<div>AbstractPurpose:<p>We report final antitumor efficacy results from a phase II study of trilaciclib, an intravenous cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, administered prior to gemcitabine plus carboplatin (GCb) in patients with metastatic triple-negative breast cancer (NCT02978716).</p>Patients and Methods:<p>Patients were randomized (1:1:1) to group 1 [GCb (days 1, 8); <i>n</i> = 34], group 2 [trilaciclib prior to GCb (days 1, 8); <i>n</i> = 33], or group 3 [trilaciclib (days 1, 8) and trilaciclib prior to GCb (days 2, 9); <i>n</i> = 35]. Subgroup analyses were performed according to CDK4/6 dependence, level of programmed death-ligand 1 (PD-L1) expression, and RNA-based immune signatures using proportional hazards regression. T-cell receptor (TCR) β CDR3 regions were amplified and sequenced to identify, quantify, and compare the abundance of each unique TCRβ CDR3 at baseline and on treatment.</p>Results:<p>Median overall survival (OS) was 12.6 months in group 1, not reached in group 2 (HR = 0.31; <i>P</i> = 0.0016), 17.8 months in group 3 (HR = 0.40; <i>P</i> = 0.0004), and 19.8 months in groups 2 and 3 combined (HR = 0.37; <i>P</i> < 0.0001). Efficacy outcomes were comparable regardless of cancer CDK4/6 dependence status and immune signatures. Administering trilaciclib prior to GCb prolonged OS irrespective of PD-L1 status but had greater benefit in the PD-L1–positive population. T-cell activation was enhanced in patients receiving trilaciclib.</p>Conclusions:<p>Administering trilaciclib prior to GCb enhanced antitumor efficacy, with significant improvements in OS. Efficacy outcomes in immunologic subgroups and enhancements in T-cell activation suggest these improvements may be mediated via immunologic mechanisms.</p></div>
e11578 Background: While only 20% of all breast cancer is HER2+, it represents a disproportionate majority of breast cancer brain metastases, and up to half of these patients will die of CNS disease. Prophylactic cranial irradiation (PCI) reduces the risk of brain metastases and improves survival in small cell lung cancer, but at the cost of neurocognitive decline in 30-40%. RTOG 0933 demonstrated a reduction in neurocognitive decline with hippocampal-avoidance (HA) whole brain radiation compared with historic controls. HA-PCI may represent an approach to reduce the risk of symptomatic HER2+ brain metastases while simultaneously reducing the risk of neurotoxicity, presuming the incidence of metastases within the HA zone is low. Methods: Patients with HER2+ breast cancer and brain metastases treated with whole brain radiation (WBRT) or stereotactic radiosurgery (SRS) from 1/2004-2/2012 were identified from registries in the Department of Radiation Oncology. Pretreatment T1-weighted, postcontrast axial MRI images were reviewed, and metastases were scored as being within a 5 mm HA zone (as done in RTOG 0933), and further subdivided by whether (1) any portion was within the avoidance zone or (2) the nidus (assuming concentric growth of the metastasis) was within the HA zone. Results: Seventy-three patients with 513 metastases were identified. The median age was 52.2. The median number of brain metastases per patient was 7.03 (range, 1-157). 40 of the patients were treated with WBRT and 21 were treated with SRS, with the remainder undergoing unknown or no radiation therapy. Eleven patients (15.1%) and 14 metastases (2.7%) had any portion of the metastasis within the HA zone while only 5 patients (6.85%) and 5 metastases (0.97%) had the tumor nidus within the HA zone. Conclusions: Metastases within the HA zone are uncommon. Use of a 5 mm expansion from the hippocampus to create a HA zone for HA-PCI would be projected to result in a 1-3% excess risk of failure. Such a low risk of failure would be acceptable, particularly with the ability to salvage such patients with techniques such as SRS. A pilot study of HA-PCI for HER2+ metastatic breast cancer is in development.
