Line Setting Research Articles

Phase II study of sitravatinib in combination with tislelizumab in patients with advanced biliary tract cancer who have failed to at least 1 prior systemic treatment.

4018 Background: In first line of advanced biliary tract cancer (BTC), immune-checkpoint inhibitor (ICI) in combination with cytotoxic chemotherapy is now standard of care supported by TOPAZ-1 and KN-966 studies. With this landscape, new drug development using ICI in second or later line setting is urgent unmet medical needs area. Anti-angiogenic agent induced improved anti-tumor immune responses by increasing tumor antigen presentation and promoting lymphocyte infiltration and migration. Methods: This study is an open-label, phase 2 trial to investigate the efficacy of sitravatinib and tislelizumab (PD1 inhibitor) combination treatment for 2L advanced BTC. Patients who received prior ICI could be enrolled. All patients received sitravatinib 120mg orally once daily in combination with tislelizumab 200mg intravenously once every 3 weeks until disease progression, unacceptable toxicity. The primary endpoint was disease control rate (DCR), with key secondary endpoints including overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Tissue biopsies were conducted three times in total: screening, the first response evaluation, and disease progression. Blood samples were collected every cycles. (NCT04727996) Results: A total of 43 patients were enrolled. Data-cut off was on July 31, 2023. Median follow-up was 10.5months (95% Confidence interval (CI), 7.03-15.6). 9 patients had received prior ICI. This study met primary endpoint as a DCR of 65.1% in all population. ORR was 20.5% in unselected per-protocol population, and PFS was 4.93 months (95% CI, 3.10-8.87). OS was 10.3months (95% CI, 6.67-18.2). Similar efficacy was observed regardless of prior ICI exposure. The most common treatment-related adverse events (AEs) were sitravatinib-related; hand-foot syndrome (any grade 60.5%, grade 3/4 0%), hypertension (any grade 34.9%, grade 3/4 11.6%). Immune-related AEs (irAEs) were 46.5%, with most irAEs being grade 1-2. In exploratory analysis, patients with homologous recombination deficiency (HRD) detected by baseline tissue NGS (frequency 18.5%) showed higher ORR (60% vs 13.6%), longer PFS (not reached vs 4.87 months) and OS (21.1 vs 8.57 months) than patients without HRD. HRD detected by circulating tumor DNA had a complementary role for patient selection. RNA sequencing showed upregulation in inflammatory signal and downregulation in angiogenesis signal between screening and on-treatment tumor tissue. Responders showed higher inflammatory signaling at baseline and on-treatment tumor tissue compared to non-responders. Conclusions: Sitravatinib/tiselizumab combination as 2L therapy in patients with advanced BTC demonstrated meaningful efficacy and an acceptable safety profile. Especially, patient selection using HRD biomarker might be a promising strategy in this setting. Clinical trial information: NCT04727996 .

Characteristics, treatment patterns, and prognostic factors in small cell lung cancer transformation of advanced non-small cell lung cancer with epidermal growth factor receptor mutation after tyrosine kinase inhibitor therapy.

e20569 Background: Small cell lung cancer transformation in advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation following tyrosine kinase inhibitor (TKI) therapy poses a challenging clinical scenario. This study aims to explore the characteristics, treatment patterns, and prognostic factors associated with this transformation. Methods: A total of 41 patients with transformed SCLC (tSCLC) were included. Patient characteristics, treatment details, and laboratory data were collected. Re-biopsy specimens and subsequent treatments were analyzed. Statistical analyses were conducted to identify factors associated with treatment response and survival outcomes. Results: The median age of the patients was 61.7 years old, with a median time from TKI treatment to small cell transformation of 22.2 months. The majority were female (58.5%), never smokers (80.5%), with 53.7% having stage IVB disease prior to EGFR-TKI treatment. The most prevalent initial EGFR mutation was exon 19 deletion (56.1%), and afatinib (46.3%) was the most commonly used EGFR-TKI. EGFR mutation analysis was performed in 68.3% of the tSCLC specimen, and acquired T790M was detected in 7.1% of the patients. Treatment patterns after transformation included various systemic therapies, with the most (63.4%) receiving etoposide plus platinum (EP) based chemotherapy in the first line setting. Among all the patients, 56.1% received EGFR-TKI and 22% received immune checkpoint inhibitors (ICI) throughout the post-transformation treatment course. Anemia (Hgb < 10g/dL) and ever use of EP were significant factors associated with post-transformation survival. The median progression-free survival (PFS) of the first line treatment was 3.27 months, and the overall survival (OS) was 10.43 months post transformation. Conclusions: Small cell lung cancer transformation in advanced NSCLC with EGFR mutation after TKI therapy is associated with diverse clinical characteristics and dismal outcomes. We presented the complexity of managing these cases in real-world practice. Anemia and ever use of EP affected post-transformation survival. Further research is warranted to optimize therapeutic strategies for this unique subset of patients.

Real-world KRAS testing and treatment utilization among patients with metastatic non-small cell lung cancer.

e20593 Background: About 30% of patients with non-small cell lung cancer (NSCLC) have been reported to harbor gene mutations of Kirsten rat sarcoma oncogene homologue (KRAS). KRAS testing is recommended at metastatic NSCLC (mNSCLC) diagnosis and targeted treatment has shown better outcomes among KRAS-positive patients. This study aimed to understand KRAS testing rates among mNSCLC patients and utilization of targeted treatment among KRAS G12C positive patients treated in the community oncology setting. Methods: A random sample of 836 mNSCLC patients from the Integra Connect PrecisionQ de-identified database was included in this retrospective observational analysis, with additional information supplemented by chart curation. The database contains ~80% community oncology and ~20% academic practices with over 3 million cancer patients across 500 sites of care. Eligible patients were those aged ≥18 years, diagnosed with mNSCLC, and who initiated treatment in the second line (2L) setting between 01-May-2021 and 01-Jan-2024. KRAS testing rates and utilization of targeted treatment use were assessed and presented for this study. Results: The median (IQR) age of 836 mNSCLC patients was 68 (62,75) years; 52.9% were female; 73.8% identified as White, 11.7% as African American, 1.9% as Asian, and 12.6% as Other. Testing for KRAS was reported in 749 (89.6%) of the mNSCLC patients any time during the evaluation period, with most of them (738/749) tested before 2L treatment initiation; 186/749 (24.8%) of those patients were positive, and 74 were KRAS G12C positive. Of the KRAS G12C positive patients, 53/74 (71.6%) reported a targeted KRAS treatment in the 2L or greater setting. Conclusions: In this real-world setting, the testing rates for KRAS are almost 90%, with about 70% of the mutated patients receiving a targeted treatment. However, there is still a proportion of patients who did not receive KRAS testing or targeted treatment in this real-world setting. Appropriate and timely testing and utilization of the targeted treatment is necessary for better patient outcomes. [Table: see text]

Safety and efficacy of osimertinib in patients with NSCLC and uncommon tumoral EGFR mutations: A systematic review and meta-analysis.

