Citations

Abstract Background: Ovarian function suppression (OFS) combined with tamoxifen (TAM) or an aromatase inhibitor (AI) is standard for premenopausal (PM) ER+, HER2- breast cancer (BC). However, > 40% PM patients (pts) are intolerant of OFS. For these pts, TAM is the only FDA approved option. In the neoadjuvant endocrine setting, pts with endocrine sensitive disease (ESD) (Ki-67 ≤ 10% at 4 weeks) have 5yr dDFS > 97%; however, only 45% of TAM pts vs >75% with AI+OFS achieve 4 wk ESD (Nitz JCO 2022). (Z)-endoxifen (ENDX) is a potent anti-estrogen superior to TAM and AI in xenograft models and with antitumor activity in endocrine-resistant postmenopausal pts. ENDX additionally targets protein kinase C beta 1 (PKCβ1) at concentrations >500 ng/mL, resulting in AKT inhibition and apoptosis (Jayaraman npj Breast Cancer 2023). We hypothesize that ENDX dual targeting of ERα and PKCβ1 will obviate the need for OFS and be non-inferior to AI plus OFS for PM pts with ER+/HER2- BC. Methods: EVANGELINE (NCT05607004) is an ongoing phase 2 multicenter neoadjuvant study with pharmacokinetic (PK) run-in assessing ENDX in PM women with ER+/HER2- BC. The primary objective for the PK run-in is to identify a dose (40 or 80 mg/day) resulting in ENDX steady state concentrations (Css) of 500-1000 ng/mL (to target both ERα and PKCβ1) without significant toxicity. Following PK run-in, the randomized phase II goal is to assess whether the ESD rate with ENDX is non-inferior to exemestane plus goserelin. Women with ESD at wk4 continue treatment for 24 weeks followed by surgery. Here we report the results from the 40 mg/day PK run-in. Results: Seven PM women (6 White, 1 Asian) aged 28-51 (median 46) received ENDX 40 mg/day. Pt characteristics on study were: ER > 90% (all pts), median Ki-67 = 13 (range 4-33%), cTstage (cT2: 6 pts, cT3: 1 pt), and tumor grade (G1: 1 pt, G2: 6 pts). The median ENDX 28 day Css (ng/mL) was 263.6 (range 180.3-376.6). One pt discontinued due to wk4 Ki-67 remaining > 10%. The remaining 6 had ESD, with either wk4 Ki-67 remaining ≤ 10% (3 pts) or decreasing to ≤ 10% (3 pts) and after 24 wks underwent surgery with surgical Ki-67 ≤ 3% (range 0-3%). MRI central review (wk12 and wk24) demonstrated target lesion decreases in all pts with 1 CR, 1 PR and 4 SD (RECIST). Treatment related toxicities included grade 3 headache (n=1), grade 2 amenorrhea (n=1), and grade 2 hot flashes (n=1). The median (range) baseline estrone (n=5) was 54 pg/mL (19-114) with median (range) fold increase from baseline of 9.0 (1.3-23.2) at wk4 and 4.7 (0.4 - 25.9) at wk24. The median baseline estradiol level (n=5) was 29 pg/mL (19-209) with median fold increases from baseline of 17.9 (0.4-57.0) at wk4 and 8.1 (0.04 - 56.6) at wk24. Additional surgical and blood biomarker data will be presented at the meeting. Conclusions: ENDX (40 mg/day) exhibits promising antitumor activity for PM ER+/HER2- BC but with ENDX Css below target. Enrollment is ongoing to the 80 mg/day dose level. Citation Format: Matthew P. Goetz, Vera J. Suman, Heather Fraser, Lida Mina, Pooja Advani, Roberto Leon-Ferre, Karthik Giridhar, Felipe Batalini, Katie N. Hunt, Swaathi Jayaraman, James Jakub, Patricia Cronin, Mara Piltin, Amy Degnim, James N. Ingle, Judy C. Boughey, Sarah Buhrow, Joel Reid, Matthew Schellenberg, John Hawse, Steven Quay. Neoadjuvant (Z)-endoxifen in premenopausal ER+, HER2- breast cancer: Evaluation of the first pharmacokinetic cohort of the EVANGELINE trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT205.

