Citations

Abstract Background: In MONARCH 2, abemaciclib plus fulvestrant significantly improved median progression-free survival (PFS, 16.4 vs 9.3 months, hazard ratio [HR], 0.553) and overall survival (OS, 46.7 vs 37.3 months; HR, 0.757) compared with placebo plus fulvestrant in hormone receptor-positive (HR-positive), human epidermal growth factor receptor 2-negative (HER2-negative) advanced breast cancer (ABC) patients who were endocrine therapy (ET) resistant, regardless of menopausal status. Here, we report findings in the premenopausal subgroup of the MONARCH 2 trial. Methods: The premenopausal subgroup included patients with natural menstrual bleeding who received a gonadotropin-releasing hormone agonist at least 4 weeks prior to study treatment start date and for the entire study duration. Of the 669 patients enrolled in the MONARCH 2 trial, 114 were premenopausal (abemaciclib plus fulvestrant, n=72; placebo plus fulvestrant, n=42), and were included in this analysis. The primary objective was investigator-assessed PFS and secondary objectives were OS, objective response rate, and safety and tolerability. Exploratory analyses included time to second disease progression (PFS2), time to chemotherapy (TTC), and chemotherapy-free survival (CFS). Results: At the primary objective cutoff (14 February, 2017), median PFS was not reached for the abemaciclib plus fulvestrant arm versus 10.52 months for the placebo plus fulvestrant arm (HR, 0.415; 95% CI, 0.246-0.698). At the pre-specified OS interim cutoff (20 June, 2019), median PFS was 28.6 months in the abemaciclib plus fulvestrant arm compared with 10.26 months in the placebo plus fulvestrant arm (HR, 0.477; 95% CI, 0.302-0.755). OS benefit was observed in the abemaciclib plus fulvestrant compared to fulvestrant alone (HR, 0.689; 95% CI, 0.379-1.252, median, not reached vs 47.3 months). Improvements were also observed for the exploratory outcomes of PFS2 (HR, 0.599), TTC (HR, 0.674), and CFS (HR, 0.642) with the addition of abemaciclib to fulvestrant. The safety profile was generally consistent with results disclosed previously. Conclusions: Results of the premenopausal subgroup in the MONARCH 2 trial were consistent with the improved clinical outcomes observed in the intent-to-treat population. The analysis provides support for the use of abemaciclib plus fulvestrant (with ovarian suppression) as an effective treatment option for premenopausal patients with HR+, HER2- ABC who are ET-resistant. Clinical trial registration: NCT02107703. Registered 08 April 2014- Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02107703

PURPOSE The ATEMPT trial was designed to determine if treatment with trastuzumab emtansine (T-DM1) caused less toxicity than paclitaxel plus trastuzumab (TH) and yielded clinically acceptable invasive disease-free survival (iDFS) among patients with stage I human epidermal growth factor receptor 2–positive (HER2+) breast cancer (BC). METHODS Patients with stage I centrally confirmed HER2+ BC were randomly assigned 3:1 to T-DM1 or TH and received T-DM1 3.6 mg/kg IV every 3 weeks for 17 cycles or T 80 mg/m 2 IV with H once every week × 12 weeks (4 mg/kg load →2 mg/kg), followed by H × 39 weeks (6 mg/kg once every 3 weeks). The co-primary objectives were to compare the incidence of clinically relevant toxicities (CRTs) in patients treated with T-DM1 versus TH and to evaluate iDFS in patients receiving T-DM1. RESULTS The analysis population includes all 497 patients who initiated protocol therapy (383 T-DM1 and 114 TH). CRTs were experienced by 46% of patients on T-DM1 and 47% of patients on TH ( P = .83). The 3-year iDFS for T-DM1 was 97.8% (95% CI, 96.3 to 99.3), which rejected the null hypothesis ( P < .0001). Serially collected patient-reported outcomes indicated that patients treated with T-DM1 had less neuropathy and alopecia and better work productivity compared with patients on TH. CONCLUSION Among patients with stage I HER2+ BC, one year of adjuvant T-DM1 was associated with excellent 3-year iDFS, but was not associated with fewer CRT compared with TH.