8642 Background: Osimertinib is broadly used for advanced EGFR-mutant NSCLC patients. However, the activity of osimertinib is not fully characterized in tumors harboring uncommon EGFR mutations, which represents about 10% of EGFR-mutated NSCLC cases. Hence, we conducted a systematic review and meta-analysis to assess the efficacy and safety of osimertinib in patients with NSCLC and uncommon tumoral EGFR mutations. Methods: PubMed, Embase, and the Cochrane Library were searched for eligible studies. Uncommon EGFR mutations were defined as any mutation other than the exon 19 deletion, L858R and T790M mutations, and exon 20 insertion, except when in compound. Efficacy was assessed by objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Heterogeneity was examined with I2 statistics and random-effect model was used for a meta-analysis. Results: Nine studies comprising 331 patients were included. Median follow-up ranged from 12.6 to 22.0 months (mos). Median age in each study ranged from 51 to 72 years old (table). Overall, 62% (205/331) of patients were female and 77% (256/331) of patients had an ECOG PS ≤1. About 78% (258/331) of patients received Osimertinib in a 1st line setting. Uncommon tumoral EGFR mutations included G719X in 40% (131/331) of patients, L861X in 27% (91/331), and S768I in 15% (49/331). Pooled analysis showed an overall ORR of 49.5% (95% CI, 42.2 – 56.9), a DCR of 90.2% (95% CI, 86.2 – 94.3), a median OS of 24.5 mos (95% CI, 11.9 – 24.5), a median PFS of 9.5 mos (95% CI, 8.2 – 11.0), and a median DOR of 17.4 mos (95% CI, 7.9 – 22.7). Intracranial (i) efficacy had an iORR of 50.3% (95% CI, 30.3 – 70.3), an iDCR of 92.8% (95% CI, 76.2 – 100), and a median iPFS of 6.1 mos (95% CI, 4.5 – 6.6). In a subgroup analysis according to EGFR mutation, overall ORR was significantly different in patients with tumoral G719X, S768I and L861 mutations (ORRs of 28.8%, 33.3%, and 67.7%, respectively, p for subgroup differences < 0.01). Overall, osimertinib was well tolerated with a frequency of all-grade AEs of 86.2% (95% CI, 61.2 – 100) and ≥ G3 of 18.0% (95% CI, 1.2 – 34.7). Conclusions: This systematic review and meta-analysis suggests that patients with NSCLC with uncommon tumoral EGFR mutations may benefit from osimertinib treatment. Patients harboring tumoral L861 mutation achieved a significantly higher ORR compared to the modest ORR in G719X, S768I cases. [Table: see text]

Overall survival analysis of first line CDK4/6 inhibitors in a large real-world cohort of patients with hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer.

e13095 Background: Multiple clinical trials have demonstrated the efficacy of the commercially available CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) as upfront therapy in patients (pts) with (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC). Recently, differences in overall survival (OS) benefit in MBC and invasive disease-free survival benefit in early-stage BC suggest greater potency of abemaciclib and ribociclib compared to palbociclib. Here we report a comprehensive OS analysis of a cohort of pts with HR+/HER2- MBC treated with ribociclib, palbociclib or abemaciclib and ET in 1st line setting. Methods: We retrieved medical records of pts with HR+/HER2- MBC receiving CDK4/6i as 1st line therapy between December 2013 and October 2023 at Memorial Sloan Kettering Cancer Center. We investigated the impact of clinico-pathological characteristics and treatment type as categorical variables on OS using uni- and multivariate Cox (proportional hazard) regression model. Any p-value (p) <0.05 was deemed to be statistically significant. Results: 854 pts were included in the analysis, 838 females (98%) and 16 males at birth. The median age was 56 (IQR: 48-65). Overall, 722 (84%) pts received palbociclib, 88 (11%) abemaciclib, and 44 (5%) ribociclib. Most pts received aromatase inhibitor (AI) as ET backbone (n=634, 74%); 214 received fulvestrant (35%), and 6 received tamoxifen (1%). After a median follow-up of 3.14 years (range: 1.7-4.6), the median OS of the full cohort was 54.7 months (95%CI: 50-63.1). Clinico-pathological characteristics that resulted independently associated with worse OS were: male gender at birth (HR:2, 95%CI:1.4-4), disease-free interval ≤ 2 years (HR:1.64, 95%CI:1.11-2.44), ER-low status (HR: 2.27, 95%CI:1.42-3.63), high grade(HR: 1.28, 95%CI:1.01-1.62), liver involvement (HR: 1.48, 95%CI:1.08-2.03), and number of disease sites >3 (HR:1.35, 95%CI:1.03-1.78). HER2-low status was associated with better OS (HR: 0.75, 95%CI:0.59-0.96). In terms of type of treatment, there was a trend toward improved OS in patients receiving AI rather than fulvestrant or tamoxifen (HR:0.76, 95%: 0.58-1), while the type of CDK4/6i did not affect the outcome. Conclusions: Clinical parameters of early relapse, high disease burden, and intrinsic tumor aggressiveness seem to be the main drivers of poor prognosis in patients with HR+/HER2- MBC in 1st line setting. In this analysis, type of CDK4/6i did not have a significant impact on OS, although pts treated with abemaciclib and ribociclib were underrepresented in the cohort due to the earlier and prevalent use of palbociclib as the first-in-class FDA-approved CDK4/6i. These data are reassuring about the use of palbociclib suggesting that a switch of CKD4/6i is not needed in pts with ongoing treatment and demonstrated benefit.

A phase 1b study of tbio-4101 (autologous selected and expanded tumor-infiltrating lymphocytes [TILs]) with pembrolizumab in patients with anti-PD-1–resistant, advanced head and neck squamous cell carcinoma (aHNSCC).

TPS6115 Background: Despite the excitement and approval of anti-PD1 therapy in first line setting of patients with aHNSCC, prognosis remains poor, with the majority experiencing disease progression after therapy. Consequently, novel strategies to improve treatment activity represent a critical and unmet need for this patient population. Cell therapies offer the advantage of a more personalized therapy for patients over standard immune checkpoint inhibitors. Historically, cell therapies have relied on bulk products that may not effectively select a tumor-reactive T cell population. TBio-4101 is produced by an industrialized manufacturing approach leveraging single-cell sorting of patient-specific neoepitope-reactive TIL with the potential to address immunologically ‘cold’ tumors. The TBio-4101 process specifically enriches polyclonal, polyfunctional, tumor-reactive T cells with an endogenous neoantigen-reactive T cell receptor repertoire that can target multiple tumor antigens. Non-tumor-reactive bystander T cells, which may negatively impact treatment efficacy via product dilution, and typically account for ≥90% of bulk TIL, are substantially reduced by this process. Inspired by the early academic clinically efficacious NCI selection and enrichment strategies (Tran et al 2014, 2016; Zacharakis et al, 2022), TBio-4101 is refined to better identify and potentially enrich to >70% tumor-reactive CD8+ and CD4+ T cells (median < 3% in bulk TIL). Methods: This is a Phase 1b, open-label, single-center study of TBio-4101 and pembrolizumab. Eligible patients are 18 to 75 years of age with aHNSCC. Prior to receiving pembrolizumab with or without chemotherapy as first line standard-of-care (SOC), these patients undergo tumor harvest for TILs followed by apheresis to collect monocytes. TILs are isolated from the tumor and expanded in vitro. Patient-specific neoepitopes are defined by whole exome and RNA sequencing of tumor versus germline to manufacture a peptide pool representing potential tumor-specific mutations. Monocytes isolated from apheresis are differentiated into dendritic cells, pulsed with the neoepitope peptides, and co-cultured with the TILs. Tumor-reactive T cells are specifically activated and selected based on upregulation of activation markers prior to expansion in culture. This process results in a patient-specific T cell product enriched for tumor-reactive T cells. Enrolled patients who progress on first line SOC therapy are preconditioned with 5 days of nonmyeloablative lymphodepletion followed by TBio-4101 infusion. Thereafter, patients receive ≤6 doses of IL-2 (600,000 IU/kg) every 8h, and pembrolizumab (200 mg) every 3 weeks until disease progression. The trial is currently open, with a target enrollment of 15 patients (NCT06236425). Clinical trial information: NCT06236425 .

