Real-world Progression-free Survival Research Articles

Immune checkpoint inhibition for the treatment of metastatic breast cancer with high tumor mutational burden: Real world clinical and genomic correlates of response.

1078 Background: Pembrolizumab has received tumor-agnostic approval for the treatment of unresectable/metastatic solid tumors carrying a tumor mutational burden (TMB) >10 mut/Mb. The registrational KEYNOTE-158 study, however, did not include any patients with metastatic breast cancer (MBC). Here we present a retrospective study of patients with TMB-high MBC treated with immune checkpoint inhibition (ICI) and report real-world efficacy endpoints, including progression free survival as well as clinical and genomic characteristics that may be associated with duration of response. Methods: All patients with MBC treated with an ICI at MSK and with TMB-high tumors (>10 mut/Mb) assessed by tumor-normal targeted sequencing (MSK-IMPACT) were included. Clinicopathological and demographic data were obtained via the MSK Breast Cancer Translational Program. Mutational signatures were determined using the Signature Multivariate Analysis (SigMA) algorithm. Real world progression free survival (PFS) was determined clinically and analyzed using Kaplan-Meier estimates. Univariate and multivariate analyses were performed using Cox-proportional hazards models. Results: Of 688 patients with TMB-high breast cancer at MSKCC, 87 had received ICI-based therapy for estrogen receptor positive (ER+), triple negative breast cancer (TNBC), and HER2+ MBC. Of those, 45 patients were treated with ICI monotherapy (29 ER+, 11 TNBC, 5 HER2), 31 were treated with ICI + chemotherapy (12 ER+, 19 TNBC), and 11 were treated with combinations of ICI and targeted therapy (8 ER+, 1 TNBC, 2 HER2). Median age at time of ICI treatment across all patients was 60. ICI was the median 5th line therapy for all patients (range 1-16). Median PFS of ICI for all patients was 3.17 months (95%CI 2.27-5.5). Multivariable analysis did not show statistically significant differences in PFS based upon treatment regimen (monotherapy vs. chemoIO HR 1.03, 95%CI 0.54-1.96, p= 0.92, monotherapy vs combination IO HR 1.66, 95%CI 0.69-4.02, p=0.26), ER status (ER- vs ER+, HR 1.20, 95%CI 0.63-2.28, p=0.57), or HER2 status (HER2- vs HER2+, HR 1.63, 95%CI 0.51-5.20, p=0.41. However, longer PFS was significantly associated with TMB>30 (HR 0.35, 95%CI 0.13-0.92, p=0.03) and dominant APOBEC signature score (APOBEC- vs APOBEC+, HR 0.49, 95%CI 0.25-0.98, p=0.04). Shorter PFS was significantly associated with later treatment line at the time of ICI exposure (continuous, HR 1.22, 95%CI 1.11-1.36, p=0.0001). Conclusions: In this heavily pretreated real-world cohort, ICI in TMB high MBC shows modest clinical activity. Our analysis suggests that ICI may be more effective in MBC patients that are less heavily pre-treated, have TMB>30, and have a predominantly APOBEC mutational signature. Further translational work is necessary to explore the mechanisms of these findings.

Real world outcomes of sequential ADC therapy in metastatic breast cancer: Patients treated with sacituzumab govitecan and trastuzumab deruxtecan.

1085 Background: Sacituzumab govitecan (SG) and trastuzumab deruxtecan (TDXd) are antibody drug conjugates (ADCs) that are approved for the treatment of HER2 low metastatic breast cancer (MBC). Both carry payloads which inhibit topoisomerase 1, and it is unknown whether these ADCs retain clinical activity when used sequentially to each other. Here we present a retrospective study of patients treated with both SG and TDXd at our institution and report real world progression free survival (PFS), clinical factors associated with longer PFS, and whether ADC sequence impacts outcome. Methods: All patients with MBC treated at MSKCC who had received both SG and TDXd (in any order) were eligible for inclusion. Clinicopathological and demographic data were obtained from retrospective chart review. PFS was determined clinically and calculated using Kaplan-Meier survival analysis. Univariate and multivariate associations of survival were assessed using Cox proportional hazards models. Results: Eighty-five patients met eligibility per the criteria above: 54 with estrogen receptor positive (ER+) MBC and 31 with triple negative breast cancer (TNBC). 33 patients received SG followed by TDXd (14 ER+, 19 TNBC), and 52 received TDXd followed by SG (40 ER+, 12 TNBC). Median age at time of second ADC treatment (ADC2) was 59 among all patients, 62 among SG first, and 58 among TDXd first. This cohort was heavily pre-treated, with median 5 prior therapies at the time of first ADC (ADC1) and 7 at the time of ADC2. Both the SG first and TDXd first cohorts had median 1 line of intervening therapy between ADCs. In the SG first group, median ADC2 (TDXd) PFS was 3.5 months (95%CI 2.7-7.7), and in the TDXd first group median ADC2 (SG) was 2.8 months (95%CI 2.6-3.7). On multivariate analysis, neither ADC sequence (SG first vs. TDXd first, HR 1.30, 95%CI 0.71-2.37, p=0.4) nor ER status (TNBC vs. ER+, HR 1.21, 95%CI 0.63-2.32, p=0.6) showed statistically significant differences in ADC2 PFS between these groups. Instead, later treatment line at the time of ADC2 was significantly associated with shorter ADC2 PFS (continuous, HR 1.11, 95%CI 1.01-1.23, p=0.03). To separately evaluate differences in PFS for each ADC depending upon whether it was first or follow-up therapy, median ADC1 vs. ADC2 PFS is summarized by ADC (Table). Conclusions: In this heavily pre-treated patient cohort, the clinical activity of both SG and TDXd appear modest in the ADC2 setting. Further studies are needed to confirm these findings and to determine whether payload cross-resistance may undermine the benefit of sequential ADC therapy. [Table: see text]

Outcomes with trastuzumab deruxtecan (T-DXd) by HER2 status and line of treatment in a large real-world database of patients with metastatic breast cancer.

