MTD) of lisaftoclax as a single agent in patients with solid tumors, as well as both the MTD and recommended phase 2 (RP2D) dose of lisaftoclax when combined with palbociclib in women with ER+/ HER2- metastatic breast cancer. Phase II of this study is a signal-seeking expansion of lisaftoclax at RP2D when combined with palbociclib in women with ER+/HER2- metastatic breast cancer. This phase is being conducted using Simon’s Minimax two-stage design. The primary objective for phase II is to determine clinical benefit response, and secondary efficacy endpoints include overall response rate, duration of response, time to response, and progression-free survival. Lisaftoclax is being administered orally once daily in a 28-day cycle at the assigned dose. Clinical trial information: NCT04946864.

Phase I study combining pembrolizumab and aromatase inhibitor in patients with metastatic hormone receptor–positive breast cancer.

1053 Background: Aromatase inhibitor (AI) is standard of care for patients with hormone receptor positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). The current phase I trial was designed to test the safety and efficacy of AI and the immune checkpoint inhibitor pembrolizumab (NCT 02648477). Methods: Key eligibility criteria were HR+ HER2- MBC per ASCO/CAP; RECIST 1.1 measurable disease; adequate organ function; and ECOG 0-1. Eligible patients received 200 mg pembrolizumab IV every 3 weeks plus AI until progression or unacceptable toxicity. Primary objectives were to evaluate the safety and efficacy of this combination. This study employed a 3-at-risk design with a lead-in at the standard dosing of both AI and pembrolizumab with a targeted accrual of 20 patients. Results: A total of 20 patients were accrued between March 2016 and April 2017. Median age was 62 (range 34-79), with 75% white, 15% Asian and 10% unknown. Median lines of therapy were 3 (0, 9). All but one patient received aromatase inhibitor and/or fulvestrant prior to enrollment. The combination was well tolerated, and the most common adverse events were grade 2 fatigue (35%), rash (15%), and hot flashes (10%). Grade 3 adverse events were elevated AST/ALT (5%), rash (5%), and lymphopenia (5%). Responses were 10% partial response and 15% stable disease, resulting in a clinical benefit rate (CBR) of 20% at 6 months. Median follow-up time was 40.1 months (range 31.3 – 46.8 months). Median progression free survival was 1.8 months (95% CI 1.6, 2.6) and median overall survival was 17.2 months (95% CI 9.4, NA). 14 tumor specimens had programmed death ligand 1–positive (PD-L1) by 22C3 testing, including 3 PD-L1-positive and 11 PD-L1 negative. No association between PD-L1 and response was found. Conclusions: The combination of pembrolizumab and AI is well tolerated in patients with HR+ HER2- MBC who were not pre-selected for PD-L1. There was minimal overall clinical activity observed beyond what was to be expected with AI alone in this group of patients. Clinical trial information: NCT 02648477.

Real world incidence and management of adverse events in patients with HR+, HER2− metastatic breast cancer receiving CDK4 and 6 inhibitors in a United States community setting

Objective To examine the real-world incidence and management of select adverse events (AEs) among female patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC), receiving a cyclin-dependent kinase 4 and 6 (CDK4 and 6) inhibitor (palbociclib, abemaciclib, or ribociclib). Methods This retrospective study analyzed data from the US Oncology Network iKnowMed electronic health record database for 396 patients with an initial MBC diagnosis on/after 1 January 2014 and receipt of first CDK4 and 6 regimen between 1 January 2017 and 31 December 2018. In this descriptive study, the proportion of patients who experienced select AEs and associated dose modifications or discontinuations were reported. The occurrence of select healthcare resource utilization categories was also reported. Results Median follow-up time was 451, 262, and 355 days for patients in the palbociclib, abemaciclib, and ribociclib cohorts, respectively. The most common AEs were neutropenia (palbociclib, 44.8%; abemaciclib, 10.6%; ribociclib, 36.3%), diarrhea (palbociclib, 8.0%; abemaciclib, 43.0%; ribociclib, 8.8%), and fatigue (palbociclib, 12.9%; abemaciclib, 17.6%; ribociclib, 16.5%). AEs resulted in a treatment hold among 91 (23.0%), a dose reduction among 86 (21.7%), and permanent discontinuation among 48 (12.1%) patients overall. Conclusions This real-world study provides insight into the occurrence of AEs which varied by CDK4 and 6 inhibitor. Compared to clinical trials, frequencies of AEs were numerically lower but dose reductions due to AEs were numerically higher. It is possible these differences reflect proactive management of AEs on the part of clinicians to help patients remain on therapy.