Real-world treatment outcomes in patients with HR+ HER2- advanced breast cancer treated with CDK4/6 inhibitors and endocrine therapy.

1067 Background: The addition of cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) to endocrine therapy (ET) improves progression-free (PFS) and overall survival (OS) in hormone receptor-positive, HER2-negative advanced breast cancer (HR+/HER2- ABC) in 1st and 2nd line setting. The international guidelines advise using 1st line CDK4/6i; however, its superiority over 2nd line use is debatable. Methods: We retrospectively analyzed clinical data of HR+/HER2- ABC pts administered palbociclib (PAL), ribociclib (RIB) or abemaciclib (ABM) added to either 1st or 2nd line ET. Results: A total of 1511 pts (PAL=507; RIB=724; ABM=280) from 11 cancer Polish centers treated between Sep 2017 and Dec 2023. Median follow-up was 29.6 (95%CI 28.2 to 30.9) months (m). Mean age was 62.6±11.9, 58.9±12.2 and 61.4±10.8 years in PAL, RIB and ABM, respectively. 815 patients (53.9%) had visceral and 1109 (73.4%) bone metastases. 1254 pts (83%) received 1st line CDK4/6i, in 841 (67%) combined with aromatase inhibitor (AI) and in 413 (33%) with fulvestrant (FUL). Second-line CDK4/6i was used in 257 pts (17%); 59 (23%) and 198 (67%) with AI and FUL, respectively. There was no difference in PFS, PFS2, and OS between three CDK4/6i in combination with AIs in 1st and 2nd line setting. Median PFS (95%CI) for 1st line AI with PAL, RIB, ABM were 29.0 (21.6-37.0), 32.0 (24.5-36.9), not reached (N/R) (21.9-N/R) m; PFS2: 37.0 (28.8-N/R), 33.0 (29.5-40.2), N/R (28.9-N/R); OS: 48.9 (42.9-N/R), 48.6 (41.9-N/R), N/R (36.7-N/R). Median PFS (95%CI) for 2nd line AI with PAL, RIB, ABM were 11.9 (9.49-N/R), 10.8 (8.27-N/R), 11.0 (6.43-N/R); PFS2: 22.7 (16.8-N/R), 32.3 (24.9-N/R), 31.0 (13.2-N/R); OS: 27.4 (24.4-N/R), 36.7 (30.1-N/R), 45.5 (29.0-N/R) (no statistical significance). In contrast, RIB+FUL was superior to PAL+FUL and ABM+FUL in both lines (Table). The safety profile was concordant with the reported data for ET + CDK4/6i. Conclusions: Identifying predictive factors of response is essential for the rational use of CDK4/6i and ET in HR+/HER2- ABC. [Table: see text]

Pulmonary toxicities in patients (pts) with metastatic breast cancer (mBC) treated with trastuzumab deruxtecan (T-DXd): The Mayo Clinic experience.

11145 Background: T-DXd is increasingly used in mBC. A T-DXd toxicity of special interest is interstitial lung disease/pneumonitis (ILD), occurring in 10-15% of pts in the DESTINY-Breast trials, and with potential lower incidence/severity in earlier line settings [Krop et al, ASCO 2023]. However, in routine practice, T-DXd may be used in pts with more heavily pre-treated mBC and previously exposed to other antibody-drug conjugates (ADC) [Premji et al SABCS 2023]. We evaluated the incidence/severity of T-DXd related ILD in mBC at Mayo Clinic. Methods: We retrospectively identified pts with mBC who received ≥1 dose of T-DXd at Mayo Clinic, Rochester, MN, between July 2022-December 2023. Demographic, mBC, and pulmonary clinical variables were abstracted from the clinical records. Data was summarized using descriptive statistics. Diagnosis of ILD was determined by treating clinicians, and severity to CTCAE V5 based on clinical documentation. Results: 77 pts with mBC received T-DXd during the study period. All were female, the majority (70, 91%) were Caucasian, and median age was 58. 53 (69%) had HER2-low mBC (37 HR+, 16 HR-) and 24 (31%) had HER2+ mBC (17 HR+, 7 HR-). 31 (40%) were active or former smokers. 11 (14%) had pulmonary comorbidities, including 6 (7.8%) with asthma, 2 (2.6%) with prior pneumonitis, and 3 (3.9%) with other pulmonary comorbidities. They had previously received a median of 1 line of endocrine therapy, and 4 lines of chemotherapy, with 20 (26%) having received another ADC. 17 (22%) developed any grade ILD [G1: 3 (4%), G2: 7 (9%), G3: 2 (3%), G4: 1 (1%), G5: 4 (5%)]. Among pts with ILD of any grade, 13 (76.5%) presented with at least 1 symptom (cough/SOB). The median number of T-DXd cycles prior to onset of any grade ILD was 6 (range 2-13), or 18 (range 6-39) weeks. 5 (29%) pts with any grade ILD received a prior ADC. Of pts with ≥G3 ILD (n=7), all were Caucasian, 2 (30%) were prior smokers, none had prior lung disease, and had received a median of 5 prior lines of chemo, with 4 (57%) having received a prior ADC. All grade ≥2 ILDs were treated with systemic steroids, and 1 also received IVIG. CT chest was used for diagnosis of all ILD. 7 pts (41%) required hospitalization, all of whom had bronchoscopy, with 5 (29%) requiring intubation. All pts with G1 ILD (3, 18%) restarted T-DXd without ILD recurrence. Conclusions: In this case series,22% of ps treated with T-DXd experienced ILD (5% G5), higher than the rate observed in the pivotal DESTINY-Breast trials, possibly due to real-world use of T-DXd in more heavily pre-treated pts and in pts with pulmonary comorbidities.

Real-world study of lazertinib as second-line or greater treatment in advanced non-small cell lung cancer.

Lazertinib is an oral, third-generation EGFR-TKI, which specifically targets the EGFR T790M mutation along with activating mutations Ex19del and L858R. More real-world data are needed to evaluate its efficacy and safety in treating locally advanced and metastatic non-small cell lung cancer (NSCLC) following prior EGFR TKI treatment. This multicenter retrospective study was conducted at seven university hospitals affiliated to the Catholic Medical Center (CMC) in Korea. A clinical data warehouse (CDW) platform was used to access and extract information. A total of 48 patients were assessed. The majority were female (75%) and diagnosed with adenocarcinoma (95.8%). All patients had the EGFR mutation at diagnosis, 27 (56.3%) had the exon 19 deletion, 20 (41.7%) had the L858R mutation, and one (2.0%) had the exon 18 mutation. The median progression-free survival (PFS) was 15.4 months. At 6, 12, and 18 months, PFS rates were 79.1%, 53.6%, and 27.3%, respectively. When PFS was analyzed by prior TKI duration (<18 months vs. >18 months), significant differences were noted at the 6 and 9-month mark (p = 0.013 and p = 0.010, respectively). In multivariate analysis for PFS, only prior TKI duration and ECOG score showed statistical significance (p = 0.026 and p = 0.049, respectively). In the multivariate analysis for OS, ECOG score showed statistical significance (p = 0.006). Among 48 patients, 34 (70.8%) experienced adverse events (AEs) related to lazertinib. The most frequent AEs were skin reaction (29.8%), diarrhea (21.3%), and peripheral neuropathy (20.8%). The results suggest that lazertinib is effective in second or more line settings, with tolerable safety profile. More patient data are necessary to find possible prognostic markers associated with patient outcome.