Abstract Background: Triple-negative invasive lobular carcinoma (TN-ILC) is a rare (0.1-1.4%) breast cancer with prognosis worse than ER positive ILC. Currently there are no targeted therapies or clinical trials specifically for TN-ILC. A comprehensive analysis of the molecular and immune landscape can help identify novel targets and pathways for TN-ILC to improve patient outcomes. Here, we characterized the molecular and immune signature of TN-ILC. Methods: 11,760 breast cancer samples (Invasive ductal (ID) TNBC, n=364; TN-ILC, n=31) were analyzed (592, NextSeq; WES, NovaSeq), (WTS; NovaSeq) (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) totaled somatic mutations per tumor (high ≥10 mt/MB) was tested by NGS. Microsatellite-instability (MSI) was tested by NGS. Immune cell fractions were calculated by deconvolution of WTS. Statistical significance was determined using chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q < 0.05). Results: TN-ILC had higher frequency of CDH1 (0.83% vs. 66.67%), ERBB2 (0.84% vs.28.57%), ARID1A (1.65% vs. 23.33%), CBFB (0.55% vs.16.67%), AKT1 (2.22% vs.16.13%) and KMT2C (3.83% vs.13.79%), but lower frequency of TP53 (89.7%5 vs. 38.71%) mutations (all p<0.05) compared to ID-TNBC. TN-ILC had higher frequency of TMB high (23.3% vs. 5.2%, p<0.05) but there was no difference in dMMR/MSI-H (0% vs 1.1%, p=1). TN-ILC had higher AR RNA (FC: 14.2), protein expression (80.6% vs. 24.8%) and higher frequency of fusion variant-AR (16.1% vs 4.9%) (all p < 0.05) compared to ID-TNBC. Analysis of inferred immune cell infiltrates showed that TN-ILC had higher infiltration of M2 macrophages (5.34% vs. 2.94%) and neutrophils (4.83% vs. 2.65%) but lower infiltration of M1 macrophages (3.46% vs 2.17%) and CD8 T cells (0.58% vs. 0.11%) (all p<0.05). TN-ILC had lower T cell inflamed signature (16.1% vs 35.7%, p<0.05), decreased immune checkpoint genes (CD274, CTLA4, FOXP3, LAG3, IDO, FC: 1.2-2.7, all p < 0.05), PD-L1 protein expression (SP142: 30.4% vs. 50.2%, p=0.06; 22c3: 15.4% vs. 42.6%, p = 0.05) and differential expression of BCL2 family genes (upregulation: BIK, FC: 2.2; downregulation: BAX, BAK1, BID, PMAIP1, MCL1, BCL2A1, BCL2L10, FC: 1.0-6.3, all p < 0.05) compared to ID-TNBC. Conclusion: These data suggest that TN-ILC had higher frequency of CDH1, ERBB2, AKT1, ARID1A mutations, higher M2 macrophages and neutrophils and lower M1 macrophages and CD8 T cells infiltration and, lower T cell inflamed signature. High TMB and AR expression can translate into use of immunotherapy (ICI) and AR antagonists in these patients. Additonal analysis to determine the optimal biomarker for ICI response in TN-ILC is needed. Results of our study need to be validated in larger studies with survival correlation. Citation Format: Pooja Advani, Sachin Deshmukh, Sharon Wu, Jacob Andring, Joanne Xiu, Jose Leone, Priya Jayachandran, Stephanie Graff, Mathew Oberley, George Sledge, Asher Chanan-Khan. Comprehensive molecular and immune profiling of triple negative invasive lobular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7037.