Cost Effectiveness of Ribociclib and Palbociclib in the Second-Line Treatment of Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer in Post-Menopausal Indian Women

In this study, we evaluate the cost and outcomes of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) plus fulvestrant, fulvestrant alone, and conventional chemotherapy as the second-line therapy for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) in India. Using a Markov model, the clinical effectiveness of managing HR+, HER2- MBC in postmenopausal women with either aCDK4/6i (either ribociclib or palbociclib) and fulvestrant, fulvestrantalone, and chemotherapy (single-agent paclitaxel or capecitabine) was measured in terms of quality-adjusted life-years (QALYs). The costs were estimated from two different points of view: scenario I, as per the prevailing market prices of the drugs; and scenario II, as per the reimbursement rates set up by the publicly financed national health insurance scheme. Incremental cost per QALY gained with a given treatment option was compared against the next best alternative and was assessed for cost effectiveness using a threshold of 1-time the per capita gross domestic product (GDP) in India from a societal perspective. In scenario I, an MBC patient was found to incur a lifetime cost of Indian Rupees (₹)2.54 million ($34,644), ₹2.53 million ($34,496), ₹512,598 ($6,984), ₹326,026 ($4,442) and ₹237,115 ($3,230) for the ribociclib and palbociclib combination arms, fulvestrant monotherapy, single-agent paclitaxel and the single-agent capecitabine treatment arms, respectively. The lifetime cost for CDK4/6i (ribociclib and palbociclib) combination therapy, fulvestrant monotherapy, paclitaxel, and capecitabine arms was estimated to be ₹1.94 million ($26,459), ₹1.92 million ($26,220), ₹315,387 ($4,296), ₹187,392 ($2,553) and ₹153,263 ($2,088), respectively, in scenario II. The mean QALYs lived per MBC patient with CDK4/6i (either ribociclib or palbociclib) combination therapy, fulvestrant, paclitaxel and capecitabine were estimated to be 1.4, 1.0, 0.9 and 0.7, respectively. None of the treatment arms are cost effective at current prices and reimbursement rates at a threshold of 1-time the per capita GDP of India. However, a 78% reduction in the current market price or a 72% reduction in the reimbursement rate of fulvestrant in the government-funded insurance program will make it a cost-effective treatment option for HR+, HER2- MBC patients in India. CDK4/6i (ribociclib and palbociclib) therapyis not a cost-effective treatment option for MBC patients. A 72% reduction in the reimbursement rate for fulvestrant monotherapy will make it a cost-effective treatment option in the Indian context.

Role of CDK4/6 inhibitors in patients with hormone receptor (HR)-positive, human epidermal receptor-2 negative (HER-2) metastatic breast cancer study protocol for a systematic review, network meta-analysis and cost-effectiveness analysis

IntroductionIt is currently unclear which cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, combined with endocrine therapy, is the preferred treatment approach in patients with hormone receptor (HR)-positive, human epidermal receptor-2 (HER2) negative...

182P Radium-223 (223Ra) in combination with exemestane and everolimus (EXE-EVE) in patients (pts) with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (MBC) with bone metastases: A phase II study

223Ra extends overall survival (OS) in pts with bone-metastatic castration-resistant prostate cancer. This study evaluated if the addition of 223Ra to EXE-EVE provided increased benefit over EXE-EVE in pts with bone dominant HR+/HER2- MBC.