1077 Background: In the clinical trial setting, T-DXd improves survival for patients with HER2+ and HER2-low metastatic breast cancer (MBC), and has also shown preliminary activity in HER2-0 MBC. Little real-world evidence is available on the performance of T-DXd. Methods: We conducted a retrospective observational study using the nationwide Flatiron Health electronic health record (EHR)-derived deidentified database to evaluate the real-world activity of T-DXd. We included patients with MBC who initiated T-DXd between 12/2019 and 1/2023. Tumors were categorized as HER2+ if positive at any timepoint, with HER2- cases further divided into HER2-low (IHC 1+ or 2+ not amplified) and HER2-0 (IHC 0) according to the last biopsy before T-DXd. Real world progression-free survival (rwPFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results: A total of 930 patients were included: 636 with HER2+, 268 with HER2-low and 26 with HER2-0 MBC. Among HER2- patients, 241 (82.0%) were HR+ and 53 (18.0%) were HR- (i.e., triple-negative). A total of 572 (61.5%) patients were White, 101 (10.9%) Black/African American, 88 (9.4%) Hispanic/Latino, 37 (4.0%) Asian and 132 (14.2%) other or missing. Median age was 59 [range 25, 84] and patients received T-DXd in the following lines of therapy (LOT): 54 (5.8%) as 1st line, 110 (11.8%) as 2nd line, 179 (19.2%) as 3rd line, 182 (19.6%) as 4th line and 405 (43.6%) as ≥5th line. Median number of LOT for advanced disease prior to T-DXd were 3 and 4, respectively, for HER2+ and HER2- patients. In patients with HER2+ MBC, rwPFS and OS were 12.1 and 26 months after initiating T-DXd, respectively. The longest rwPFS, 14.9 months, was observed in the 1st or 2nd LOT, followed by 14.1 months in LOT 3, 12.4 months in LOT 4, and 10.8 months in LOT ≥5. In patients with HER2- MBC, median rwPFS and OS were 6.3 and 15.5 months, respectively. The longest median rwPFS of 8.1 months was observed in the 1st or 2nd LOTs, followed by 6.9 months in LOT 4, 6.2 months in LOTs ≥5, and 6.0 months in LOT 3. Outcomes with T-DXd by HER2 and HR status are provided (Table). Updated data with a larger sample size will be presented. Conclusions: In the largest dataset to date, T-DXd showed favorable real-world activity for treating MBC, although rwPFS appeared shorter than what observed in clinical trials. Encouraging rwPFS was observed in understudied groups, such as patients with triple-negative and HR+/HER2-0 MBC. [Table: see text]

CCNE1 amplification as marker of poor prognosis and novel therapeutic target in advanced breast cancer.

1040 Background: Cyclin E1 (CCNE1) overexpression or gene amplification is linked to dismal outcomes in various tumors, including breast cancer (BC). Recent studies suggest that CCNE1 amplification is a potential target for new synthetic lethality-based treatments, including CDK2-selective and PKMYT1 inhibition. This study explores the clinical and genomic characteristics of CCNE1-amplified BCs. Methods: We analyzed genomic and clinical data from consecutive BCs that underwent clinical tumor-normal targeted panel sequencing (MSK-IMPACT) between April 2014 and December 2021. Allele-specific copy number, including CCNE1 amplification, and fraction genome altered (FGA) were calculated by FACETS. Mutual exclusivity and co-occurrence analyses were performed using CoMEt. Benjamini–Hochberg method for multiple testing correction (q) was applied. Real-world progression-free survival (rwPFS) was assessed by the Kaplan Meier method and Cox models, focusing on patients with available pre-treatment samples. Results: Out of 3,753 BCs, 125 (3.3%) had CCNE1 amplification. A higher occurrence of CCNE1 amplification was noted in post-treatment (n=2,368) compared to treatment-naïve tumors (n=1,385; 4% vs 2.4%, p=0.007). CCNE1 amplification was less common in hormone receptor (HR)+/HER2- BCs (2%) compared to HER2+ (7.6%) and triple-negative (7.2%) tumors (p<0.001). BCs with CCNE1 amplification showed higher median FGA, indicating increased genomic instability. In primary BC, TP53 alterations were more frequent in CCNE1-amplified tumors (q<0.001), while CDH1 alterations were mutually exclusive (q<0.001) suggesting that lobular BCs rarely harbor CCNE1 amplification. Similar trends were seen in post-treatment samples. CCNE1 amplification detected at baseline was linked to shorter median rwPFS in HR+/HER2- metastatic BCs treated with CDK4/6 inhibitors plus endocrine therapy (8.8 vs 15.2 months in CCNE1-amplified [n=9] vs CCNE1-non amplified [n=402]; hazard ratio [HR] 2.82, 95% CI 1.38-5.75), and in HER2+ metastatic BCs treated with first-line THP regimen (7.3 vs 20.8 months in CCNE1-amplified [n=5] vs CCNE1-non amplified [n=106]; HR 3.1, 95% CI 1.24-7.87). In a CCNE1-amplified triple-negative cell model (HCC1569), treatment with the PKMYT1 inhibitor RP-6306 significantly reduced tumor growth. Conclusions: CCNE1 amplification in BCs is associated with greater genomic instability and characterizes a group of metastatic BCs with poor response to standard of care therapies. Novel therapies targeting CCNE1-amplified tumors are under evaluation in preclinical and clinical studies.

Comparison of antitumor efficacy of first-line palbociclib, ribociclib, or abemaciclib in patients with HR+/HER2- aBC: Results of the multicenter, real-world, Italian study PALMARES-2.

1014 Background: The Cyclin Dependent Kinase 4/6 inhibitors (CDK4/6i) Palbociclib, Ribociclib and Abemaciclib in combination with Endocrine Therapy (ET) represent the standard-of-care, 1st line treatment for patients with Hormone Receptor-positive, Human Epidermal growth factor Receptor 2-negative, advanced Breast Cancer (HR+/HER2- aBC). So far, no large real-world studies have compared the efficacy of the three CDK4/6i in this clinical setting. Methods: The multicenter, population-based study PALMARES-2 evaluated the antitumor efficacy of 1st line Palbociclib, Ribociclib or Abemaciclib in combination with ET in consecutive HR+/HER2- aBC patients treated in 18 Italian cancer centers between 1st January 2016 and 1st September 2023. The primary study endpoint was real-world Progression-Free Survival (rwPFS), as defined as the time interval between ET plus CDK4/6i initiation and disease progression. Multivariate Cox regression model was used to adjust the association between individual CDK4/6i and rwPFS for clinically relevant variables. Results: With a data cut-off date of January 1st, 2024, we enrolled 1850 patients, 750 (40.6%), 676 (36.5%) and 424 (22.9%) of whom received Palbociclib, Ribociclib and Abemaciclib, respectively. Among 1226 (66.3%) patients with endocrine-sensitive disease, 1087 (89%) received concomitant Aromatase Inhibitors, whereas 441 (70.7%) out of 624 (33.7%) patients with endocrine-resistant disease received concomitant Fulvestrant. Patients treated with Abemaciclib were more likely to have endocrine-resistant disease, liver metastases, lobular tumor histology and lower PgR tumor expression, and less likely to have de novometastatic disease (p<0.001). Median rwPFS in the whole study cohort was 34.9 months (95% CI 32.0-37.4). Abemaciclib and Ribociclib were independently associated with better rwPFS when compared to Palbociclib (Table), whereas Abemaciclib and Ribociclib showed no significantly different efficacy (aHR 0.91, 95% CI 0.70-1.19; p=0.505). Other covariates independently associated with rwPFS are shown (Table). Conclusions: The real-world study PALMARES-2 revealed different antitumor efficacy of individual CDK4/6i in HR+/HER2- aBC patients. Longer follow-up is required to study if Palbociclib, Ribociclib and Abemaciclib are associated with different overall survival. [Table: see text]

Impact of prior anticancer treatments on palbociclib (PAL) clinical outcomes in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced breast cancer (ABC) in real-world settings.