Abstract Background: POLARIS is an ongoing, prospective, real world, noninterventional study in patients (pts) with HR+/HER2– ABC receiving PAL. This interim report describes real-world PAL use in preMeno pts. Methods: POLARIS has a targeted enrollment of 1500 pts from ~110 sites in the United States and Canada. Using patient data collected from medical charts and physician surveys, baseline demographics, clinical characteristics, and treatment patterns were analyzed descriptively in self-reported preMeno pts with ABC. Results: At the data cutoff of May 20, 2020, 1208 pts were enrolled; 134 (11.1%) from 61 sites were preMeno, of whom 14.2% completed ≥6 months of PAL treatment. Among 134 preMeno pts (74.6%) who received first-line (1L) therapy, 69.0% received PAL+letrozole (LET) or anastrozole, 28.0% PAL+fulvestrant, and 3.0% PAL+exemestane. Median disease-free interval was 39.3 (range: 0 to 236) months; median treatment-free interval was 14.8 (-3 to 134) months. Of 34 pts (25.4%) who received PAL as second or later line (≥2L), 23.8% previously received hormonal therapy, 28.6% chemotherapy, and 14.3% both. The majority of pts (96.27%) initiated PAL at 125 mg regardless of line of therapy (Table). During the first PAL treatment cycle, 2.9% of all preMeno pts, 1% of 1L pts, and 8.8% of ≥2L pts had a dose reduction; 8.2%, 9%, and 5.9%, respectively, had an interruption. Dose reductions/interruptions peaked in cycle 2 (11.9%/15.7%); 56.67% of these modifications were due to adverse events. Conclusions: PAL is routinely prescribed in clinical practice for preMeno women with HR+/HER2- ABC. The majority of preMeno pts in this real-world dataset received PAL+LET as 1L ABC treatment; PAL was primarily initiated at the recommended dose (125 mg) and was well tolerated with few dose modifications required. Clinical trial identification: Pfizer (NCT03280303) Table.CharacteristicFirst-Line Pre/Perimenopausal Patients (n=100)Second or Later Line Pre/Perimenopausal Patients (n=34)Pre/Perimenopausal Patients (N=134)Age at study enrollment, yMedian (range)44 (22-61)42.5 (27-58)44 (22-61)Distribution, n (%)<4032 (32.0)12 (35.3)44 (32.8)40–5045 (45.0)17 (50.0)62 (46.3)51–6923 (23.0)5 (14.7)28 (20.9)Race, n (%)White73 (73.0)26 (76.5)99 (73.9)Black or African American16 (16.0)4 (11.8)20 (14.9)Asian1 (1.0)1 (2.9)2 (1.5)Native Hawaiian or other Pacific Islander2 (2.0)0 (0.0)2 (1.5)American Indian or Alaska Native1 (1.0)0 (0.0)1 (0.7)Other3 (3.0)2 (5.9)5 (3.7)Not reported because of confidentiality regulations4 (4.0)1 (2.9)5 (3.7)Hispanic/Latino ethnicity, n (%)10 (10.0)3 (8.8)13 (9.7)Disease status, n (%)Visceral35 (35.0)13 (38.2)48 (35.8)Nonvisceral61 (61.0)17 (50.0)78 (58.2)Not reported4 (4.0)4 (11.8)8 (6.0)Bone metastases at mBC diagnosis, among patients with metastatic (stage IV) disease at study enrollment, n (%)Bone only40 (40)8 (23.5)48 (35.8)Bone plus other metastases32 (32)13 (38.2)45 (33.6)Disposition of patient ABC/mBC diagnosis at study at study enrollment, n (%)Recurrent from earlier stage (Stage 0-III)72 (72.0)18 (52.9)90 (67.2)De novo (Newly diagnosed Stage IV at enrollment)26 (26.0)15 (44.1)41 (30.6)Not reported2 (2.0)1 (2.9)3 (2.2)ECOG performance status at study enrollment (N, %)041 (41)15 (44.1)56 (41.8)126 (26)7 (20.6)33 (24.6)28 (8)3 (8.8)11 (8.2)32 (2)0 (0)2 (1.5)Not reported23 (23)9 (26.5)32 (23.9)Starting dose, first cycle of PAL treatment n (%)125 mg96 (96.0)33 (97.1)129 (96.3)100 mg2 (2.0)1 (2.9)3 (2.2)75 mg2 (2.0)0 (0.0)2 (1.5)Reason for first cycle starting dose <125 mg, n (%)Patient preference0 (0.0)1 (100)1 (25.0)Other3 (100)0 (0.0)3 (75.0) Citation Format: Meghan S Karuturi, Adnan Garrett, Joanne L Blum, Jay Anderson, Erin Jepsen, Timothy Pluard, Thomas Stanton, Kenneth Manning, Joseph C Cappelleri, Faith Beery, Yao Wang, Debu Tripathy. Pre/perimenopausal (preMeno) women receiving palbociclib (PAL) for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) in a real-world setting: Treatment patterns from POLARIS [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-19.