Overall survival with palbociclib plus endocrine therapy versus capecitabine in postmenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer in the PEARL study

BackgroundAn earlier analysis of the PEARL phase III study showed that palbociclib plus endocrine therapy (ET) does not improve progression-free survival (PFS) over capecitabine in aromatase inhibitor-resistant, hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer (MBC) patients. Here, we report the final overall survival (OS) analysis. MethodsPostmenopausal patients (N = 601) were randomized 1:1 to capecitabine or palbociclib plus ET (exemestane, Cohort 1; fulvestrant, Cohort 2). OS was analysed in Cohort 2, the wild-type ESR1 population and the overall population. Additionally, we analysed subsequent systemic therapies and explored PFS2 (time from randomization to the end of the first subsequent therapy/death). ResultsOS was 31.1 months for palbociclib plus fulvestrant and 32.8 months for capecitabine (adjusted hazard ratio [aHR] 1.10, 95% confidence interval [CI] 0.81–1.50, P = 0.550). In the wild-type ESR1 population, OS was 37.2 months for palbociclib plus ET and 34.8 months for capecitabine (aHR 1.06, 95% CI 0.81–1.37, P = 0.683). In OS analyses, no subgroup showed superiority for palbociclib plus ET over capecitabine. OS in the overall population was 32.6 months for palbociclib plus ET and 30.9 months for capecitabine (P = 0.995). Subsequent systemic therapy was given to 79.8% and 82.9% of patients with palbociclib plus ET and capecitabine, respectively. Median PFS2 was similar between study arms (Cohort 2, P = 0.941; wild-type ESR1 population, P = 0.827). No new safety findings were observed. ConclusionsPalbociclib plus ET did not show a statistically superior OS compared to capecitabine in MBC patients progressing on aromatase inhibitors. Trial registrationNCT02028507 (ClinTrials.gov), 2013-003170-27 (EudraCT).

Cyclin-dependent kinase 4 and 6 inhibitors in combination with neoadjuvant endocrine therapy in estrogen receptor-positive early breast cancer: a systematic review and meta-analysis.

The combination of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors and endocrine treatment has benefited patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER + /HER2-) metastatic breast cancer; however, its effects in the neoadjuvant setting for ER + /HER2- early breast cancer (EBC) are unclear. Systematic searches were performed in PubMed, Embase, Cochrane Library, and major oncological meetings for trials of CDK4/6 inhibitors plus neoadjuvant endocrine treatment (NET) vs. NET/neoadjuvant chemotherapy (NACT) alone up to January 30, 2021. We assessed the efficacy of CDK4/6 inhibitors plus NET vs. NET/NACT alone in ER + /HER2- EBC. Six studies that included 803 patients treated with CDK4/6 inhibitors plus NET vs. NET/NACT alone were used. Compared with NET/NACT alone, CDK4/6 inhibitors plus NET increased the complete cell cycle arrest (CCCA) rate (OR, 9.00; 95% CI, 5.42-14.96; P < 0.001). Nonsignificant differences between CDK4/6 inhibitors and NET/NACT alone occurred in the preoperative endocrine prognostic index (PEPI)-0 rate (OR, 1.13; 95% CI, 0.59-2.18; P = 0.71), pathological complete response (pCR) rate (OR, 0.75; 95% CI, 0.13-4.29; P = 0.74), objective response rate (ORR) (OR, 0.70; 95% CI, 0.21-2.29; P = 0.55), and disease control rate (DCR) (OR, 1.16; 95% CI, 0.47-2.89; P = 0.74). CDK4/6 inhibitors plus NET indicated a high risk of neutropenia (OR, 56.43; 95% CI, 15.76-202.11; P < 0.001) as an adverse effect (AE) and elevated alanine aminotransferase (ALT) level (OR, 15.30; 95% CI, 2.02-115.98; P = 0.008) as grade 3/4 AEs. Compared with NET/NACT alone, CDK4/6 inhibitors plus NET increased CCCA rate in ER + /HER2- EBC patients. CDK4/6 inhibitors plus NET did not substantially improve the PEPI-0 rate, pCR rate, ORR, or DCR. The combination increased the risk of neutropenia and elevated ALT levels. In the neoadjuvant setting, addition of CDK4/6 inhibitors to NET may be an option for treating ER + /HER2- EBC.