TPS1111 Background: Chest wall recurrence is a subtype of breast cancer that is challenging to treat, and associated with a short duration of response to treatment and an increased risk of development of distant metastases. Given the inflammatory nature of this disease and the association of chest wall disease with lymphovascular invasion, which is correlated with higher programmed cell death 1 (PD-1) expression, we hypothesized that immunotherapy may be beneficial as treatment. Combinations of immunotherapy and chemotherapy have a synergistic effect and demonstrated efficacy in the treatment of metastatic triple negative breast cancer (TNBC). This study is evaluating the efficacy of pembrolizumab, an anti-PD-1 antibody, in combination with carboplatin, in patients with chest wall infiltration from breast cancer. This drug combination has shown efficacy in advanced lung cancer. Methods: This is a multicenter, 2:1 randomized phase II study of pembrolizumab/carboplatin (Arm A, 56 patients) vs. carboplatin (Arm B, 28 patients) in 84 patients with chest wall disease from breast cancer, with or without distant metastases. Patients may have TNBC, hormone receptor positive/HER2 negative (following receipt of 2 prior hormone therapies), or HER2 positive breast cancer (with option to continue trastuzumab on study). Pembrolizumab is administered as 200 mg IV every 3 weeks, and carboplatin as AUC 5 IV every 3 weeks. Patients on Arm A may continue pembrolizumab +/- carboplatin (Arm Ax) after completion of 6 cycles of treatment, while patients in Arm B can cross-over to pembrolizumab (+/- carboplatin) on progression (Arm Bx). Patients must have adequate organ function, performance status ≤ 2, and may have received any number of lines of prior chemotherapy. Patients undergo serial chest wall photography and imaging (CT chest, abdomen, and pelvis, and bone scan) at baseline and every 6 weeks, as well as blood collection for correlative studies and chest wall biopsies at baseline and after 2 cycles of treatment. The primary endpoint is disease control rate (RECIST 1.1) at 18 weeks of treatment, and the study is powered to determine a 20% difference in disease control rates between arms (HR 0.52, a = 0.10, ß = 0.20). An interim analysis will occur for Arm B after 18 patients are enrolled, with a stopping rule for futility. Secondary endpoints include progression-free survival, toxicity (NCI CTCAE), and response based on irRECIST and tumor programmed death ligand 1 (PD-L1) expression. Exploratory objectives include evaluating changes in soluble PD-L1, tumor and peripheral blood immune composition, circulating tumor cells and cell-free DNA, and MYC oncogene expression. This study (NCT03095352) is open at 7 sites in the Translational Breast Cancer Research Consortium (TBCRC). 52 patients are enrolled. Grant funding is provided by Merck and UCSF. Clinical trial information: NCT03095352 .

TPS1110 Background: PARP inhibitors are approved for the treatment of HER2 negative metastatic breast cancer (MBC) with germline BRCA1/2 mutations, based on phase III studies demonstrating an improvement in progression-free survival (PFS) compared to chemotherapy in this population and better patient reported outcomes (Robson, NEJM, 2017; Litton, NEJM, 2018). However, germline BRCA1/2 mutations account for only 5-10% of breast cancer, limiting the current clinical applicability of PARP inhibitors. Somatic BRCA1/2 mutations are detectable in circulating cell-free DNA (cfDNA) in ̃13.5% of patients with MBC; in pre-clinical models, pathogenic somatic BRCA1/2 mutations have been shown to respond to PARP inhibition (Vidula, CCR, 2020). The purpose of this study is to evaluate the efficacy of talazoparib, a PARP inhibitor, in patients with MBC who have somatic BRCA1/2 mutations detectable in cfDNA, in the absence of a germline BRCA1/2 mutation, which we hypothesize will be effective in this setting. This study may help expand the population of patients with MBC who benefit from PARP inhibitors. Methods: This is an investigator initiated multicenter, single arm, phase II clinical trial studying the efficacy of talazoparib in 30 patients with MBC who have pathogenic somatic BRCA1/2 mutations detected in cfDNA. Patients with MBC who are found to have pathogenic somatic BRCA1/2 mutations detected in cfDNA in the absence of a germline BRCA1/2 mutation are eligible. Patients may have triple negative (with ≥ 1 prior chemotherapy), or hormone receptor positive/HER2 negative breast cancer (with ≥ 1 prior hormone therapy). Patients may have received any number of prior lines of chemotherapy, including a prior platinum (in the absence of progression). They must have adequate organ function and ECOG performance status ≤2, and should not have previously received a PARP inhibitor. Patients are treated with talazoparib 1 mg daily until disease progression or intolerability, with serial imaging using CT chest/abdomen/pelvis and bone scan performed at baseline and every 12 weeks, and cfDNA collection every 4 weeks. Primary endpoint is PFS by RECIST 1.1. Patients are being enrolled in a two-stage design with 80% power to demonstrate that the treatment is associated with “success” (PFS > 12 weeks) in ≥53% patients (4% alpha). Secondary endpoints include objective response rate and safety (NCI CTCAE v 5.0). Exploratory analyses include studying serial changes in cfDNA BRCA1/2 mutant allelic frequency and comparing pre-and post-treatment cfDNA for the emergence of BRCA1/2 reversion and resistance mutations. This study is activated and open at Massachusetts General Hospital, where 2 patients are completing screening. It is also opening soon at 6 other academic centers (NCT03990896). Grant support includes a Pfizer ASPIRE award and 2020 Conquer Cancer Foundation of ASCO – Breast Cancer Research Foundation – Career Development Award. Clinical trial information: NCT03990896 .