1051 Background: H3B-6545 — a novel selective ER covalent antagonist (SERCA) that potently inactivates wild-type and mutant ERα — has shown preliminary antitumor activity and tolerable safety in pts with advanced/metastatic, ER+, HER2– BC. Palbociclib (palbo), an oral CDK4/6 inhibitor, has shown activity in metastatic disease when combined with endocrine therapy. The dose escalation part of this open-label, multicenter, phase 1b study of H3B-6545 + palbo in pts with ER+, HER2– BC aimed to identify the recommended phase 2 dose (RP2D) of H3B-6545 + palbo and characterize safety and efficacy. Methods: Females aged ≥18 years with ER+, HER2–, locally advanced/recurrent/metastatic BC, ECOG PS 0–1, and progression on/after standard therapy were eligible. In the dose escalation phase, pts had to have received ≥2 prior hormonal therapies. Palbo was to be escalated no higher than 125 mg orally QD (days 1–21) and H3B-6545 no higher than 450 mg orally QD (days 1–28). The MTD was the highest dose at which ≤1 of 6 pts had a dose-limiting toxicity (DLT). The primary endpoint was determination of the MTD and/or RP2D. Secondary endpoints included safety and efficacy (by investigator per RECIST v1.1). Results: At data cutoff (16 Sept 22), 31 pts were treated: Cohort (C) 1: H3B-6545 300 mg + palbo 100 mg (n=7); C2: H3B-6545 300 mg + palbo 125 mg (n=8); C3: H3B-6545 450 mg + palbo 125 mg (n=8); C3b: H3B-6545 450 mg + palbo 100 mg (n=8). 3 DLTs (grade 3/4 neutrophil count decreased [n=2] and grade (G) 3 QTcF prolongation [n=1]) were observed in C3 (5 DLTs were observed at C3b); C2 dose was deemed the MTD. Of all pts, 90.3% had G ≥3 TEAEs, 32.3% had serious TEAEs, and 6.5% had TEAEs leading to drug withdrawal. Sinus bradycardia (67.7% [G ≥3, 0%]) and anemia (54.8% [G ≥3, 19.4%]) were the most frequent TEAEs. QT prolongation and rash occurred in 19.4% [G ≥3, 12.9%] and 16.1% [G ≥3, 9.7%] of pts, respectively. ORR in response evaluable pts was 23.1% (95% CI 9.0–43.6). The Table shows additional results. Conclusions: H3B-6545 300 mg + palbo (100/125 mg) had manageable safety and encouraging preliminary antitumor activity. Further studies are warranted to identify the RP2D. Clinical trial information: NCT04288089 . [Table: see text]
1015 Background: H3B-6545 is a novel selective ER covalent antagonist (SERCA) that inactivates wild-type and mutant ERα. This phase 1/2 study aimed to identify the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), and characterize safety and efficacy of H3B-6545 in women with advanced/metastatic ER+, HER2– BC. Methods: This multicenter, open-label study included dose-escalation [ph1] and -expansion [ph2] phases. Females (postmenopausal or concurrently receiving a luteinizing hormone-releasing hormone agonist) with ER+, HER2–BC who had disease progression on standard therapy were eligible. Prior therapy must have included a minimum of 2 hormonal therapies (HTs), or 1 HT + 1 chemotherapy, or 1 HT + a CDK4/6 inhibitor. H3B-6545 was administered orally QD at doses of 100-600 mg. The MTD was the highest dose at which ≤1 of 6 patients (pts) had a dose-limiting toxicity (DLT). In ph2, efficacy of the RP2D was examined. The primary endpoints were determination of RP2D (ph1) and efficacy (ph2; including objective response rate [ORR], duration of response [DOR], and progression-free survival [PFS] per RECIST v1.1 by investigator, and overall survival [OS]). Safety and PK were secondary endpoints. Results: At data cutoff (30 Nov 22), 151 pts received ≥1 dose of H3B-6545 during ph1 or ph2. Pts had a median (m [range]) of 2 (1-7) prior endocrine- and 1 (1-6) non-endocrine–containing therapies; 90.1% of pts received prior CDK4/6 inhibitors. During ph1, DLTs of grade (G) 3 rash (n=1) and G 3 fatigue (n=1) were observed at 600 mg; thus, 450 mg was determined to be the MTD/RP2D. In the full analysis set (N=151), 100% and 50.3% of pts had any grade and G ≥3 treatment-emergent adverse events (TEAEs), respectively. TEAEs leading to drug interruption, dose reduction, and withdrawal occurred in 38.4%, 20.5%, and 8.6% of pts, respectively. Nausea (45.7% [2.0% G ≥3]), sinus bradycardia (44.4% [0% G ≥3]), and diarrhea (41.1% [1.3% G ≥3]) were the most common TEAEs. QT prolongation occurred in 9.9% [3.3% G ≥3] of pts. Among 94 response-evaluable pts treated at 450 mg, ORR was 20.2% (95% CI 12.6–29.8) and clinical benefit rate (CBR) was 41.5% (95% CI 31.4–52.1); mPFS (95% CI) was 5.06 (3.15–7.26) months. Among all pts treated at 450 mg (n=115), mOS (95% CI) was 21.52 (16.56–25.46) months. Plasma concentration of H3B-6545 increased as dose increased. Additional results are shown (Table). Conclusions: H3B-6545 had a low rate of G ≥3 TEAEs and showed clinically meaningful antitumor activity in heavily pretreated female patients with ER+, HER2– BC. Clinical trial information: NCT03250676 . [Table: see text]