Serial circulating tumor DNA monitoring of CDK4/6 inhibitors response in metastatic breast cancer.

Cyclin‐dependent kinase 4/6 inhibitors (CDK4/6i) significantly improve progression‐free survival and have become the standard therapy for estrogen receptor‐positive/human epidermal growth factor receptor 2‐negative metastatic breast cancer patients. Treatment surveillance by radiological imaging has some limitations in detection and repeated biopsy genomic profiling is not clinically feasible. Serial circulating tumor DNA (ctDNA) analysis may provide insights into treatment response. Here we performed serial ctDNA analysis (n = 178) on 33 patients. Serial ctDNA analysis identified disease progression with sensitivity of 75% and specificity of 92%. In eight of 12 patients (61%) responding to CDK4/6i who eventually developed progressive disease, serial sampling every 3 or 6 months captured the initial rise of ctDNA with an average lead time of 3 months. In three of eight patients that did not respond to CDK4/6i (progressive disease at first radiological assessment, 3 months), biweekly sequencing within the first cycle of CDK4/6i treatment (1 month) detected sustained ctDNA levels (≥0.2% variant allele frequency), with lead time of 2 months. Serial ctDNA analysis tracked RECIST response, including clinically challenging scenarios (bone metastases or small‐sized target lesions), as well as detecting acquired genetic alterations linked to CDK4/6i resistance in the G1 to S transition phase. Circulating tumor DNA analysis was more sensitive than carcinoembryonic antigen or cancer antigen 15‐3 serum tumor markers at monitoring tumor response to CDK4/6i treatment. Our findings indicated the possible clinical utility of serial ctDNA analysis for earlier progressive disease detection and real‐time monitoring of CDK4/6i response.

The Resistance of Cancer Cells to Palbociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, is Mediated by the ABCB1 Transporter

Palbociclib was approved by the United States Food and Drug Administration for use, in combination with letrozole, as a first-line treatment for estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) postmenopausal metastatic breast cancer. However, recent studies show that palbociclib may be an inhibitor of the ABCB1 transporter, although this remains to be elucidated. Therefore, we conducted experiments to determine the interaction of palbociclib with the ABCB1 transporter. Our in vitro results indicated that the efficacy of palbociclib was significantly decreased in the ABCB1-overexpressing cell lines. Furthermore, the resistance of ABCB1-overexpressing cells to palbociclib was reversed by 3 μM of the ABCB1 inhibitor, verapamil. Moreover, the incubation of ABCB1-overexpressing KB-C2 and SW620/Ad300 cells with up to 5 μM of palbociclib for 72 h, significantly upregulated the protein expression of ABCB1. The incubation with 3 µM of palbociclib for 2h significantly increased the intracellular accumulation of [3H]-paclitaxel, a substrate of ABCB1, in ABCB1 overexpressing KB-C2 cells but not in the corresponding non-resistant parental KB-3-1 cell line. However, the incubation of KB-C2 cells with 3 μM of palbociclib for 72 h decreased the intracellular accumulation of [3H]-paclitaxel due to an increase in the expression of the ABCB1 protein. Palbociclib produced a concentration-dependent increase in the basal ATPase activity of the ABCB1 transporter (EC50 = 4.73 μM). Molecular docking data indicated that palbociclib had a high binding affinity for the ABCB1 transporter at the substrate binding site, suggesting that palbociclib may compete with other ABCB1 substrates for the substrate binding site of the ABCB1. Overall, our results indicate that palbociclib is a substrate for the ABCB1 transporter and that its in vitro anticancer efficacy is significantly decreased in cancer cells overexpressing the ABCB1.

Efficacy and safety of palbociclib plus endocrine therapy for patients with HR+/HER2- advanced breast cancer in real-world clinical practice.