1055 Background: Cyclin-dependent kinase 4/6 inhibitors (eg, PAL) combined with endocrine therapy (ET) is a standard of care for patients with HR+/HER2− ABC. The impact of prior anticancer treatments on clinical outcomes of patients with HR+/HER− ABC treated with palbociclib in routine care is not well known and was investigated in the POLARIS study. Methods: POLARIS is a prospective, observational, multicenter, real-world study in the US and Canada. Enrolled patients were adults (≥ 18 y) with HR+/HER2− ABC who received PAL + ET as standard of care. Real-world progression-free survival (rwPFS) and overall survival (OS) were described by prior treatment. Results: A total of 1250 patients were enrolled. Median age was 64 years (range, 22–97), 67.9% had recurrent disease, and 72.1% received PAL as first-line treatment (1LOT) vs 27.9% as ≥ 2LOT. Prior anticancer therapies (1LOT: adjuvant/neoadjuvant setting; ≥ 2LOT: metastatic setting) were received by 912 patients (73.0%), which included ET-alone (n=254), chemotherapy-alone (n=235), chemotherapy + ET (n=338) or other (n=85). The median follow-up duration was 35.7 months for rwPFS and 39.1 months for OS. In 1LOT, both rwPFS and OS were numerically shorter for patients who received prior chemotherapy (either alone or with ET) when compared with patients who received ET-alone or had no prior therapy (Table). In ≥ 2LOT, patients who received prior chemotherapy-alone or ET-alone had comparable rwPFS, which was numerically longer than for patients with prior chemotherapy + ET; OS was comparable regardless of prior treatment. Conclusions: Overall, patients with HR+/HER2− ABC with prior chemotherapy receipt tended to have shorter clinical benefit. Regardless of LOT, numerically longer rwPFS was achieved in patients who received prior ET-alone. In 1LOT, OS was longer in patients who received prior ET-alone while in ≥ 2LOT, OS was comparable across prior treatment subgroups. Small sample sizes of some ≥ 2LOT subgroups as well as observational nature of the study may limit interpretation. [Table: see text]

Real-world comparison of the efficacy of three CDK4/6 inhibitors (CDK4/6i) in the first-line treatment of endocrine-sensitive advanced breast cancer (aBC): Single institution experience.

e13080 Background: The combination of CDK4/6i and endocrine therapy (ET) is the standard of care in the first-line treatment of hormone receptor positive (HR+), HER2- aBC. In registrational studies, the progression-free survival (PFS) of all three CDK4/6i ranged from 23.8 to 28.12 months and overall survival (OS) from 53.9 to 66.8. In Croatia, both ribociclib and palbociclib were approved for clinical use in August 2018 and abemaciclib in November 2019. Methods: This retrospective study included patients with endocrine-sensitive HR+, HER2- aBC treated with aromatase inhibitor (AI) and CDK4/6i in the first-line setting between August 2018 and October 2023 at University Hospital Centre Zagreb. Ethics committee approval was obtained before the study was commenced. Patient demographics, clinical presentation, tumor characteristics and treatment data were collected. Real-world PFS (rwPFS) and OS analyses were done with the final data cut-off date of December 31, 2023, using type 1 right censoring. Data were analyzed using the Kaplan-Meier method. Results: Of the 274 patients treated with a combination of CDK4/6i and ET in the first-line setting, 172 with endocrine-sensitive tumors (98 de novo metastatic and 74 with treatment-free interval longer than 12 months) were eligible for the study, of which 41.86% (72/172) received ribociclib, 44.19% (76/172) palbociclib, and 13.95% (24/172) abemaciclib. Overall rwPFS was 48 months (95% CI:35-53). In the abemaciclib group, median rwPFS and OS were not reached in the follow-up period. The rwPFS was 48 (95% CI:27-53) for ribociclib and 47 (95% CI:30-49) for palbociclib. The overall OS was 62 months (95% CI:47-62). Median OS in the ribociclib group was 62 months (95% CI:40-62) and in the palbociclib group 52 (95% CI:42-54) months. Conclusions: The PFS and OS results for palbociclib and ribociclib in this retrospective real-world study correlate with results from randomized clinical trials, confirming some inferiority of palbociclib compared to ribociclib in the context of OS. Due to the later availability of the drug, larger sample size and longer follow-up will be needed to make definitive conclusions on the efficacy of abemaciclib.

Real world experience of trastuzumab deruxtecan for the treatment of metastatic breast cancer in the UK.

1024 Background: Trastuzumab deruxtecan (TDXd), an antibody drug conjugate, was first approved in the UK for the treatment of human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer (mBC) in 2021. We aimed to review the efficacy and tolerability of TDXd in a real-world UK setting. Methods: We collected clinical and demographic data from medical records on HER2+ mBC patients treated with TDXd in the UK from Jan 2021 to Dec 2023 inclusive. This included: radiological response, the frequency of dose reductions and treatment delays, and reasons for discontinuation. Clinical trial patients were excluded. Descriptive statistical techniques were applied. Results: Data was collected from 26 UK cancer centres on 280 patients. The median age at TDXd initiation was 56 years (range 29-85). Median treatment duration was 9 cycles (range 1-40). 239 patients (85%) had visceral disease. 257 and 196 patients (92% and 70%, respectively) had received prior Trastuzumab and Pertuzumab, respectively. 233 patients (83%) had received prior TDM1. The median number of lines of treatment prior to TDXd was 3 (range 1 to 9). 20 patients (7%) were initiated on a reduced dose and 115 further patients (41%) required at least one dose reduction. 151 patients (54%) had at least one dose interruption due to: infection or neutropenia (n=61), other toxicity (n=85), interstitial lung disease (ILD) investigation (n=39), patient request (n=81), other concurrent illness (n=10), and cardiac investigation (n=6). Of these, 55 patients had more than one treatment break. 157 patients (56%) had discontinued TDXd treatment due to: disease progression or death (n=100), drug toxicity (n=39) of which 22 were due to ILD, and patient choice (n=8). 123 patients remained treatment at the time of analysis. The overall response rate of TDXd was 63% overall: stable disease 23%, partial response 56%, complete response 7%. Conclusions: The real-world data set is not directly comparable to either the DB02 or DB03 trials, as it included patients who had received TDXd in both the second line and later line settings. However, the majority (80%) of these patients were treated in the third line and beyond. The rates of drug interruption and reduction were higher in the real-world data set than in DB02, which may impact on efficacy in the real-world setting. Overall response rate is similar between trial data and our real-world data, although the latter was not measured by RECIST. Data collection is ongoing, including an analysis of real-world progression free survival. [Table: see text]

Multicenter retrospective cohort study of the sequential use of the antibody-drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) in patients with HER2-low metastatic breast cancer (MBC): Updated data and subgroup analyses by age, sites of disease, and use of intervening therapies.