Abstract Background: Residual disease after neoadjuvant chemotherapy (NAC) in breast cancer (BC) confers poor outcomes. Trastuzumab emtansine (T-DM1) is approved for HER2+ patients with residual disease after NAC. However, many patients still develop recurrence. H2NVAC is a multi-epitope CD4 helper T cell activating vaccine that includes a pool of 4 degenerate HER2-derived HLA-DR epitopes admixed with GM-CSF. Our previous phase I trial showed that this vaccine was safe and generated robust, long-lasting T and B cell immune responses. Method: We conducted a safety run-in phase of H2NVAC in combination with T-DM1 in stage II-III HER2+ BC with residual disease after NAC. Patients were treated with H2NVAC and T-DM1 for 6 cycles, followed by 2 boosters at 3 and 12 months. Dose-limiting toxicity (DLT) was defined as any grade (G) ≥ 3 toxicity occurring within 21 days after the first vaccination. Results: 20 patients were enrolled (median age 51; 27-69 years), including 80% White and 15% Black. 90% had hormone receptor-positive disease. There was no DLT observed in the safety run-in cohort. All adverse events (AEs) during the DLT period were grades 1 and 2, with fatigue being the most common (60% G1, 5% G2), followed by peripheral sensory neuropathy (55% G1, 5% G2), and injection site reaction (50% G1). Across all treatment cycles, the 10 most common AEs that were at least possibly related to treatment in all cycles are summarized in the table below. The injection site reaction was the most common AE, with 85% G1 and 15% G2. Conclusion: H2NVAC, in combination with T-DM1, was safe, with a favorable side effect profile. There was no DLT observed. The most common AE was injection site reaction, with the majority being G1. A multicenter, randomized, placebo-controlled, phase II trial of H2NVAC vs. placebo in combination with trastuzumab emtansine is currently ongoing through the ACCRU consortium (NCT04197687). Adverse Events Grades 1 2 N % N % Injection site reaction 17 85.0 3 15.0 Aspartate aminotransferase increase 13 65.0 Alanine aminotransferase increase 9 45.0 Fatigue 7 35.0 2 10.0 Peripheral sensory neuropathy 7 35.0 2 10.0 Alkaline phosphatase increase 8 40.0 Nausea 7 35.0 1 5.0 Arthralgia 7 35.0 Myalgia 5 25.0 1 5.0 Platelet count decrease 6 30.0 Citation Format: Saranya Chumsri, Sharmila Giri, Andy J. Ness, David W. Hillman, Nadine Norton, Davitte Cogen, Brian M. Necela, Aziza Nassar, Donald W. Northfelt, Pooja Advani, Rohit Rao, Kostandinos Sideras, Alvaro Moreno-Aspitia, Brenda J. Ernst, Kathryn J. Ruddy, Matthew P. Goetz, Keith L. Knutson. Safety and tolerability of multi-epitope HER2 peptide vaccines in combination with trastuzumab emtansine in HER2-positive breast cancer patients with residual disease after neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5005.

Background: Music therapy (MT) offers benefits of improved symptom relief and quality of life at the end of life, but its impact on hospice patients and caregivers needs more research. Objective: To assess the impact of MT intervention on symptom burden and well-being of hospice patients and caregivers. Methods: A total of 18 hospice patients, selected based on scores ≥4 on the revised Edmonton Symptom Assessment System (ESAS-r) items on pain, depression, anxiety, or well-being, participated in MT sessions provided by a board-certified music therapist. Over a period of 2-3 weeks, 3-4 MT sessions were conducted for each. Patient Quality of life (QOL) was assessed using the Linear Analogue Self-Assessment (LASA). Depression and anxiety were measured with the Patient Health Questionnaire-4 (PHQ-4). For the 7 caregivers enrolled, stress levels were measured using the Pearlin role overload measure and LASA. Results: Patients reported a reduction in symptom severity and emotional distress and an increase in QOL. All patients endorsed satisfaction with music therapy, describing it as particularly beneficial for stress relief, relaxation, spiritual support, emotional support, and well-being. Scores on overall QOL and stress were worse for caregivers. Conclusion: This study provides evidence that MT reduces symptom burden and enhances the quality of life for hospice patients. Hospice patients and their caregivers endorsed satisfaction with MT. Given the benefits observed, integrating MT into hospice care regimens could potentially improve patient and caregiver outcomes. Larger studies should be conducted to better assess the impact of MT in this population.