Insights for clinical management from the real-life data of the centralized West of Scotland biliary cancer clinic.

With the increasing of novel therapeutics for the treatment of Biliary Tract Cancers (BTC), and the need to assess their socio-economic impacts for national licence approvals, it is as important as ever to have real-life data in national populations. We performed an audit of the first 2 year-activity (Sep 2019-Sep 2021) of the centralized West-of-Scotland-BTC clinic. 122 patients accessed the service, including 68% with cholangiocarcinoma (CCA), 27% with gallbladder cancer (GBC), and 5% with ampulla of Vater carcinoma with biliary phenotype (AVC). Median age at diagnosis was 66 (28-84), with 30% of newly diagnosed patients being younger than 60 years-old. Thirty-five cases (29%) underwent surgery, followed by adjuvant-chemotherapy in 66%. 60% had recurrent disease (80% with distant relapse). Sixty-four patients (58%) started first-line Systemic-AntiCancer-Treatment (SACT). Of these, 37% received second line SACT, the majority of which had iCCA and GBC. Thirty-% of those who progressed received third line SACT. About 30% of BTC were eligible for curative surgery. Fifty-eight and twenty% of the overall cohort of advanced BTC patients received first and second line SACT. Our data suggest that reflex genomic profiling may not be cost-effective until molecularly driven strategies are limited to second line setting.

Pan-Canadian Analysis of Practice Patterns in Small Cell Carcinoma of the Cervix: Insights from a Multidisciplinary Survey.

Small-cell neuroendocrine carcinoma of the cervix (SCNECC) is a rare cancer with poor prognosis, with limited data to guide its treatment. The objective of this study was to evaluate practice patterns in the management of SCNECC. A 23-question online survey on management of SCNECC was disseminated to Canadian gynecologic oncologists (GO), radiation oncologists (RO) and medical oncologists (MO). In total, 34 practitioners from eight provinces responded, including 17 GO, 13 RO and four MO. During staging and diagnosis, 74% of respondents used a trimodality imaging approach, and 85% tested for neuroendocrine markers. In early-stage (1A1-1B2) SCNECC, 87% of practitioners used a surgical-based approach with various adjuvant and neoadjuvant treatments. In locally advanced (1B3-IVA) SCNECC, 53% favored primary chemoradiation, with cisplatin and etoposide, with the remainder using surgical or radiation-based approaches. In metastatic and recurrent SCNECC, the most common first-line regimen was etoposide and platinum, and 63% of practitioners considered clinical trials in the first line setting or beyond. This survey highlights diverse practice patterns in the treatment of SCNECC. Interdisciplinary input is crucial to individualizing multimodality treatment, and there is a need for prospective trials and intergroup collaboration to define the optimal approach towards managing this rare cancer type.

Abstract PO3-17-12: Safety and efficacy of Atezolizumab in combination with nab-Paclitaxel in patients with PD-L1 positive metastatic or locally advanced triple-negative breast cancer: A pan-UK cancer centre experience

Abstract BACKGROUND Within the United Kingdom (UK), combination chemo-immunotherapy with Atezolizumab and nab-Paclitaxel is National Institute for Health and Care Excellence (NICE) approved as a first line palliative systemic treatment option for patients with advanced triple-negative breast cancer (aTNBC) with programmed death-ligand 1 (PD-L1) expression ≥1%. Trials demonstrated progression-free survival (PFS) and overall survival (OS) benefits. Treatment-related toxicities may impact on quality of life and result in treatment delay or discontinuation. We conducted a National Service Evaluation (SE) to assess the safety and efficacy in a “real-world” dataset. METHODS Data from patients with aTNBC who received Atezolizumab/nab-Paclitaxel between 9th March 2019 and 2022 across 10 UK Cancer Centres were analysed. All grade 1-4 toxicities were recorded in accordance with Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 scoring system. Participation was contingent on local approval for this project, and data transferred following receipt of a data sharing agreement. Kaplan-Meier curves for PFS and OS were calculated. RESULTS 129 patients were included in the analysis with a median age of 55 (30-82). 42.6% (n=55) had a PS of 0, 51.2% (n=66) a PS of 1 and 3.9% (n=5) had a PS of 2. Atezolizumab/nab-Paclitaxel was given in the first line setting in most patients (84.5%, n= 109), but in 15.5% (n=20) in the second line setting (privately insured). 21.7% (n=28) of patients presented with de novo metastatic disease, 58.1% (n=75) of patients were post-menopausal and 6.2% (n=8) had a BRCA1 or 2 mutation. 76.7% of patients (n=99) had previous neo-/adjuvant treatment in the non-metastatic setting: 55.8% had prior treatment with a taxane, 51.2% anthracycline, 22.5% platinum, and 66.7% had prior radiotherapy. 83.7% (n= 108) had invasive ductal breast cancer, and 84.5% (n=109) presented with 0-3 number of metastatic sites with 15.5% (n=20) having ≥ 4 metastatic sites. Here, the nodal metastatic site dominated in 78.3% of patients. Grade ≥ 3 events occurred in 21.7% (n=28) of patients. These were decreased neutrophil count (10.1%, n=13), pyrexia (2.3%, n=3), diarrhoea (1.6%, n=2), hypothyroidism (1.6%, n=2), peripheral neuropathy (1.6%, n=2), anaemia (1.6%, n=2), GGT rise (0.8%, n=1), fatigue (0.8%, n=1), hypophysitis (0.8%, n=1), pneumonitis (0.8%, n=1), nausea (0.8%, n=1), mucositis (0.8%, n=1), platelet count decreased (0.8%, n=1), infections (0.8%, n=1). Increased rates of Grade ≥ 3 colitis (2.3%, n=3) and hepatitis (3%, n=2.3) were observed. 20.2% (n=26) of patients required steroids to treat toxicities. Reason for treatment discontinuation included in 58.1% (n=75) disease progression, and 7.8% (n=10) unacceptable toxicity. In 22.5% of patients’ treatment was still ongoing at time of data lock. At approximately 12 weeks, 7.8% of patients had a complete and 51.2% a partial response, 10.1% had stable and 22.5% progressive disease and for 8.5% the response was not known as they have not yet reached 12 weeks since treatment start. Median PFS was 5 months and OS was 14 months. CONCLUSIONS The toxicity profile of Atezolizumab/nab-Paclitaxel was comparable to literature, however, both PFS and OS were shorter. In comparison to the IMpassion130 trial data, patients within this national SE project were less fit and more heavily pre-treated. A higher number of any grade hyperthyroidism and fatigue, and of grade ≥ 3 colitis and hepatitis were noticed. Baseline patient characteristics XX- XX Citation Format: Jasmin V Waterhouse, Alexandra Holdich, Florentia Mina, Mariam Obeid, Kroopa Joshi, Sophie Barrett, Lavarniya Rajakumar, Gemma McCormick, Sally Seymour, Panagiotis Koliou, Rushan Sylva, Olubukola Ayodele, Ashram Gautam, Jenny Smith, Jenny McKeon, Thomas Strawson-Smith, Rosalie Douglas, Annabel Borley, Apostolos Konstantis, Sophie McGrath. Safety and efficacy of Atezolizumab in combination with nab-Paclitaxel in patients with PD-L1 positive metastatic or locally advanced triple-negative breast cancer: A pan-UK cancer centre experience [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 PO3-17-12.