1083 Background: T-DXd and SG are both FDA-approved treatments for patients (pts) with HER2-low MBC, but little data exists on the sequential use of these ADCs. Methods: In this multicenter retrospective cohort study, we identified pts with HER2-low MBC treated sequentially with both T-DXd and SG in either order, with or without intervening therapies (IntTx), at 5 academic centers between 2020-2023. We previously reported real-world progression free survival (rwPFS) and real-world overall survival (rwOS) by HR-status and ADC sequence order. Here we provide updated rwPFS and rwOS data, as well as new subgroup analyses by age, sites of disease, and use of IntTx between ADCs for HR- and HR+ disease. Results: 84 pts with HER2-low MBC treated with both T-DXd and SG were included, including 56 pts with HR+/HER2-low MBC (66.7%) and 28 pts with HR-/HER2-low MBC (33.3%). Prior to the start of ADC1, median age was 58 yrs and 22 pts were >65 yrs (26.2%), 65 pts (77.4%) had visceral disease, and 14 pts (16.7%) had central nervous system (CNS) disease. 36 pts (42.9%) had an IntTx between ADCs. Table 1 shows updated rwPFS and rwOS data by HR-status and ADC sequence order. For pts with HR+ and HR- MBC, there was no difference in ADC1 rwPFS or ADC2 rwPFS by age ≤65 vs. >65 yr or by presence vs. absence of visceral disease. For pts with HR- MBC, ADC1 rwPFS and rwOS was shorter for pts with CNS disease vs. pts without CNS disease (rwPFS 5.4 mo (n=6) vs. 8.5 mo (n=22), p=0.03; rwOS 11.6 mo vs. 21.1 mo, p<0.01 respectively). For pts with HR+ and HR- MBC, there was no difference in ADC2 rwPFS with or without receipt of IntTx. There was no difference in time to treatment failure for first IntTx vs. ADC2 if no InTx was given. Conclusions: This is one of the largest multicenter cohorts of pts treated with sequential ADCs for HER2-low MBC. Median rwPFS was longer for ADC1 than ADC2 in all subgroups, regardless of HR-status, ADC sequence order, age ≤65 or >65 yr, presence of visceral disease, or use of IntTx. Among pts with HR-/HER2-low MBC, pts with CNS disease had shorter ADC1 rwPFS and rwOS than pts without CNS disease. [Table: see text]

A deep learning–enabled workflow to estimate real world progression-free survival in patients with metastatic breast cancer.

11176 Background: Progression-free survival (PFS) is frequently measured in oncology clinical trials. In analyses outside of the trial setting, various strategies have been utilized to assess real-world PFS (rwPFS), including manual abstraction of clinical records, natural language processing (NLP) of oncology notes and radiology reports, and longitudinal analyses of radiologic images. Here we develop and validate a new semi-automated workflow that combines NLP of clinical notes with structured electronic health record data to facilitate the evaluation of rwPFS in patients with metastatic breast cancer (mBC). Methods: This study analyzes de-identified EHR data using nference nSights. The data is extracted following privacy-preserving protocols and is HIPAA compliant. The overall cohort included 316 patients with HR-positive, HER2-negative mBC who initiated Palbociclib and Letrozole combination therapy between January 1, 2015 and December 31, 2021. We developed and implemented an ensemble of deep-learning NLP frameworks to capture progression events from unstructured clinical notes and radiology reports. A change in the line of therapy, as determined by structured drug order/administration records, was also considered a progression event. We used manually curated “ground-truth” datasets to evaluate the performance of the progression-event capture workflow at the levels of both sentences (N = 1000) and patients (N = 100) by calculating sensitivity, specificity, precision, accuracy, and F1 scores. Progression events and censoring events (death, loss to follow-up, end of study period) were considered to compute rwPFS. Results: At the sentence level, progression events were captured from clinical notes and radiology reports with a sensitivity of 99.8%, specificity of 96.7%, and accuracy of 98.2% (Table). At the patient level, initial progression was correctly captured within a window of +/-30 days with a sensitivity of 92.5%, specificity of 83.0%, and accuracy of 88.0% (Table). In a sample of 100 patients, the median rwPFS was determined to be 25 months (95% CI; 15-35 months) by manual curation and 22 months (95% CI; 15-35 months) by the semi-automated workflow. In the overall cohort, median rwPFS was 20 months (95% CI; 18-25 months). Conclusions: An ensemble of NLP algorithms extracted progression events from clinical notes and radiology reports with high accuracy. A semi-automated workflow enabled rapid and accurate determination of rwPFS in mBC patients receiving a combination chemotherapy regimen. Further evaluation of this workflow to estimate rwPFS in other cancers and therapeutic settings is warranted. [Table: see text]

Clinical characteristics, treatment patterns, and outcomes in adult patients with germline BRCA1/2-mutated, HER2-negative advanced breast cancer: a retrospective medical record review in the United States.

To examine clinical characteristics, real-world treatment patterns, and health outcomes among patients with germline BRCA1/2-mutated, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC). A retrospective analysis was conducted using medical records from patients with HER2-negative ABC with BRCA1/2 mutation who received cytotoxic chemotherapy. Data were stratified into groups with triple-negative breast cancer (TNBC) or hormone receptor-positive (HR+)/HER2-negative diagnoses. Time-to-event outcomes (i.e., real-world progression-free survival [rwPFS] and overall survival [OS]) were calculated to summarize health outcomes. When diagnosed with ABC, most patients were younger than 60 years (mean age = 57.3 years), were white (76.4%), and had a family history of BRCA-related cancer (71.5%). A total of 305 patient records were examined; 194 patients (63.6%) had advanced TNBC, and 111 patients (36.4%) had HR+/HER2-negative ABC. Chemotherapy was primarily used as first-line treatment for both subgroups, but the TNBC subgroup received poly (ADP-ribose) polymerase (PARP) inhibitors at triple the rate as a second-line treatment and double the rate as a third-line treatment compared with the HR+/HER2-negative subgroup. Two-year OS rates were similar between the TNBC (73.9%) and the HR+/HER2-negative subgroups (77.0%), and anemia, nausea, and neutropenia were the most commonly reported toxicities across all treatments. Clinicians should consider the use of targeted agents such as PARP inhibitors in earlier lines of therapy for ABC given the growing evidence that PARP inhibitors may improve PFS compared with chemotherapy while potentially offering a more manageable toxicity profile and improved quality of life.

Abemaciclib for the Treatment of HR+HER2- Metastatic Breast Cancer: An Institutional Experience.