Importance Adding fulvestrant to anastrozole (A+F) improved survival in postmenopausal women with advanced estrogen receptor (ER)–positive/ERBB2 (formerly HER2)–negative breast cancer. However, the combination has not been tested in early-stage disease. Objective To determine whether neoadjuvant fulvestrant or A+F increases the rate of pathologic complete response or ypT1-2N0/N1mic/Ki67 2.7% or less residual disease (referred to as endocrine-sensitive disease) over anastrozole alone. Design, Setting, and Participants A phase 3 randomized clinical trial assessing differences in clinical and correlative outcomes between each of the fulvestrant-containing arms and the anastrozole arm. Postmenopausal women with clinical stage II to III, ER-rich (Allred score 6-8 or >66%)/ERBB2-negative breast cancer were included. All analyses were based on data frozen on March 2, 2023. Interventions Patients received anastrozole, fulvestrant, or a combination for 6 months preoperatively. Tumor Ki67 was assessed at week 4 and optionally at week 12, and if greater than 10% at either time point, the patient switched to neoadjuvant chemotherapy or immediate surgery. Main Outcomes and Measures The primary outcome was the endocrine-sensitive disease rate (ESDR). A secondary outcome was the percentage change in Ki67 after 4 weeks of neoadjuvant endocrine therapy (NET) (week 4 Ki67 suppression). Results Between February 2014 and November 2018, 1362 female patients (mean [SD] age, 65.0 [8.2] years) were enrolled. Among the 1298 evaluable patients, ESDRs were 18.7% (95% CI, 15.1%-22.7%), 22.8% (95% CI, 18.9%-27.1%), and 20.5% (95% CI, 16.8%-24.6%) with anastrozole, fulvestrant, and A+F, respectively. Compared to anastrozole, neither fulvestrant-containing regimen significantly improved ESDR or week 4 Ki67 suppression. The rate of week 4 or week 12 Ki67 greater than 10% was 25.1%, 24.2%, and 15.7% with anastrozole, fulvestrant, and A+F, respectively. Pathologic complete response/residual cancer burden class I occurred in 8 of 167 patients and 17 of 167 patients, respectively (15.0%; 95% CI, 9.9%-21.3%), after switching to neoadjuvant chemotherapy due to week 4 or week 12 Ki67 greater than 10%. PAM50 subtyping derived from RNA sequencing of baseline biopsies available for 753 patients (58%) identified 394 luminal A, 304 luminal B, and 55 nonluminal tumors. A+F led to a greater week 4 Ki67 suppression than anastrozole alone in luminal B tumors (median [IQR], −90.4% [−95.2 to −81.9%] vs −76.7% [−89.0 to −55.6%]; P < .001), but not luminal A tumors. Thirty-six nonluminal tumors (65.5%) had a week 4 or week 12 Ki67 greater than 10%. Conclusions and Relevance In this randomized clinical trial, neither fulvestrant nor A+F significantly improved the 6-month ESDR over anastrozole in ER-rich/ERBB2-negative breast cancer. Aromatase inhibition remains the standard-of-care NET. Differential NET response by PAM50 subtype in exploratory analyses warrants further investigation. Trial Registration ClinicalTrials.gov Identifier: NCT01953588

Abstract Background: Activation of the RAS/MAPK pathway is associated with reduced tumor-infiltrating lymphocytes and poor outcomes in triple-negative breast cancer (TNBC). This trial evaluated the efficacy of pembrolizumab and MEK inhibitor, binimetinib. Here we evaluated potential biomarkers in peripheral blood to predict response. Methods: Patients with unresectable locally advanced or metastatic TNBC with ≤ 3 prior lines of therapy were enrolled. Treatment includes a 2-week run-in with binimetinib followed by pembrolizumab. There were 2 dose levels (DL) with binimetinib at 45 mg at DL 0 and 30 mg at DL -1. A standard 3+3 design was used in phase I, and Simon’s two-stage Optimal design was used in phase II. Circulating tumor cells (CTC) and circulating cancer-associated macrophage-like cells (CAML) were isolated using CellSieve microfilters and immunofluorescently labeled with PD-L1 and p-ERK. Wilcoxon rank sum test and Cox regression model were used for