Abstract PO4-15-05: Genomic characterization and molecular predictive biomarkers for chemotherapy in a real-world population with metastatic triple-negative breast cancer

Abstract Background: The genomic landscape of metastatic triple-negative breast cancer (mTNBC) in a real-world population is poorly defined and despite recent advances in precision oncology, molecular biomarkers for chemotherapy are largely lacking. The presence of specific genomic alterations and alterations in oncogenic pathways have the potential to provide prognostic as well as predictive information for chemotherapy, which remains the backbone treatment strategy for mTNBC. Methods: We conducted next-generation sequencing (NGS) with the FoundationOne CDx panel on tissue from the primary tumor and/or metastasis of 112 consecutive patients with mTNBC that were treated between 1998 and 2019 at 4 different Swedish hospitals. Every genomic alteration was, if applicable, subdivided into 1 of 10 canonical oncogenic pathways and noted for its involvement in the homologous recombination pathway (HRP). Frequently altered genes and pathways were then correlated with overall survival (OS) and evaluated regarding their association with progression-free survival (PFS) and response rate (RR) in patients treated with different chemotherapy agents. Tumor samples of patients with rapid progression or exceptional response to chemotherapy underwent exploratory comparison with regards to frequently altered genes and pathways and known clinical prognostic factors were compared between the two patient groups. Results: After excluding 15 patients due to insufficient quantity/quality of tumor tissue or absence of clinical data, 97 patients were analyzed. The median age at diagnosis of metastatic disease was 61 (range: 28-90), 80 % had visceral disease and 26 % received platinum-based chemotherapy in the first line setting. The most frequently altered genes were: TP53 (82 %), RAD21 (25 %), PIK3CA (23 %), MYC (22 %) and BRCA 1 or 2 (16 %). The most frequently altered pathways were TP53 (86 %), PI3K (60 %), RTK/RAS (47 %) and cell cycle (36 %). In total, 26 % of patients had an alteration in the HRP. None of the most frequently occurring genomic alterations were associated with OS. Variants of clinical significance in the HRP and BRCA1/BRCA2 genes were associated with a longer PFS in patients treated with platinum-based chemotherapy in the first line setting (HR 0.12-0.84 and 0.12-0.92). Exceptional responders to chemotherapy exhibited a more favorable clinical profile than rapid progressors (median age 51.5 vs 66.5, median Charlson comorbidity index 0.5 vs 3) whereas some numerical difference in the genomic profiling in terms of genomic alterations in MYC and RAS/RTK pathways (more often in exceptional responders) could be observed. Conclusions: We found no genomic alteration with prognostic significance in a cohort of mTNBC patients treated with chemotherapy in a real-world setting. Somatic variants of clinical significance in BRCA 1 and 2 and other HRP-related genes seem to define subgroups of patients with mTNBC that respond favorably to platinum-based chemotherapy. Further research into the genomic landscape of tumors from patients with rapid progression or exceptional response to specific treatment strategies can provide insights into mechanisms of resistance and identify new predictive biomarkers. Citation Format: Erik Olsson, Henrik Lindman, Evangelos Digkas, Viktoria Thurfjell, Haidar Mir Ali, Ute Krüger, Anna-Karin Wennstig, Marie Sundqvist, Antonis Valachis. Genomic characterization and molecular predictive biomarkers for chemotherapy in a real-world population with metastatic triple-negative breast cancer [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 PO4-15-05.

Abstract PO4-14-09: A computational model of the mechanisms of action of combined endocrine therapy and CDK4/6 inhibition predicts outcome in patients with Luminal B breast cancer

Abstract Background: Hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer (BC) is clinically and biologically heterogeneous. CDK4/6 inhibitors (CDK4/6i) are proven to be effective in different molecular subtypes of HR+/HER2- BC, including the PAM50 luminal B. However, not all patients benefit to the same extent and new biomarkers for response are needed. The aim of this study was to develop a computational workflow to predict the response of patients with luminal B BC to treatment with CDK4/6i in combination with endocrine therapy (ET). Methods: The main part of the workflow is a computational model representing the mechanisms of action of the drugs and their influence on protein signaling and cell proliferation in the tumor. The model was trained on publicly available data from BC cell lines (Western blot time courses and viability dose-response data). The model was then used to predict response in patients by incorporating gene expression profiles obtained at baseline. The output of the model was a score indicating how strongly the tumor responded to the treatment. Gene expression data determined using the nCounter BC360 panel was available at baseline from two patient cohorts: 1) the CORALLEEN phase II trial which evaluated neoadjuvant ribociclib plus letrozole vs multi-agent chemotherapy in postmenopausal patients with luminal B by PAM50, HR+/HER2- early BC (Prat et al. Lancet Oncology. 2020), 2) a retrospective study of postmenopausal patients with HR+/HER2-/Luminal B advanced BC treated with CDK4/6i plus ET in the first line setting at Hospital Clinic Barcelona (hereafter CDK cohort). PAM50 risk of relapse (ROR) and Ki67 levels were considered as outcome for the CORALLEEN patients. Progression free survival (PFS) was available in the CDK cohort. Area under the ROC Curve (AUC) was used to estimate the discrimination performance of the model. Differences were tested for statistical significance using Wilcoxon rank-sum test. Hazard ratios were estimated using Cox regression to investigate the association with PFS. Results: The computational model used here describes the dynamics of relevant protein-protein and drug-protein interactions to the treatment of CDK4/6i plus ET. The model showed high agreement with the training data obtained from cell lines (Pearson correlation of 0.88 and 0.95). The ability of the trained model to predict treatment outcome in patients was validated in baseline samples of the CDK4/6i arm (n=51) and the chemotherapy arm (n=52) of the CORALLEEN trial, and baseline Luminal B primary tumors of the CDK cohort (n=19). For each patient, a response score was calculated by the model using the expression of 6 genes at baseline as input. This response score was significantly associated with patient response in both cohorts. The model identified patients with high Ki67 (AUC of 0.80 (95% CI 0.64 - 0.92)) and high ROR (AUC of 0.78 (95% CI 0.64 - 0.89)) after treatment in the CDK4/6i arm of the CORALLEEN cohort and was used to stratify patients into different response groups. The AUC in the chemotherapy arm of CORALLEEN for identifying high Ki67 was 0.44 (95% CI 0.29 - 0.58), indicating that the predictions are specific to CDK4/6i plus ET treatment. Additionally, stratification of patients in the CDK cohort into either two or three groups based on the response score was linked to PFS (HR=3.71 (95% CI 0.97 - 14.16), p=0.055 and HR=2.92 (95% CI 1.08 - 7.86), p=0.034, respectively). Conclusion: A mechanistic model was developed, trained on cell line data, and then used to predict treatment outcome of patients with HR+/HER2-/PAM50 Luminal B BC treated with CDK4/6i plus ET. This approach showed significant association with observed outcome and could be used to assign patients to different response groups, indicating the usefulness of the model as a potential marker for response. Citation Format: Leonard Schmiester, Fara Brasó-Maristany, Vessela Kristensen, Arnoldo Frigessi, Aleix Prat, Alvaro Köhn-Luque. A computational model of the mechanisms of action of combined endocrine therapy and CDK4/6 inhibition predicts outcome in patients with Luminal B breast cancer [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 PO4-14-09.