(1) Background: Abemaciclib combined with endocrine therapy is a standard first- or later-line of treatment for HR+/HER2- metastatic breast cancer (MBC). The aim of this retrospective cohort study was to describe the outcomes of patients treated in a real-world setting, with particular focus on elderly patients. (2) Patients and methods: Patients treated with abemaciclib between November 2019 and February 2022 were included in the study. Data were collected from electronic medical records. The primary objective was to determine real-world progression-free survival (rwPFS), and secondary objectives included median overall survival (mOS) and safety. (3) Results: Analysis included 134 patients, with a median follow-up of 42 months. Median age was 62 years, with 29.9% aged 70+ years. A total of 51.5% of patients received abemaciclib in first-line, predominantly with aromatase inhibitor (68.1%). Median rwPFS was 21 in first-line and 20 months in the second-line, with no significant difference between treatment lines (HR 0.96; p = 0.88). Patients treated in the third- or later-line had a significantly shorter rwPFS, at 7 months (HR 1.48, p = 0.003). mOS was not reached in the first-line setting. For second- and third- or later-lines, mOS was 29 and 19 months, respectively. There was no significant difference in mOS between first- or second-line (HR 1.37, p = 0.36). In the 70+ group, median rwPFS was 15 months and mOS was 25 months with no significant difference compared to younger patients (rwPFS HR 1.1; p = 0.65; OS HR 1.4; p = 0.21). Most common adverse events (AEs) were diarrhoea (68.7%), anaemia (64.9%), and increased serum creatinine (63.4%). Grade 3/4 AEs were reported in 21.6% of patients. Dose reductions occurred in 30.6% of patients and were more frequent in patients 70+ (40%) compared to younger patients (28%); the difference was not significant (p = 0.22). At study cut-off, 64.9% of patients discontinued abemaciclib, primarily due to disease progression (73.5%). (4) Conclusions: Our study provides valuable insights into the effectiveness and safety of abemaciclib for the treatment of MBC. We observed comparable outcomes in terms of rwPFS and OS between the first two lines, suggesting consistent effectiveness across treatment lines. In addition, our findings suggest that older age (70+) does not significantly impact the effectiveness and tolerability of abemaciclib, although the careful monitoring and management of AEs are warranted.

Natural history of SCLC patients treated in third-line and beyond: A retrospective real world study

ObjectivesTo describe treatment patterns and estimate outcomes among real-world small cell lung cancer (SCLC) patients in the US who received three or more lines of therapy. Materials and methodsWe conducted a retrospective analysis of adult patients with SCLC who received a front-line platinum-based regimen and two additional lines of therapy (ie., a cohort of at least three lines of therapy). De-identified patients were selected from a United States Flatiron Health oncology database of electronic health records. Treatment patterns were captured by line of therapy. Outcomes evaluated by line of therapy included real-world overall survival (rwOS), real-world progression free survival (rwPFS), real-world response rate (rwRR) and real-world duration of response (rwDOR). ResultsThe analysis included 326 3L SCLC patients, of which 103 (32 %) received 4L treatment, and 38 % (39/103) of 4L treated received 5L of therapy. Among the 3L cohort, the average age was 67 years, 49 % were male, and nearly all had a history of smoking (96 %). In the 3L setting, the median rwOS was 5.3 months (95 % Confidence Interval (CI): 4.5, 6.0), median rwPFS was 2.5 months (95 % CI: 2.1, 2.7), rwRR was 19.3 % (95 % CI: 15.2, 24.0) and median DOR was 3.4 months (95 % CI: 2.8, 4.4). No differences were seen in outcomes between the overall cohort and a subgroup of patients treated with front-line platinum-based regimen with an anti-programmed cell death ligand 1 (PD-L1) agent (atezolizumab or durvalumab), in each respective line of therapy. ConclusionResults from this large, real-world study of US patients with SCLC in the 3L setting and beyond highlight the poor treatment outcomes in advanced SCLC patients with existing therapies and underscore the dire need for new therapies for SCLC patients.

Efficacy and safety of crizotinib in the treatment of advanced non-small cell lung cancer with ROS1 gene fusion: a systematic literature review and meta-analysis of real-world evidence

BackgroundCrizotinib was approved to treat patients with advanced non-small cell lung cancer (aNSCLC) with ROS proto-oncogene 1 (ROS1) gene fusion in 2016. We conducted a systematic literature review to identify real-world evidence (RWE) studies and estimated the efficacy and safety of crizotinib using meta–analyses (MA) for objective response rate (ORR), real-world progression-free survival (PFS), and overall survival (OS). MethodsWe searched MEDLINE®, Embase, and Cochrane CENTRAL from January 2016 to March 2023 using Ovid® for published single-arm or comparative RWE studies evaluating patients (N ≥ 20) receiving crizotinib monotherapy for aNSCLC with ROS1 gene fusion. Pooled estimates for ORR and grade 3/4 adverse events (AEs) were derived using the metafor package in R while pooled estimates for median real-world PFS (rwPFS) and OS were derived using reconstructed individual patient data from published Kaplan-Meier curves. The primary analysis included all studies regardless of crizotinib line of therapy; a subgroup analysis (SA) was conducted using studies evaluating patients receiving first-line crizotinib. ResultsFourteen studies met the eligibility criteria and were considered feasible for MA. For the primary analysis, the pooled ORR (N = 9 studies) was 70.6 % (95 % confidence interval [CI]: 57.0, 81.3), median rwPFS was 14.5 months (N = 11 studies), and OS was 40.2 months (N = 9 studies). In the SA, the pooled ORR (N = 4 studies) was 81.1 % (95 % CI: 76.1, 85.2) and the median rwPFS (N = 4 studies) and OS (N = 2 studies) were 18.1 and 60 months, respectively. All MAs were associated with significant heterogeneity (I2 > 25 %). Grade 3/4 AEs occurred in 18.7 % of patients (pooled estimate). ConclusionThe results from this study are consistent with clinical trial data and, taken collectively, supports crizotinib as a safe and effective treatment across different lines of therapy in patients with ROS1 aNSCLC in the real-world setting.