analysis. Results: A total of 22 patients were enrolled, with a median age of 58 years old. Dose-limiting toxicity (DLT) was observed in 2 out of 4 patients in DL 0, with grade 3 ALT abnormality, flank pain, and nausea. In the next 6 patients in DL -1, there was 1 DLT with grade 3 AST/ALT abnormality. There were 17 patients treated with DL -1 and were evaluable for response. The objective response rate (ORR) was 29.41% (95% CI: 10.31-55.9) with 1 complete response (CR) and 4 partial responses (PR). The clinical benefit rate (CBR ≥ 24 weeks) was 35.29% (95% CI: 14.21-61.67). ORR in patients without liver metastases was 55.56% (95% CI: 21.20 - 86.30), and CBR was 66.67% (95% CI: 29.93-92.51). There was no response observed in all 5 patients with liver metastases. Baseline mean CTC count was 1.3 cells, and CAML count was 8.9 cells/7.5 mL. Baseline PD-L1 in CAML (p 0.04) and decline in CAML size (p 0.02) after 1 cycle were significantly associated with CBR. However, baseline CTC count, CAML count (p 0.64), CAML size (p 0.46), p-ERK in CAML (p 0.23), and changes in CTC count, CAML count (p 0.83), p-ERK (p 0.07), and PD-L1 (p 0.08) in CAML were not significantly associated with responses. Using Cox regression analysis, a reduction in CAML count (p 0.02), CAML size (p 0.01), and PD-L1 in CAML (p 0.03) were associated with significant improvement in overall survival but not the reduction in p-ERK (p 0.6). Conclusions: Pembrolizumab and binimetinib at 30 mg are safe with manageable toxicities. Promising activity was observed in patients without liver metastases. Baseline PD-L1 expression, early reduction in CAML count, size, and PD-L1 expression were significantly associated with subsequent responses, providing potential noninvasive biomarkers to predict response to this combination. Future larger clinical trials are warranted to further evaluate the efficacy of this combination. Citation Format: Saranya Chumsri, Joseph J. Larson, Daniel L. Adams, Kathleen S. Tenner, Cha-Mei Tang, Morgan T. Weidner, Amanda N. Arnold, Dana L. Haley, Pooja Advani, Kostandinos Sideras, Alvaro Moreno-aspitia, Edith A. Perez, Keith L. Knutson. Peripheral blood biomarkers in Phase II study of pembrolizumab in combination with oral binimetinib in patients with unresectable locally advanced or metastatic triple-negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5454.

e24161 Background: Pertuzumab-induced gastrointestinal toxicities (PIGT), particularly diarrhea, is the most common adverse event reported in over 70% of patients receiving pertuzumab in combination with chemotherapy. PIGT can result in dose reduction, treatment delay, and discontinuation of chemotherapy. Rifaximin is a minimally absorbed oral antibiotic approved for gastrointestinal tract infections and bacterial overgrowth. Our aim was to evaluate the efficacy of rifaximin in reducing PIGT. Methods: Patients with stage I-III HER2-positive (HER2+) breast cancer who received pertuzumab in combination with docetaxel, carboplatin, and trastuzumab (TCHP) were enrolled. PIGT included diarrhea, abdominal distention, abdominal pain, dyspepsia, stomach pain, and typhlitis. Patients with any PIGT ≥ grade 2 after the first cycle of TCHP received rifaximin 550 mg orally twice daily on days 1-5 in all subsequent cycles of chemotherapy. Patients with PIGT grade < 2 were observed without rifaximin. Simon's Two-Stage design was used. Results: Between 2018-2022, a total of 21 patients were enrolled. One patient was excluded due to significant anemia not meeting the eligibility criteria to proceed with rifaximin after the first cycle of TCHP. Of 20 patients, the median age was 52.5 (39-69) years. 