BackgroundPalbociclib is the first cyclin dependent kinase 4/6 (CDK4/6) inhibitor approved in China to be combined with endocrine therapy (ET) for patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer. However, palbociclib has only been used in China for a short amount of time, and there is limited data on its real-world applications. This study observed the efficacy and safety of palbociclib plus ET in a real-world setting in southwest China and we hope to provide some references for the treatment of patients with breast cancer in China.MethodsThis was an observational study of patients with HR+/HER2− advanced breast cancer (ABC) who received palbociclib plus ET. The primary endpoint of the study was progression-free survival (PFS) and the 6- and 12-month progression-free rates. The secondary endpoint included the objective response rate (ORR) and the clinical benefit rate (CBR).ResultsA total of 64 patients were enrolled in this study, and 54.7% of them received palbociclib plus ET as the first-line treatment for ABC. The median PFS was 21.6 months (95% CI: 11.2–32.0 months) after a median follow-up period of 13.8 months (95% CI: 11.9–15.7 months). The 6-month progression-free rate was 75.4%, and 48.9% of patients remained progression-free at 12 months. Overall, the ORR was 21.6% and the CBR was 76.5%. Patients with the molecular typing of Luminal A (P=0.035), a lower Ki67 level (P<0.001), sensitivity or acquired resistance to ET (P=0.003), less than 3 visceral metastases lesions (P=0.001), and those who received palbociclib plus ET as first-line or second-line of treatment for ABC (P=0.001) showed longer PFS. A total of 53.1% of patients had grade 3–4 adverse events (AEs), but only 4.7% of patients experienced permanent discontinuation of treatment due to intolerable AEs.ConclusionsThe efficacy of palbociclib plus ET is worthy of recognition and the toxicity was acceptable in this study, which is similar to previously reported data from randomized clinical trials and other real-world evidence. Treatment for ABC using palbociclib plus ET should be recommended more widely in China due to the efficacy and safety.

Abstract P5-13-16: A real-world assessment of PIK3CA testing and alpelisib treatment patterns among metastatic breast cancer patients in a community oncology setting

Abstract Background: Alpelisib (PIQRAY®) in combination with fulvestrant was approved by the US- FDA in May of 2019 for patients with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) PIK3CA mutant advanced or metastatic breast cancer (aBC or mBC) following progression on aromatase inhibitors. Prior to the US-FDA approval of alpelisib, routine molecular profile testing for this patient population was not supported by NCCN guidelines. Thus, data on the natural history of HR+/HER2- mBC patients, particularly in terms of biomarker testing and treatment patterns in a real-world patient setting, are limited. To understand integration of alpelisib into clinical practice for this patient population, this retrospective non-interventional study assessed biomarker testing, treatment patterns, and patient characteristics for patients at Texas Oncology (TxO) from 2015 to 2020.Methods: The study index date was defined as the first date of a new diagnosis of advanced BC (de novo or recurred mBC) between January 2015 and June 2020 with a minimum follow-up opportunity of 6 months follow-up. Treatment patterns were assessed until December 2020, allowing assessment of alpelisib real-world utilization post the US-FDA approval. Databases curated included the EMR (iKM), the TxO Precision Medicine (PM) Molecular databases. Information mined included total number of mBC patients, HR and HER2 status, and the presence and classification of PIK3CA mutations. Treatment patterns were also examined. Results: Study cohort consisted of 1093 patients for whom PIK3CA, HR, HER2 status and systemic treatment were known. Of these, 768 (70%) were HR+/HER2-, 220 (20%) were HR-/Her2HER2-, 73 (7%) were HR+/Her2HER2+ and 32 (3%) were HR-/Her2HER2+. Among all subtypes, 410 (38%) were PIK3CA mutant, and within HR+/HER2- cohort, 333 (43%) were PIK3CA mutant. Of the 105 patients treated with alpelisib, 102 (97%) were treated after drug approval, and the remaining 3 patients (3%) received alpelisib via compassionate use program. Within the HR+/HER2-/PIK3CA mutant patient cohort (n=333), 97 (29%) were treated with alpelisib. The most frequent alpelisib-containing regimen is alpelisib+fulvestrant, given to 84 (87%) of patients. It is most frequently given as a second- (n=28, 29%), third- (n=16, 16%) and fourth-line (n=16, 16%) lines of therapy. Out of 97 patients, 69 (71%) were treated previously with a cyclin-dependent kinase 4/6 inhibitor. The median duration of alpelisib therapy was 4.6 months. As of December 30, 2020, 34 of the 97 patients had treatment with alpelisib ongoing, 24 expired, 14 were referred to hospice,18 completed last recorded line of therapy prior to study end date, and 7 patients progressed to the next line of therapy. There was no noteworthy difference in patients treated vs. not treated with alpelisib with respect to age (mean 61.5 vs. 59.3 yrs.) or performance status (Karnofsky) (29% vs. 25% at 100%, 42% vs. 49% at 90% respectively). In PIK3CA mutant cancers, the most frequent PIK3CA mutations were H1047R, E545K, E542K, N345K and H1047L, and 43 (10%) had 2 or more mutations. Patient outcomes including the median progression free survival was also determined for this cohort and will be reported. Conclusions: This retrospective study demonstrates that 38% of mBC patients’ cancers across all sub-types harbored a PIK3CA mutation where multiple testing platforms were utilized in the community setting. Approximately 30% of patients with HR+/HER2-/PIK3CA mutant status did receive alpelisib. Co-morbidities and other clinically relevant factors between PIK3CA mutant patients who did and did not receive alpelisib, such as those on oral diabetes medication, insulin or had elevated HgbA1c, should be studied further. Citation Format: Joyce O'Shaughnessy, MD, Steven Paulson, MD, Lorraine Brisbin, M.S, James Lindsey, Anna Williford, Ph.D, Monica Lisi, Rohan C. Parikh, Ph.D, Stacey Simmons, MD and Sanjeev Balu, Ph.D. A real-world assessment of PIK3CA testing and alpelisib treatment patterns among metastatic breast cancer patients in a community oncology setting [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-16.