Real-world effectiveness of CDK4/6 inhibitors on patients with HR+/HER2– advanced breast cancer in South Korea, focusing on underrepresented patients

Objective We assessed the real-world effectiveness of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors as first-line treatments in postmenopausal patients with HR+/HER2− advanced breast cancer, focusing on younger (<45 years) and older (>78 years) populations not considered in clinical trials. Methods We analyzed nationwide claims data from the Health Insurance Review and Assessment Service between November 2016 and February 2021. In this retrospective cohort study, patients using CDK4/6 inhibitors and aromatase inhibitors were selected and grouped by age as follows: 45–78 years (trial-enrolled), <45 years (younger), and >78 years (older). We estimated the median real-world progression-free survival (rwPFS) and overall survival (OS) using the Kaplan-Meier method. We conducted Cox regression analysis using a sub-distribution hazard model to evaluate risk factors (age, history of prior systemic treatment, presence of metastasis, comorbidity index, and type of provider) and estimated hazard ratios (HR). Results Among the 2,830 patients who received CDK4/6 inhibitors as first-line therapy, we identified 358 (12.65%) younger and 148 (5.23%) older underrepresented patients. The younger patient group (50.84%) had the highest rate of prior systemic therapy, followed by the trial-enrolled (25.39%) and older patient groups (8.11%). The median rwPFS was shorter in the older group (19.30 months) than those in the younger and the trial-enrolled age groups (30.33 and 34.53 months, respectively; p = .002). The HR of older age for death was 1.59 (95% confidence interval (CI) = 1.24–2.03). For rwPFS, the HR of prior systemic therapy was 1.19 (95% CI = 1.04–1.37). Conclusions The younger age group, which was underrepresented in the trial, did not show a significant difference in risk compared with the enrolled age group. However, the older age group, which was also underrepresented in the trial, faces a risk of mortality but not progression. Patients who fall outside the specified age groups for the clinical trial can still expect the same level of effectiveness in terms of progression.

Abstract PO3-04-10: Real-world progression-free survival and overall survival of palbociclib plus endocrine therapy in Japanese patients with HR+/HER2- ABC in the first- or second-line setting: A multicenter observational study

Abstract Introduction Palbociclib (PAL), a selective, oral inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), plus (+) endocrine therapy (ET) is standard therapy for the treatment of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) and was launched in December 2017 in Japan. Efficacy and safety of PAL + ET was shown by randomized clinical studies, PALOMA-2 and PALOMA-3. Further, recent large real-world studies, P-REALITY/P-REALITY X, confirmed effectiveness of PAL+ aromatase inhibitor (AI) for HR+/HER2- ABC in routine United States clinical practice. However, there is limited real-world evidence (RWE) for PAL in Japan. To strengthen the RWE of PAL+ET for HR+/HER2- ABC treatment under different clinical practice and healthcare system, we examine the real-world effectiveness of PAL + ET as 1st line (1L) and 2nd line (2L) treatment for HR+/HER2- ABC in Japan. Methods In this multicenter, observational study, patients with HR+/HER2- ABC, who initiated PAL + ET from 15 December 2017 to 31 December 2020 were enrolled. To reduce selection bias, all patients who started PAL during the above period were listed and their eligibility confirmed. Eligible patients had 1) diagnosis of HR+/HER2- ABC; 2) received PAL + ET as 1L or 2L treatment; 3) at least 6 months of follow up from start of PAL or died within that period. The 1L treatment was defined as the first systemic therapy received for ABC regardless of recurrence timing if receiving adjuvant treatment. The subsequent treatment after 1L treatment was defined as a 2L treatment. The primary endpoint was real-world progression-free survival (rwPFS) defined as the time from PAL+ET start to physician-documented disease progression or death due to any cause, whichever occurs first. Secondary endpoints included overall survival (OS), and chemotherapy-free survival (CFS). Results were stratified by treatment line (ie. 1L or 2L). rwPFS, OS, and CFS were analyzed with the Kaplan-Meier method (NCT05399329). Results In this study, 677 patients were enrolled. Among them, 419 (62%) patients and 258 (38%) patients received PAL + ET as 1L and 2L, respectively. The median age was 59.0 (range 29-87) and 470 patients (69.8%) were postmenopausal. 49.0% patients had visceral involvement and 63.8% had a disease-free interval &amp;gt;24 months, defined as date of breast cancer surgery to the diagnosis date of recurrence, and 26.9% had de novo metastatic disease. The starting dose of PAL was 125 mg (89%), 100mg (9%), and 75mg (2%); dose reductions during the treatment period were required for 72% of patients. The most common ET combined with PAL was fulvestrant (FUL; 56.3% in 1L, 76.7% in 2L) followed by letrozole (LET; 37.9% in 1L, 16.3% in 2L). After a median follow-up of 36.2 months, the median rwPFS (95% CI) was 24.5 months (19.9-29.4) for 1L treatment and 14.5 months (10.2-18.3) for 2L treatment. Among the 604 patients initiating at 125 mg/day, the median rwPFS was 25.6 months (21.3-30.4) for 1L treatment and 14.3 months (9.7-18.3) for 2L treatment. Although median OS was not reached (NR) in 1L, median OS of 2L was 44.1 months (39.2 -NR). The 48-months OS rates for 1L and 2L treatment were 62.0% (55.4-67.9) and 48.4 % (40.4-55.9), respectively. The median CFS was 36.7 months (31.8-43.9) for 1L treatment and 23.8 months (20.5-27.3) for 2L treatment. Conclusions Our real-world data are consistent with findings form the PALOMA-2 and PALOMA-3 studies and those from RWE in routine United States clinical practice. FUL was the most commonly endocrine partner with PAL regardless of treatment lines. These observations add to the body of evidence supporting PAL effectiveness in clinical practice for Japanese ABC patients. Citation Format: Norikazu Masuda, Masaya Hattori, Tersuhiro Yoshinami, Takuho Okamura, Ken-ichi Watanabe, Takahiro Nakayama, Hiroko Masuda, Michiko Tsuneizumi, Daisuke Takabatake, Michiko Harao, Hiroshi Yoshino, Natsuko Mori, Hiroyuki Yasojima, Chiya Oshiro, Madoka Iwase, Miki Yamaguchi, Takafumi Sangai, Shinsuke Sasada, Takanori Ishida, Manabu Futamura, Nobuyoshi Kosaka, Yoshiyuki Shibasaki, Shigenori Nagai. Real-world progression-free survival and overall survival of palbociclib plus endocrine therapy in Japanese patients with HR+/HER2- ABC in the first- or second-line setting: A multicenter observational study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-04-10.

Abstract PO4-05-04: Comparative effectiveness of Palbociclib plus Aromatase inhibitor versus fulvestrant alone as initial endocrine therapy for HR+/HER2- advanced breast cancer in Chinese clinical practice: a real-world study