Abstract PO1-19-09: Integrating gene signatures to guide HR+ MBC therapy in a diverse cohort (INSIGHT)

Abstract Background: Black women with breast cancer (BC) have a 40% higher mortality rate compared to Non-Hispanic White (NHW) women. Among women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) BC, Black women have worse outcomes than NHW despite comparable systemic therapies. Gene expression profiling assays have been used in early-stage BC to provide prognostic and sometimes predictive information beyond standard immunohistochemical classifications. The 80-gene molecular subtype signature (BluePrint) with the 70-gene risk of distant recurrence signature (MammaPrint®) (Agendia, Irvine, CA) further classify HR+/HER2- BC into luminal A-type, luminal B-type, HER2-type, and basal-type tumors. Luminal B, HER2, and basal-type tumors (non-luminal A) are more aggressive with worse survival outcomes and are overrepresented among Black women. In the metastatic setting, the role of molecular subtype signatures in guiding therapeutic decisions has not yet been determined. We hypothesize that patients with metastatic HR+/HER2- non-luminal A-type BC post-progression on endocrine therapy +/- CKD4/6 inhibition will derive more benefit from chemotherapy than standard-of-care endocrine therapy in the second line setting. We also hypothesize that the impact of the intervention will be more pronounced in Black women compared to NHW women. Methods: This is a randomized phase II study that will evaluate the anti-tumor effect of capecitabine compared to physician’s choice endocrine therapy as second line therapy for adult ( &amp;gt;18 years) patients with non-Luminal A HR+/HER2- metastatic or unresectable locoregional invasive carcinoma (NCT 05693766). The study plans to enroll up to 62 patients. This trial enriches for racial/ethnic minority patients through collaborations with the University of Texas Southwestern and the University of Alabama at Birmingham, two health systems that serve a large minority population. Eligible patients who have received prior endocrine therapy with a CDK4/6 inhibitor will have their tumor tissue analyzed using the MammaPrint® and BluePrint assays. Patients with Luminal A tumors will receive standard of care and will be followed for survival only. Patients with non-Luminal A tumors will be randomized (1:1) to receive physician’s choice endocrine therapy versus capecitabine (dosed at 2000mg twice daily for 7 days on, 7 days off) with stratifications by molecular subtype and race. Patients will be evaluated for response every three cycles using the Response Evaluation Criteria in Solid Tumors. Therapy will be continued until evidence of disease progression or unacceptable major toxicity. The primary endpoint is progression free survival; secondary endpoints are overall response rate, clinical benefit rate, overall survival, and patient reported outcomes. The study will have 80% power to detect a minimal hazard ratio of 0.5 at one-sided significance level of 0.05. Cell-free DNA will be collected at baseline and at three times post-baseline to investigate potential genetic markers of disease response and resistance. Enrollment opened on June 1, 2023. We anticipate opening the trial at the external sites before the end of 2023. Citation Format: Moriah Forster, Jennifer Whisenant, Ben Park, Erica Stringer-Reasor, William Audeh, Andrea Menicucci, Fei Ye, Heather McArthur, Sonya Reid. Integrating gene signatures to guide HR+ MBC therapy in a diverse cohort (INSIGHT) [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 PO1-19-09.

Abstract PO5-15-12: Spatial immune correlates of response to eribulin and pembrolizumab in metastatic triple negative breast cancer (mTNBC) on the ENHANCE1 trial

Abstract Background: PD-L1 is the only approved biomarker for pembrolizumab in metastatic breast cancer for response to combination chemo-immunotherapy. As it is not predictive of response in all cases, additional biomarkers are needed. Previously we have demonstrated that stromal tumor infiltrating lymphocytes (sTILs) are associated with response to therapy in patients treated with front-line combination chemoimmunotherapy on the ENHANCE-1 study with eribulin and pembrolizumab. However, sTILs was not predictive of response in patients treated with prior lines of chemotherapy in the metastatic setting. We used multiplexed immunofluorescence on whole slide images to characterize associations between specific immune populations and outcomes in patients treated prospectively on the ENHANCE-1 study. Methods: ENHANCE-1 was a single arm phase Ib/II trial which evaluated the efficacy and safety of eribulin and pembrolizumab in 167 patients (pts) with mTNBC who had received 0-2 prior lines of therapy (66 pts in the first line setting [stratum 1] and 101 pts with 1-2 prior lines of therapy [stratum 2]). 138 patient samples were evaluable for our study: 58 samples from stratum 1 and 80 samples from stratum 2. Objective response rate (ORR) was defined as percentage of pts with either complete response (CR) or partial response (PR) by RECIST 1.1. The ORR was 25.8% in stratum 1 and 22.5% in stratum 2 for the 138 patients analyzed. We utilized whole tissue sections and quantitative multiplexed immunofluorescence (qmIF) stained with: CD4, FoxP3, CD8, CD56 and pancytokeratin to characterize T-cells, NK cells and tumor cells. Halo (Indica labs) was used to segment and threshold cells for positive markers as well as to identify tumor and stromal tissue areas. Results: We found that the ratio of CD8+ to CD4+FoxP3+ T-cells were associated with response, irrespective of stratum (p=0.005). As biopsies were not required immediately prior to enrollment on ENHANCE-1, we also evaluated samples based on prior number of treatments since biopsy to enrollment. We found that only 58/138 patient samples evaluated were obtained without intervening treatment: 35 out of 58 from stratum 1 and 12 out of 80 from stratum 2. When samples were evaluated by stratum and the timing of tissue acquisition we found the ratio of CD8+ to CD4+FoxP3+ T-cells was more significantly associated with response (&amp;lt; 0.001) in patients whose sample were collected prior to enrollment, regardless of patient stratum. The ratio was not predictive in samples taken prior to treatments before enrollment. In addition, we found stromal and intratumoral CD8+ T-cell density is associated with response (p=0.02 and p=0.03 respectively) across both stratum. We did not find any significant changes assessed by qmIF in patient samples which had intervening treatment between sample collection and enrollment onto ENHANCE-1 trial. Conclusion: In this population of patients with mTNBC treated prospectively with eribulin and pembrolizumab, we find that a higher ratio of CD8+ to CD4+FoxP3+ T-cells and stromal and intratumoral CD8+ T-cell density is associated with response in patients with biopsy samples obtained prior to enrollment without intervening treatments after sample collection. The tumor microenvironment on patient samples obtained before one or more lines of therapy prior to enrollment on study are not predictive of response to treatment. Further characterization of the TME via quantitative immunofluorescence is ongoing. This study was funded by Eisai Citation Format: Matthew Kearney, Hua Guo, Rami Vanguri, Qi Wang, Eileen Connolly. Spatial immune correlates of response to eribulin and pembrolizumab in metastatic triple negative breast cancer (mTNBC) on the ENHANCE1 trial [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 PO5-15-12.