Abstract Background: The medical, financial and insurance concerns of patients throughout the cancer trajectory are well documented. Over a quarter of patients report at least one financial problem. Due to the financial burden of cancer care, patients report that they delay filling prescriptions, have difficulty making ends meet, are concerned about their household’s financial situation and skip doses of medication. These are significant findings as consistent use of medication is necessary for treatment and those with increased financial problems also have lower scores on physical and mental health quality of life measures. While most providers agree that the burden of metastatic breast cancer (MBC) is also significant, little information is known about the specific medical, financial and insurance needs of those with MBC. Methods: Saint Luke’s Cancer Institute (SLCI) employs providers in the fields of medical and surgical oncology, gynecologic oncology, hematology and radiation oncology who subspecialize in every type of cancer. In October of 2016, the Koontz Center for Advanced Breast Cancer was established within the Saint Luke’s Cancer Institute. This center focuses exclusively on patients with MBC with a dual focus of improving outcomes and quality of life of those with MBC. In addition to a robust therapeutic research program, genomics, and immunotherapy, a comprehensive supportive/integrative team, including social worker, is imbedded in the center. Social workers see patients throughout the entirety of SLCI and the Koontz Center for Advanced Breast Cancer. As part of their patient interactions, social workers document the date of intervention, patients’ name, concern addressed, and length of every interaction. The following data compares the reported needs of those with MBC in the Koontz Center for Advanced Breast Cancer to the non-MBC patients within the SLCI population from September 1st of 2017 to August 31st of 2018. Results: In total, there were 2,072 interactions with non-MBC patients during this period. The top three reported concerns were medication assistance (n=335, 16.15%), being uninsured (n=298, 14.37%) and transportation (n=284, 13.69%). For those with MBC, there were a total of 476 interactions within the same time frame and the top three reported concerns were medication assistance (n=166, 34.87%), insurance issues (n=75, 15.76%) and financial distress (n=66, 13.87%). About 55% of non-MBC patients (n=334, 55.95%) have repeat appointments and meet with social work on average 5 times. Of MBC patients, 60.67% (n=54) have repeat appointments and meet with social work on average 7 times. For one time encounters with social work, those with non-MBC patients lasted 21 minutes and 9 seconds and encounters with MBC patients lasted 24 minutes and 34 seconds. Conclusion: Results indicate differences and similarities for MBC patients compared to non-MBC patients. This could be explained by the fact that both populations share several concerns such as financial barriers to medications, high insurance premiums and decreased ability to work. However, due to the nature of MBC, patients with MBC often deal with these concerns for longer periods of time and are often required to utilize expensive specialty medication. The top three concerns of MBC patients including medication assistance, insurance issues, and financial distress, are closely related to one another as it relates to gaps in healthcare coverage. The high cost of treatment for advanced disease, coupled with the specific and unique needs of those living with MBC, can directly impact patients’ ability to access necessary care. These potential causes, as well as how the Koontz Center for Advanced Breast Cancer works to mitigate these issues, will be addressed in further detail. Citation Format: Savannah Joy Geske, Katie Ambrosier, Timothy J. Pluard. Medical, financial and insurance related concerns of metastatic breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-11-18.
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