Abstract Background: In the real world, there are still a large number of HR+/HER2- advanced breast cancer patients receiving initial endocrine therapy with fulvestrant monotherapy in China, especially patients with bone metastases only. It is due to lack of data comparing the effective between Palbociclib combined with AI and fulvestrant monotherapy as initial endocrine therapy. On the other hand, there are economic factors and access issues. According to the National Cancer Center's previous clinical experience, Palbociclib combined with AI is superior to fulvestrant monotherapy in HR+/HER2- advanced breast cancer patients receiving initial endocrine therapy. Therefore, we collected and summarized the previous clinical data in our center to compare the effective of Palbociclib combined with AI and fulvestrant monotherapy for HR+/HER2-advanced breast cancer patients receiving initial endocrine therapy in China. Patients and methods: This is a retrospective real-world study of multicenter studies. It aimed at verifying the effective of Palbociclib combined with AI and fulvestrant monotherapy for HR+/HER2-advanced breast cancer patients receiving initial endocrine therapy in China. A total of 392 patients with ≥3 months of follow-up received Palbociclib plus AI or fulvestrant alone in the first-line setting between April 1, 2015 and February 1, 2023. Stabilized inverse probability treatment weighting (sIPTW) was used to balance baseline demographic and clinical characteristics. Real-world progression-free survival (rwPFS) and overall survival (OS) were analyzed. Results: After sIPTW adjustment, a median follow-up of 37 months (range 34-40) in the Palbociclib group and 59 months (range 56-61) in those taking fulvestrant alone. Palbociclib combination regiment was associated with significantly longer median rwPFS compared to fulvestrant alone (22.0 vs 14.0 months; HR,0.469;95% CI 0.370–0.594, p&amp;lt; 0·0001). Median OS was not reached in the Palbociclib group and was 57 months (95% CI 54.0–66.0) in the fulvestrant group(HR,0.666; 95% CI 0.437–1.017, p&amp;lt; 0·94). Conclusion: In the real-world population of patients, palbociclib combined with AI endocrine therapy is superior to fulvestrant monotherapy in HR+/HER2- advanced breast cancer patients receiving initial endocrine therapy. PFS and OS before IPTW PFS and OS after IPTW Table patient characteristics Citation Format: Jian Yue, Xue Wang, Jie Ju, Zixiang Yang, Tong Wei, Peng Yuan, Min Gao, Ling Xu, Yin Guan. Comparative effectiveness of Palbociclib plus Aromatase inhibitor versus fulvestrant alone as initial endocrine therapy for HR+/HER2- advanced breast cancer in Chinese clinical practice: a real-world study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-05-04.

Abstract PO2-19-06: An Open-label, Interventional, Multicenter Study of Trastuzumab Deruxtecan Monotherapy in Patients With Unresectable and/or Metastatic HER2-Low or HER2 Immunohistochemistry 0 Breast Cancer: DESTINY-Breast15

Abstract Background Approximately 50% of all breast cancer (BC) tumors express low levels of HER2, defined by HER2 immunohistochemistry (IHC) scores of 1+ or IHC 2+/in situ hybridization negative (ISH−), and are referred to as HER2-low BC. Trastuzumab deruxtecan (T-DXd), a HER2-directed antibody-drug conjugate, has been approved in the United States, European Union, and other countries for the treatment of adult patients with unresectable or metastatic HER2-low BC (IHC 1+ or IHC 2+/ISH−), regardless of hormone receptor (HR) status, who previously received chemotherapy in the metastatic setting or who have developed disease recurrence within 6 months of completing adjuvant chemotherapy. The DESTINY-Breast04 trial that formed the basis of T-DXd approval in HER2-low BC included only 63 patients who were HR–negative and patients with HER2 IHC 0 status were not enrolled. However, the phase 2 DAISY trial demonstrated clinically meaningful activity of T-DXd in patients with HER2 IHC 0 BC. Along with HER2 status, HR–positive or HR-negative tumor status could confer variation in prognosis and sensitivity to systemic therapy. Few targeted agents are available for patients with HR-negative, HER2 IHC 0 metastatic BC, particularly for patients without pathogenic BC gene mutations or programmed cell death ligand 1 expression. Therefore, there is an unmet medical need for therapeutic treatment options in this patient population. Study Description DESTINY-Breast15 is a multicenter, open-label, single-arm, phase 3b trial designed to evaluate the efficacy and safety of T-DXd in patients with HR-positive or HR-negative unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH−) or HER2 IHC 0 BC who received 1 or 2 lines of prior therapy in the metastatic setting, including (but not limited to) targeted agents or endocrine therapy per cohort. Patients must have an ECOG PS score of 0 or 1, have never previously been HER2-positive (IHC 3+ or IHC 2+/ISH+), and have never previously received anti-HER2 therapy in the metastatic setting. At least 250 patients will be enrolled from approximately 80 sites in Belgium, Brazil, China, Ireland, Italy, Netherlands, Portugal, Spain, and the United States to receive T-DXd and will be assigned to 1 of 4 cohorts according to their HR and HER2 status (tested per local practice in accordance with ASCO/CAP 2018 guidelines). The 4 cohorts are cohort 1, HR-negative, HER2-low (n ≈ 100); cohort 2, HR-negative, HER2 IHC 0 (n ≈ 50); cohort 3, HR-positive, HER2-low (n ≈ 50); and cohort 4, HR-positive, HER2 IHC 0 (n ≈ 50). Cohort 3 will specifically recruit patients with rapid disease progression, defined as recurrent disease &amp;lt; 2 years from starting adjuvant endocrine therapy, progression within 12 months of completing adjuvant CDK4/6 inhibitor, or progression within 12 months of starting CDK4/6 inhibitor therapy in the metastatic setting. T-DXd will be administered at a dose of 5.4 mg/kg intravenously once every 3 weeks until disease progression, unacceptable toxicity, or 2 years after the first dose of T-DXd. The primary end point is time from the start of T-DXd treatment to initiation of subsequent anticancer treatment or death. Secondary end points are real-world progression-free survival (defined as time from the date of first administration of T-DXd to date of first observed instance of disease progression per RECIST version 1.1 or death from any cause), time to treatment discontinuation or death, objective response rate per RECIST version 1.1, safety, and patient-reported quality-of-life–related outcomes. Time-to-event endpoints will be evaluated using Kaplan-Meier methods. Citation Format: Shanu Modi, Roberto Salgado, Valentina Guarneri, Divi Alagappan, Natalie Dennis, Amy Hanlon Newell, Aislyn Boran, Ouzna Morsli, Antonio Llombart-Cussac. An Open-label, Interventional, Multicenter Study of Trastuzumab Deruxtecan Monotherapy in Patients With Unresectable and/or Metastatic HER2-Low or HER2 Immunohistochemistry 0 Breast Cancer: DESTINY-Breast15 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-19-06.