Abstract PO2-17-08: A RETROSPECTIVE ANALYZES OF 4,885 PATIENTS OF HORMONAL RECEPTOR POSITIVE, HER2 NEGATIVE BREAST CANCER TREATED IN A REFERENCE CENTER, A REAL-WORLD DATA

Abstract Background: Hormonal receptor positive Her2 negative also described as luminal breast cancer (LBC) is the most frequent tumor corresponding to about 60-65% of cases. There is great heterogeneity in these tumors and a great difference between treatments due to lack of access, mainly in developing countries. Clinical trials are important to understand the benefit of the treatments but only 5% of the breast cancer patients are enrolled in these trials and is because of that that Real World Data (RWD) is It's becoming more and more frequent. Objectives: To evaluate LBC and describe treatments and overall survival (OS) of patients treated in public hospital in São Paulo Brazil. Methods: This was a retrospective, single cohort study, that included female patients over 18 years of age, with a diagnosis of LBC. Clinical and pathological data was collected (date of diagnose, first treatment, type of treatment, stage, type of surgery, DFS and OS). This study was approved by our local ethics committee. Results: We’ve enrolled 5,510 patients in Perola Byington ’database from 2010 to 2021. After excluding patients without minimal complete records, a total of 4,885 patients were analyzed. Most patients were diagnosed in stage I (26,9%) and II (38,2%). There was 23,4% in stage III, 3,1% in stage IV and 5,7% in stage 0. In 2,6% the of the patient’s information was not complete. Mean age at diagnosis was 57.6 years. We identified 4,761 (86.4% of 5510) patients who underwent 4,848 surgical procedures. Of the total, 47.2% were mastectomies, 50.9% partial mastectomies and 1.9% were skin sparing mastectomy. Immediate reconstruction was done in 470 patients (69.8% underwent reconstruction with an expander, 22.3% with flap rotation and 7.9% reconstruction with implants). The mean and median time between diagnosis and the beginning of treatment was analyzed, in the sample it was observed that patients who were diagnosed in stages I, II and IV had the same mean of 2.6 months, but stage IV had the lowest median 1 ,9 months. 474 patients were treated in the first line setting during the follow up, 43 % received hormone therapy (HT) and 57% received chemotherapy (CT) as first line. The duration of the treatment in first line was 17,7 months for HT and 7,7 months for CT (p &amp;lt; 0,01). OS for patients diagnosed in stages I and II did not reach the median in the available period, for patients in stages III and IV, a median of 80.4 months and 41.2 months of overall survival was identified, respectively. Conclusions: These are the first results of this large cohort of luminal patients treated in the public reference center. Most patients are diagnosed in stage I or II and more than half undergo conservative surgery. Immediate reconstruction is not routinely performed. In the public setting CDK4/6 inhibitors are not available and that led to more chemotherapy use in first line (57%) and worse survival when compared to clinical trials. Discussions on the incorporation of drugs consolidated in the literature are important to improve the treatment of advanced cancer. Citation Format: Andre Mattar, Marcelo Antonini, Marina Diogenes, Andressa Amorim, Francisco Pimentel Cavalcante, Luiz Henrique Gebrim. A RETROSPECTIVE ANALYZES OF 4,885 PATIENTS OF HORMONAL RECEPTOR POSITIVE, HER2 NEGATIVE BREAST CANCER TREATED IN A REFERENCE CENTER, A REAL-WORLD DATA [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 PO2-17-08.

Abstract PO1-06-04: Immune checkpoint inhibitors for triple-negative inflammatory breast cancer (INCORPORATE): an international multicenter retrospective analysis

Abstract Background: Inflammatory breast cancer (IBC) is an aggressive clinical presentation of breast cancer (BC). Immune checkpoint inhibitors (ICIs) combined with chemotherapy provided an overall survival (OS) benefit in the metastatic setting and an even-free survival (EFS) benefit in patients (pts) with early triple-negative (TN) BC, respectively. Patients with TN-IBC were under-represented or excluded in pivotal trials and commonly not evaluated in subgroup analyses. Methods: We conducted a retrospective, multicenter, international, observational study to evaluate the clinical benefit of ICIs in pts with TN-IBC (defined as cT4d per AJCC TNM, 8th ed., ER &amp;lt; 1% and PgR &amp;lt; 1%, HER2: negative). Pts with early-stage TN-IBC were included if they received an ICI combined with neoadjuvant chemotherapy (NACT) (Group 1). Pts with metastatic TN-IBC were included if they received ICI monotherapy or in association with first-line chemotherapy (Group 2). Treatment was administered according to guideline recommendations (in PD-L1+ metastatic IBC and regardless of PD-L1 in early IBC), in clinical trials, or off-label (regardless of PD-L1 expression status in metastatic IBC). Endpoints were pathological complete response (pCR) and 1-year EFS rate for group 1 (calculated from date of first cycle of NACT to any recurrence or death), and progression-free survival (PFS) for group 2. Correlative analyses were provided (significance at p-value &amp;lt; 0.05). Results: We included 59 pts from 8 international referral centers. 15 pts had early IBC (Group 1), and 44 pts had metastatic disease (Group 2). Patient characteristics and outcomes are shown in Table 1. Among the 15 pts from Group 1, 10 received anthracycline, taxane and carboplatin-based (AC-CbT) NACT with pembrolizumab, 3 neoadjuvant paclitaxel-carboplatin chemotherapy with pembrolizumab, 2 neoadjuvant nab-paclitaxel with atezolizumab. One pt progressed on NACT, 2 pts are still receiving NACT. Among 13 pts evaluable for response, 6/13 (46%) achieved a pCR. After a median follow-up of 7.1 months, the median EFS was 12.9 months and the 1-year EFS rate was 70%. The median OS was 15.7 months. Among pts from Group 2, PD-L1 status was positive (IC 1% or CPS 10) in 27/44 pts (61%), negative in 5/44 pts (11%) and unknown in 6/44 pts (13%). At a median follow-up of 24.3 months, median PFS and OS were 4.1 and 15.7 months. As backbone chemotherapy in first line setting, 6 pts received AC-CbT regardless of PD-L1 status (mPFS: 8.6 months), 21 taxane-based/anthracycline-free chemotherapy (mPFS: 5.3 months), 14 other chemotherapy regimens (mPFS: 2.1 months) and 3 single-agent immunotherapy (mPFS: 50.1 months). Three of 6 patients who received AC-CbT underwent surgery and radiotherapy. In Group 2, after adjusting for the number of metastatic sites (&amp;gt;1 vs. 0-1), PD-L1 status (positive vs. negative vs. unknown) and de novo metastatic disease (yes vs. no), AC-CbT chemotherapy (HR 0.05; 95% CI: 0.01-0.56; p=.015) and taxane-based chemotherapy (HR 0.20; 95% CI: 0.06-0.68; p=.009) were both associated with longer PFS. Conclusions: This multicenter retrospective analysis of TN-IBC treated with combination of chemotherapy and IOs showed relatively low pathology response, EFS and clinical benefit suggesting need to further investigate the role of immunotherapy in this aggressive disease. Table 1. Patient characteristics and outcomes Citation Format: Carmine Valenza, Dario Trapani, Paola Zagami, Gabriele Antonarelli, Luca Boscolo Bielo, Eleonora Nicolò, Joana Mourato Ribeiro, Lorenzo Guidi, Carolina REDUZZI, Martina Spotti, Elisabetta Munzone, Javier Cortés, Barbara Pistilli, Sara Tolaney, Naoto Ueno, Rachel Layman, Massimo Cristofanilli, Lisa Carey, Filipa Lynce, Wendy Woodward, Giuseppe Curigliano. Immune checkpoint inhibitors for triple-negative inflammatory breast cancer (INCORPORATE): an international multicenter retrospective analysis [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 PO1-06-04.