18/20 (90.0%) patients had PIGT ≥ grade 2 after 1 cycle of TCHP with PIGT grade 2 in 15 (83.3%) and grade 3 in 3 (16.7%). PIGT ≥ grade 2 included diarrhea in 14 (70.0%) with grade 2 in 12 (60.0%) and grade 3 in 2 (10.0%), abdominal pain in 9 (45.0%) with grade 2 in 8 (40.0%) and grade 3 in 1 (5.0%), abdominal distension in 3 (15.0%), dyspepsia in 5 (25.0%), and stomach pain in 4 (20.0%) patients. Among 18 patients who received rifaximin, 15 (83.3%; 95% CI 0.586-0.964) had at least 1 cycle with a maximum PIGT grade < 2. This result surpassed the threshold of the Two-Stage analysis. Reduction of individual PIGT symptoms for patients who experienced > grade 2 at baseline after the first cycle of rifaximin was reported in 2/3 (66.7%) for abdominal distention, 8/9 (88.9%) for abdominal pain, 6/14 (42.9%) for diarrhea, 3/4 (75.0%) for stomach pain, and 4/5 (80.0%) for dyspepsia. No patients experienced > grade 2 typhilitis at baseline and during treatment. Treatment is well tolerated, with no significant grade 3+ adverse event related to rifaximin observed. Among patients who received rifaximin, there was no treatment delay or discontinuation of pertuzumab related to PIGT. Conclusions: PIGT is a debilitating side effect observed in most patients receiving pertuzumab. A short course of rifaximin after each cycle of treatment is a well-tolerated treatment option that significantly reduces PIGT in patients receiving pertuzumab in combination with chemotherapy. Clinical trial information: NCT04249622 .

TPS633 Background: Ovarian function suppression (OFS) when combined with tamoxifen or an aromatase inhibitor is the standard of care for premenopausal estrogen receptor positive (ER+) human epidermal growth factor receptor 2 negative (HER2-) breast cancer (BC) based on SOFT (Francis 2022) and TEXT (Pagani 2022) clinical trials and confirmed in a metanalysis (EBCTCG 2022). However, estrogen deprivation in premenopausal women is associated with significant morbidity and up to 40% of premenopausal women with ER+/HER2- BC are intolerant of OFS. For these women, tamoxifen monotherapy is the only FDA approved option. Therefore, there is substantial room to improve endocrine therapy for premenopausal women with ER+/HER2- BC. (Z)-endoxifen is one of the most active anti-estrogen tamoxifen metabolites, with preclinical data demonstrating superiority to tamoxifen and letrozole in aromatase expressing xenograft models and evidence for antitumor activity in early phase clinical trials in patients with prior progression on endocrine therapy including tamoxifen. In addition to its ability to potently block ERa, (Z)-endoxifen at clinically achievable concentrations inhibits protein kinase C beta 1 (PKCβ1), resulting in downstream AKT inhibition and apoptosis. It is hypothesized that (Z)-endoxifen, when delivered as monotherapy at doses that dually target both ERα and PKCβ1, will potently inhibit BC proliferation while obviating the need for OFS in premenopausal women. If successful, this innovative approach could spare women with endocrine sensitive BC from the side effects of OFS. Methods: To further study (Z)-endoxifen in premenopausal women, a multicenter study in the United States, with possible expansion to other countries was designed (EVANGELINE; NCT05607004). This is a Phase 2, open-label, randomized, neoadjuvant study in premenopausal women with Stage IIA or IIB ER+/HER2- BC. Subjects are randomized 1:1 to either exemestane plus goserelin or (Z)-endoxifen. The primary objective is to determine whether the endocrine sensitive disease (ESD) rate (defined as Ki-67 ≤ 10% after 4 weeks of neoadjuvant therapy) with (Z)-endoxifen is non-inferior to exemestane plus goserelin. Subjects will be enrolled with the intent of surgical treatment in the involved breast(s) after completing 6 months of neoadjuvant treatment. Safety, tolerability, response rates and surgical outcomes will be assessed. Disease progression will be monitored throughout study participation. Paired tumor biopsies and blood sampling will allow for a robust biomarker evaluation. Prior to initiating the Treatment Cohort (162 subjects), up to 12 subjects will be enrolled in a pharmacokinetic (PK) Run-in Cohort to identify the optimal dose for the Treatment Cohort. Enrolment in the PK Run-in cohort began in February 2023. Clinical trial information: NCT05607004 .