Abstract PO1-17-05: Real-world effectiveness of palbociclib plus aromatase inhibitors (AI) in metastatic breast cancer patients with cardiovascular diseases

Abstract Background Breast cancer survivors are at risk for mortality from cardiovascular diseases (CVD). CVD and their treatments can impact breast cancer treatment selection and clinical outcomes. A cyclin dependent kinase 4/6 inhibitor (CDK4/6i) combined with endocrine therapy (ET) is more effective than ET alone for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2) metastatic breast cancer (MBC). CDK4/6i plus ET is now the standard of care in the first-line setting for HR+/HER2 MBC. However, data on the effectiveness of CDK4/6i in MBC patients with CVD are limited. We compared overall survival (OS) and real-world progression-free survival (rwPFS) of palbociclib plus AI (PAL+AI) vs AI alone in HR+/HER2 MBC patients with CVD in routine US clinical practices. Methods The Flatiron Health longitudinal database contains electronic health records from &amp;gt;280 cancer clinics, representing &amp;gt;3 million actively treated cancer patients in the US. Using the Flatiron database, we conducted a retrospective analysis of 469 patients with HR+/HER2 MBC and CVD who started PAL+AI or AI as first-line therapy between February 2015 and March 2020. CVD prior to the initiation of PAL+AI or AI were identified based on their definitions within the National Cancer Institute-Comorbidity Index (NCI-CI), including myocardial infarction, congestive heart failure, peripheral vascular diseases, and cerebrovascular diseases. Patients were assessed from start of PAL+AI or AI to September 30, 2020 (data cutoff date), death, or last visit, whichever came first. OS was defined as months from start of PAL+AI or AI to death. rwPFS was defined as months from start of PAL+AI or AI to death or disease progression, evaluated based on clinical assessment or radiographic scan/tissue biopsy. Stabilized inverse probability treatment weighting (sIPTW) as primary analysis was used to balance baseline demographics and clinical characteristics. Cox proportional-hazards models were used to estimate the relative effectiveness of PAL+AI vs AI alone. Results Of the 469 eligible patients, 160 (34.1%) were treated with PAL+AI and 309 (65.9%) were treated with AI alone. Compared with AI-alone patients, those treated with PAL+AI were younger and were more likely to have de novo MBC, ≥2 metastatic sites, and lung/liver involvement. After sIPTW, patient characteristics were generally balanced. After sIPTW, median OS (95% confidence interval [CI]) was 40.7 months (30.956.0) in PAL+AI patients and 26.5 months (23.337.3) in AI patients (hazard ratio [HR]=0.732, 95% CI=0.5370.997, p=0.0476). Median rwPFS (95% CI) was 20.0 months (11.7–27.5) in PAL+AI patients and 12.5 months (9.718.3) in AI patients (HR=0.679, 95% CI=0.5120.900, p=0.0070). Consistent results were observed with multivariate Cox proportional-hazards models as sensitivity analysis. See Table for baseline patient characteristics and outcome results. Conclusions First-line PAL in combination with AI is associated with prolonged OS and rwPFS in patients with HR+/HER2 MBC and CVD in a real-world setting compared with AI alone. Further studies with larger cohorts and comprehensive assessments of comorbidities are needed to provide additional evidence of outcomes and safety of CDK4/6i plus AI for MBC patients with various comorbid conditions in routine clinical practice. Citation Format: Adam Brufsky, Xianchen Liu, Benjamin Li, Lynn McRoy, Connie Chen, Doris Makari, Rachel Layman, Hope Rugo. Real-world effectiveness of palbociclib plus aromatase inhibitors (AI) in metastatic breast cancer patients with cardiovascular diseases [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-17-05.

Abstract PO1-16-06: LuciA-15 - A real-world prospective study of PARP inhibitors for the treatment of Latin American patients with HER-2 negative metastatic breast cancer with mutation of BRCA1/2 genes or in the Homologous Recombination Repair genes

Abstract Background PARP inhibitors (PARPi) improves progression free survival among patients with HER2 negative (HER2-ve) advanced breast cancer (ABC) and a BRCA1 or BRCA2 mutation compared to physician choice of chemotherapy (CT). The AIM of this prospective study was to evaluate the clinical benefit of PARPi treatment in terms of response, outcomes and survival by breast cancer type and treatment in a Latin-American population. Methods We analyzed data of patients with HER2-ve ABC with germline and/or somatic mutation of BRCA 1 or BRCA 2 or in the Homologous Recombination Repair genes, treated with olaparib or talazoparib in daily clinical practice by oncologist from Argentina and México. From September 2019 and April 2023, we collected baseline characteristics, previous systemic treatments, type and pattern of use, treatment beyond PARPi progression, and patient predisposition. Objective responses, best response rate, real-world progression-free survival (rwPFS) and real-world overall survival (rwOS) were analyzed with R software and RStudio version 14.0. Results After a median follow-up of 18.07 months (CI95% 10.53 - 30.07), 51 patients were treated with PARPi. Mean age at start treatment was 47,08 years. 62.7% had ER+ve/HER2-ve and 35.3% had triple negative breast cancer (TNBC). 62.7% and 37.3% of patients received talalaparib and olaparib, respectively. BRCA 1 and 2 germline mutations were the most common alterations found in 96% of patients. 37.5% of patients received platinum-based CT (PbCT) in the (neo)adjuvant/metastatic setting. 57.5% had visceral metastasis and the median number of metastatic sites were 2 (range 1-4). Median number of lines at the time to start PARPi was 2 (range 0-8), 23.5% and 31.4% received PARPi in the 1st line and 2nd line, respectively. The rwORR was 47.0%, and the median rwPFS1 was 7.77 months (CI95% 5.67-14.7). There was a tendence of better rwPFS1 in patients without previous CT versus previous CT in the advance setting, 14.30 months (CI95% 6.47-NR) versus 6.37 months (CI95% 5.03-8.73), respectively (p 0.084). The median rwOS was 26.97 months (CI95% 13.50-NR) and higher in the subgroup of patients naïve for CT versus previous exposure to CT in the advance setting, the median rwOS was 32.1 months (CI95% 27.0-NR) versus 13.0 (IC95%10.1-NR), respectively (p 0.022). 23.5% of patients progressed on PARPi during the first 6 months of treatment, 32.4% with visceral compromise, 27.8% with visceral crisis, and 26.5% with ≥2 metastatic sites. CT was the treatment of choice in most patients (55.3%). The medium rwPFS2 (next treatment after PARPi failure) was 4.00 months (CI95% 3.43 – 7.13). Treatment was discontinued for adverse events in 4.0 % of patients. Conclusion This is the first Latin-American evidence that replicate the data already published in randomized clinical trials and other scanty real-world evidence studies in this field, positive results in rwORR and rwPFS, encouraging data in rwOS. Notably, high proportion of patients with visceral progression even with visceral crisis and need for CT. Interestingly, similar rwOS results among subgroups (TNBC versus ER+ve/HER2-ve, talazoparib versus Olaparib, etc). &amp;lt;graphic&amp;gt; Citation Format: Fernando E. Petracci, Cynthia Villarreal-Garza, Facundo Argañaraz, Gonzalo Gómez Abuin, José Peñaloza, Marcos A. Flores, Luciano Piazzoni, Cecilia Riggi, Lucía Fabiano, Lucía González, Belén Cieplinski, Sergio Rivero, Ernesto Korbenfeld, Pablo Mandó. LuciA-15 - A real-world prospective study of PARP inhibitors for the treatment of Latin American patients with HER-2 negative metastatic breast cancer with mutation of BRCA1/2 genes or in the Homologous Recombination Repair genes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-16-06.