Abstract PO2-04-09: Combination of the PLK1 Inhibitor Onvansertib and the PI3Kα Inhibitor Alpelisib Overcomes Palbociclib Resistance in PIK3CA-mutated HR+ Breast Cancer

Abstract In the 1st line setting of hormone receptor-positive HER2 negative (HR+/HER2-) metastatic breast cancer, cyclin dependent kinase 4 and 6 (CDK4/6) inhibitors (palbociclib, abemaciclib and ribociclib) are typically used in combination with endocrine therapy. Though initially effective, acquired resistance to either CDK4/6 inhibitors or endocrine therapy eventually leads to disease relapse in most patients. Activating mutations in PIK3CA, the gene encoding alpha catalytic subunit of phosphatidylinositol-4,5-bisphosphat 3-kinase (PI3K) are found in approximately 40% of HR+ breast cancer patients and have been implicated in mediating resistance to CDK4/6 inhibitors. The PI3Kα inhibitor alpelisib is currently approved for PI3KCA-mutant HR+ breast cancer after progression on CDK4/6 inhibitors. However, drug-associated resistance mechanisms may limit its clinical benefit. Synergistic combination therapies have the potential to improve efficacy and overcome resistance mechanisms. Polo-like kinase 1 (PLK1) is a serine-threonine-protein kinase, key cell cycle regulator that controls G2/M entry and mitotic progression, and that has been shown to mediate resistance to palbociclib in HR+ breast cancer. Onvansertib is an oral and highly specific PLK1 inhibitor currently on clinical development in solid tumors and hematological malignancies. Here we evaluated the potential of onvansertib to increase the activity of alpelisib in PIK3CA-mutant HR+ breast cancer preclinical models. The combination of onvansertib and alpelisib synergistically inhibited cell viability and/or colony formation in three PI3KCA-mutant HR+ breast cancer cell lines, MCF-7 (PIK3CA E545K), EFM-19 (PIK3CA H1047L), and T-47D (PIK3CA 1047R). A significant increase in apoptosis was observed in cells treated with the combination compared to either agent alone. We next tested the combination of onvansertib and alpelisib in patient-derived xenograft (PDX) models. For this purpose, palbociclib-resistant PIK3CA-mutant HR+ breast cancer PDXs were established from primary breast tumor (PDX HBCx-86, PIK3CA E545K) or from metastatic bone biopsies of patients who had progressed on endocrine therapy plus palbociclib (HBCx-180, PIK3CA H1047R) or on PI3Kα inhibitor (HBCx-134palboR31, PIK3CA H1047R). PDX tumors were grafted subcutaneously in nude mice and mice were treated with vehicle, onvansertib (45 mg/kg, oral, 5 days a week), alpelisib (25mg/kg, oral, 5 days a week) or the combination. The combination was well tolerated and showed superior anti-tumor activity than the single agents in the 3 PDX models. In the HBCx-86 PDX, although none of the single agents showed activity, the combination induced potent tumor growth inhibition. In the metastasis-derived PDX HBCx-134palboR31, the combination treatment induced pronounced tumor regression in 62% of mice (5/8), with complete response in 25% (2/8), while mice treated with the single agents showed tumor progression. Finally, in the HBCx-180 PDX, established from a patient with primary resistance to palbociclib, the efficacy of the combination was greater and more durable, with significant survival advantage, compared to the monotherapies. Collectively, our preclinical findings suggest that co-targeting PLK1 and PI3Kα with onvansertib and alpelisib respectively, may constitute a promising therapeutic combination strategy for patients with PIK3CA-mutant HR+ breast cancer failing to respond to first-line standard of care therapies. Citation Format: Sreeja Sreekumar, Pierre Painsec, Davis Klein, Dalia Gonzalez, Laura Sourd, Elodie Montaudon, Tod Smeal, Elisabetta Marangoni, Maya Ridinger. Combination of the PLK1 Inhibitor Onvansertib and the PI3Kα Inhibitor Alpelisib Overcomes Palbociclib Resistance in PIK3CA-mutated HR+ Breast Cancer [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 PO2-04-09.

Abstract PO1-17-02: Real-world outcomes of systemic therapy for advanced triple-negative breast cancer: a tertiary centre experience

Abstract Background Despite recent therapeutic developments for advanced triple-negative breast cancer (aTNBC), outcomes are still suboptimal for a significant proportion of patients. Clinical trials focus on a single line of therapy and do not examine outcomes across the whole treatment pathway involving multiple lines of therapy and may not be representative of outcomes in the real world. We evaluated the efficacy of sequential lines of systemic therapies (SACT) in patients with aTNBC treated at our Institution. Methods We conducted a retrospective analysis of patients with aTNBC who commenced SACT at our Institution between 1/12/2011 and 31/12/2020. Patients’ demographics and tumour characteristics were recorded, along with SACT regime used and treatment outcomes. Median overall survival (mOS) was calculated, as was overall response rate (ORR), median progression survival (mPFS) for each line of therapy. Results In total, 239 patients were eligible for inclusion, with a median age of 55 years at diagnosis of aTNBC (range 26-91). Of these, 65 (27.2%) were ≥65. Two hundred and eleven patients (88.3%) had ECOG performance status (PS) 0 or 1 at first-line SACT initiation. Thirty-two (13.4%) had de-novo aTNBC. Of those with recurrent disease (N=207), 110 (53.1%) received neoadjuvant treatment in the early disease setting. Of these, only 8 (7.3%) achieved pathological complete response. In the recurrent disease cohort, 75 (36.2%) had a disease-free interval (DFI) ≤12 months. There was visceral involvement in 144 (60.2%) patients and 10 (4.2%) had bone only disease. The most common histology was invasive ductal (n=142, 59.4%) at metastatic biopsy and 30 (12.6%) were germline BRCA 1/2 mutation carriers. Number of SACT lines ranged from 1 to 8, with most patients (n=140, 58.6%) receiving 1 to 2 lines of treatment only; with 99 (41.4%) receiving ≥3 lines, 60 (25.1%) ≥4 lines and 36 (15.1%) ≥5 lines. Fluoropyrimidines was most commonly used drug class in 1st and in 2nd lines (40.6% and 32.7%, respectively). Eribulin was the most common choice in 3rd line and 4th lines (37.4% and 30%, respectively). Check-point inhibitor-based therapy was used in 6.3% of patients in 1st line, 2.5% in 2nd line and 3.0% in 3rd line. Overall, 25.5% (n=61) of patients were enrolled onto clinical trials. Clinical trial enrolment was most common in third-line (12.1%, n=12). ORR and mPFS were 42.2% (95% CI 35.7-49) and 3.7 months (95% CI 3.0-5.0) respectively in 1st line, 38.5% (95% CI 30.8-46.6) and 3.5 months (95% CI 2.8-4.0) in 2nd line, 30.2% (95% CI 21.3-40.4) and 2.5 months (95% CI 2.1-3.0) in 3rd line, 23.7% (95% CI 13.6-36.6) and 2.1 months (95% CI 2.0-2.8) in 4th line Patients with a DFI &amp;gt;12 months had a longer mPFS compared to patient with DFI ≤12 months at 5.4 (95% CI 3.7– 6.4) and 2.75 (95% CI 2.2– 3.6) months, respectively (P=0.009). At the censor date 18 patients (7.5%) were still alive and mOS was 11.8 months. Conclusions Our real-world data shows that over half of patients only receive one or two lines of systemic therapy for aTNBC, emphasising the importance of therapy choice in the early line setting for aTNBC. These data are important to inform decision-making, discussions with patients and considerations of clinical trials. Table 1. ORR and PFS to First, second, third and fourth-line systemic treatment. Citation Format: Shuai Zhang, Matilde Coriano, Colm Mac Eochagain, Dorothy Yang, Daniel Yiu, Alistair Ring, Nicolo M.L. Battisti. Real-world outcomes of systemic therapy for advanced triple-negative breast cancer: a tertiary centre experience [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 PO1-17-02.