Abstract Background: Two poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) are currently FDA-approved for the treatment of HER2-negative metastatic breast cancer (MBC) in carriers of germline pathogenic variants (PVs) in BRCA1 or BRCA2 (BRCA1/2). This study explores the clinical outcomes of MBC patients treated with a PARPi. Methods: In this retrospective study, we included MBC patients treated with a PARPi between January 2017 and February 2022 at Mayo Clinic (Minnesota, Arizona, Florida, and Mayo Clinic Health Systems). We used the Kaplan Meier method to estimate the time-to-treatment-failure (TTF) and the log-rank test to compare different subsets. In addition, predictors of TTF were identified in a multivariate cox-proportional hazard regression model, including age at PARPi initiation, race, ethnicity, histology, estrogen receptor (ER), progesterone receptor (PR), and HER2 expression of the tumor, the number of prior therapies, type of PARPi, and PV carrier status (germline BRCA1/2 or PALB2 vs. somatic BRCA1/2 vs. other). Results: Sixty-five patients treated with PARPi (olaparib: 51; talazoparib: 14) were included in the final analysis. Fifty-five patients were carriers of germline PVs in BRCA1 (n=24, 37%), BRCA2 (n=27, 42%) or PALB2 (n=4, 6%), whereas ten patients (15%) had no germline PVs but the tumor had a somatic mutation in the homologous recombination-related (HRR) genes (7 in BRCA1/2, 2 in ATM, and 1 in CDKN2A and CDH1). At the data cutoff, 48 (74%) patients had discontinued PARPi due to progression or death. Fifteen (23%) patients required a dose reduction due to side effects. Occurrence of grade ≥ 3 side effects: anemia in 8, fatigue in 4, neutropenia in 2, and thrombocytopenia in 2 patients. Eight (15.7%) patients in the olaparib group and seven (50%) patients in the talazoparib group required a dose reduction for side effects. No patient on olaparib required drug discontinuation due to side effects, whereas two patients on talazoparib were switched to olaparib due to cytopenias and could tolerate olaparib. Median TTF in the overall population was 8 months (95% confidence interval [CI]: 6.4 – 9.6), and there was no difference (p=0.64) in TTF between the olaparib and talazoparib groups. Median TTF in the germline BRCA1, BRCA2, and PALB2 PV carriers were 7, 8, and 11 months, respectively (p=0.57). Among patients with somatic BRCA1/2 mutations, the median TTF was 4 months. Numerically, patients with HER2-positive tumors (n=8) had a shorter TTF compared to HER2-negative tumors (Median TTF: 4 vs. 8 months, p=0.098). No significant difference in TTF was observed by ER or PR status of the tumor, age at initiation of PARPi, the number of prior therapies, and prior use of platinum-based chemotherapy or CDK4/6 inhibitors. In multivariate analysis, HER2 positivity (hazard ratio [HR]: 8.0, 95% CI: 2.2 – 29.4, p=0.002), somatic BRCA1/2 mutations (HR: 7.6, 95% CI: 1.2 – 50.0, p=0.03) and somatic mutations in other HRR genes (HR: 19.1, 95% CI: 3.1 – 118.6, p=0.002) were associated with worse TTF. Conclusions: In the real world, PARPi were well-tolerated with promising time-to-treatment-failure (TTF) benefits comparable to data from clinical trials. Notably, relatively shorter TTF was observed in patients with somatic BRCA1/2 and other HRR gene mutations and HER2-positive MBC. These findings improve our understanding of the role of PARPi in MBC and will help to guide treatment decisions with PARPi in the clinical setting. Citation Format: Nusrat Jahan, Jodi Taraba, Karthik V. Giridhar, Roberto A. Leon-Ferre, Amye J. Tevaarwerk, Elizabeth Cathcart-Rake, Ciara C. O’Sullivan, Prema Peethambaram, Timothy J. Hobday, Kathryn Ruddy, Lida A. Mina, Pooja Advani, Felipe Batalini, Matthew P. Goetz, Tufia C. Haddad, Fergus J. Couch, Siddhartha Yadav. Clinical outcomes of metastatic breast cancer patients treated with poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi): the Mayo Clinic experience [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-22.