Abstract P1-16-06: In real world, a high percentage of premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer receive chemotherapy as first-line treatment: A study of the National Cancer Center, China

Abstract Background: In this study, we aimed to observe initial palliative treatment choices and clinical outcomes for premenopausal hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer patients (MBC) in the Chinese population in real life.Methods: The China National Cancer Center database was used to identify 2194 MBC patients diagnosed between 2004 to 2015. Premenopausal patients with HR+ HER2- MBC were included. Clinicopathological features, initial palliative treatment choices and survival information were extracted. First-line progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method and compared using the log-rank test. Prognostic factors associated with OS were analyzed using Cox regression model with 95% confidence interval (95%C.I.).Results: A total of 451 premenopausal patients meeting study criteria were identified. Median age was 44 years. The number of patients receiving chemotherapy alone, endocrine therapy and chemotherapy followed by endocrine therapy as initial palliative treatment strategy were 222(49.2%), 80 (17.7%), and 149 (33.0%), respectively. Patients receiving initial chemotherapy were more likely to be luminal B subtype, had more de novo stage IV disease than recurrent disease and had more liver metastasis, compared with patients receiving initial endocrine therapy. Both PFS and OS were significantly longer for chemotherapy-endocrine therapy group (median PFS 18.9 months and OS 75.0 months), than for endocrine therapy group (median PFS 11.7 months and OS 53.5 months). Chemotherapy alone group presented with worst survival outcomes (median PFS 7.1 months and OS 43.9 months). However, in multivariate analysis, none of the three treatment strategies were independently associated with PFS or OS.Conclusions: In real world, a high percentage of premenopausal patients with HR+ HER2- disease received chemotherapy as initial palliative treatment in China, which was not associated with worsened survival. This unexpected guideline non-adherence reflects the unmet need of establishing treatment guidelines specifically for premenopausal patients in the Chinese population. Further studies with larger sample size across China are needed to explore the relationship between this guideline non-adherence and clinical outcomes. Citation Format: Yiqun Li, Hongnan Mo, Xiuwen Guan, Shaoyan Lin, Zijing Wang, Yimeng Chen, Shanshan Chen, Qiao Li, Ruigang Cai, Jiayu Wang, Yang Luo, Ying Fan, Peng Yuan, Pin Zhang, Qing Li, Fei Ma, Binghe Xu. In real world, a high percentage of premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer receive chemotherapy as first-line treatment: A study of the National Cancer Center, China [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-16-06.