Abstract Background: Previous studies demonstrated that activation of the RAS/MAPK pathway is associated with reduced tumor-infiltrating lymphocytes and poor response to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC). Further in vivo study showed that inhibition of the MAPK pathway with a MEK inhibitor is synergistic with immune checkpoint inhibitors (ICIs). Methods: Patients with unresectable locally advanced or metastatic TNBC with ≤ 3 prior lines of therapy were treated with pembrolizumab 200 mg every 3 weeks plus an oral MEK inhibitor binimetinib. Treatment was started with a 2-week run-in period with single-agent binimetinib. There were 2 dose levels in phase I, including dose level 0 (DL 0) with binimetinib at 45 mg orally twice daily continuously and dose level -1 (DL -1) at 30 mg twice daily. A standard 3+3 design was used in phase I to identify the recommended phase II dose (RP2D) and Simon’s two-stage Optimal design was used in phase II. Results: A total of 22 patients were enrolled. The median age was 58 years old (range 37-77). 14 (63.6%) patients had no prior systemic therapy in the metastatic setting and 8 (36.4%) patients had 1-2 prior lines of therapy. There were 4 patients treated in DL 0. Dose-limiting toxicity (DLT) was observed in 2 out of 4 patients in DL 0 with grade 3 ALT abnormality in one patient and grade 3 flank pain together with grade 3 nausea and vomiting &gt; 48 hours despite anti-emetic therapy in the other patient. Binimetinib dose was reduced to DL -1. In the next 6 patients, there was 1 DLT observed with grade 3 AST/ALT abnormality. Thus, DL -1 was the RP2D, and an additional 12 patients were treated with DL -1 in phase II. Overall, 18 patients were treated in DL -1 and were included in phase II efficacy evaluation. 17 patients were evaluable for response. Objective responses were observed in 5 patients (29.41% 55.96) with 1 complete response (CR) and 4 partial responses (PR). The clinical benefit rate (CBR) was 35.29% (95% CI: 14.21 - 61.67) with 6 out of 17 having had CR, PR, or stable disease &gt;= 24 weeks. Since previous studies showed poor responses to ICIs in patients with liver metastases due to macrophage-mediated T cell elimination, we further conduct exploratory analysis to evaluate responses among patients with and without liver metastases. Among all 5 patients with liver metastases, no response was observed. The objective response rate (ORR) in patients without liver metastases was 55.56% (95% CI: 21.20 - 86.30) and CBR was 66.67% (95% CI: 29.93-92.51), when excluding 3 patients who discontinued treatment due to adverse events prior to follow-up scans. Median progression-free survival in DL 0 was 2.4 (95%CI: 0.5-NE) and in DL -1 was 8.3 (95% CI: 3.9-NE) months. Median overall survival in DL 0 was 7 (95%CI: 0.5-NE) and in DL -1 was 33.2 (95% CI: 10.3-NE) months. Among patients who responded, 3 out of 5 (60%) had a duration of response greater than 12 months and ongoing even after stopping treatment (range: 5.4 - 32.0 months). Adverse events (AEs) were mostly grade 1-2 including anemia, CPK increase, fatigue, diarrhea, nausea, peripheral neuropathy, acneiform rash, AST increase, cardiac troponin increase, and constipation. Additional correlative studies are ongoing and will be presented at the meeting. Conclusions: Pembrolizumab in combination with binimetinib at 30 mg twice daily appears to be safe with manageable toxicities. Promising activity with durable responses was observed with this combination without chemotherapy, particularly in patients without liver metastases. Future studies are warranted to further evaluate the efficacy of this combination. Citation Format: Saranya Chumsri, Joseph J. Larson, Kathleen S. Tenner, Jun He, Mei-Yin Polley, Morgan T. weidner, Amanda N. Arnold, Dana Haley, Pooja Advani, Kostandinos Sideras, Alvaro Moreno-Aspitia, Edith A. Perez, Keith L. Knutson. Phase I/II study of pembrolizumab in combination with oral binimetinib in patients with unresectable locally advanced or metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-17.