508 Background: I-SPY 2 is a multicenter, phase 2 trial using response-adaptive randomization within molecular subtypes defined by receptor status and MammaPrint (MP) risk to evaluate novel agents as neoadjuvant therapy for women with high-risk breast cancer. SD-101 is an investigational Toll-like receptor 9 (TLR9) agonist CpG-C class oligodeoxynucleotide that stimulates the production of IFN-α and interleukin (IL)-12, functional maturation of plasmacytoid dendritic cells, and production of cytotoxic antibodies. IT SD-101 was combined with systemic anti-PD-1 antibody Pb to investigate the antitumor and immunologic activity of this novel immunotherapeutic strategy. Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only pts (pts) with HER2- disease were eligible for this treatment. Treatment included weekly P x 12 in combination with IT SD-101 2 mg/ml (1 ml for T2 tumors, 2 ml for >T3 tumors) weekly x 4, then q3 weeks x 2, and IV Pb q3 weeks x 4, followed by doxorubicin/cyclophosphamide (AC) q2-3 weeks x 4 (SD-101+Pembro 4). Pts in the control arm received weekly P x 12 followed by AC q2-3 weeks x 4. The I-SPY 2 methods have been previously published. This investigational arm was eligible for graduation (>85% chance of success in a 300-person phase 3 neoadjuvant trial) in 3 of 10 pre-defined signatures: HER2-, hormone receptor (HR)+/HER2- and HR-/HER2-. Results: 75 pts were randomized and evaluable in SD-101+Pembro 4 treatment arm. The control arm included 329 historical controls enrolled since April 2010. The study arm was stopped due to maximal patient accrual. Pt characteristics were balanced; 56% HR+, 44% HR-. The probability that SD-101+Pembro4 was superior to control exceeded 97% for all eligible tumor signatures, but did not reach the threshold for graduation in any of the signatures. However, it is notable that the rate of pCR/Residual Cancer Burden 1 (RCB1) in the HR+/HER2- signature was 51%. Preliminary safety events for SD-101+Pembro 4 include increased rates of fever, neutropenia, febrile neutropenia, transaminitis, and immune-related events, including adrenal insufficiency. Conclusions: The SD-101+Pembro 4 regimen was active but did not meet the pre-specified threshold for graduation in I-SPY 2. pCR/RCB 1 analysis suggests improved response in the HR+/HER-negative signature compared to control. The clinical significance of these findings needs to be weighed against the potential risk of immune-related toxicities. Clinical trial information: NCT01042379. [Table: see text]

Background: The management of patients with triple-negative breast cancer (TNBC) is challenging with several controversies and unmet needs. During the 12th Breast-Gynaecological & Immuno-oncology International Cancer Conference (BGICC) Egypt, 2020, a panel of 35 breast cancer experts from 13 countries voted on consensus guidelines for the clinical management of TNBC. The consensus was subsequently updated based on the most recent data evolved lately. Methods: A consensus conference approach adapted from the American Society of Clinical Oncology (ASCO) was utilized. The panellists voted anonymously on each question, and a consensus was achieved when ≥75% of voters selected an answer. The final consensus was later circulated to the panellists for critical revision of important intellectual content. Results and conclusion: These recommendations represent the available clinical evidence and expert opinion when evidence is scarce. The percentage of the consensus votes, levels of evidence and grades of recommendation are presented for each statement. The consensus covered all the aspects of TNBC management starting from defining TNBC to the management of metastatic disease and highlighted the rapidly evolving landscape in this field. Consensus was reached in 70% of the statements (35/50). In addition, areas of warranted research were identified to guide future prospective clinical trials.

This letter to the editor responds to Badoui et al. regarding data on abemaciclib dosages and adverse events.

Abstract Background: I-SPY 2 is a multicenter, phase 2 trial using response-adaptive randomization within molecular subtypes defined by receptor status and MammaPrint (MP) risk to evaluate novel agents as neoadjuvant therapy for women with high-risk stage II/III breast cancer. The primary endpoint is pathologic complete response (pCR, ypT0/Tis ypN0). SGN-LIV1A is an investigational antibody drug conjugate consisting of an antibody to LIV1A, a zinc transporter highly prevalent in breast cancer, and a highly potent microtubule inhibitor, monomethyl auristatin E. Retrospective IHC analysis of LIV1A expression levels amongst tumor samples from 100 previous ISPY-2 patients showed 88% of breast tumor samples with moderate to high expression of LIV1A (Yau, C. et al SABCS 2018).Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment, hormone-receptor positive (HR+) patients had to have MP high molecular profile. Treatment included SGN-LIV1A 2.5 mg/kg (max dose 250 mg) every 3 weeks x 4, followed by doxorubicin/cyclophosphamide (AC) every 2-3 weeks x 4. The control arm was weekly paclitaxel x 12 followed by AC every 2-3 weeks x 4. All patients undergo serial MR imaging where response at 3 & 12 weeks combined with accumulating pCR data are used to estimate, and continuously update, predicted pCR rate for the trial arm. Analysis set was modified intention to treat with patients who switched to non-protocol therapy counted as non-pCR and not as their pCR status at time of surgery. The goal is to identify/graduate regimens with ≥85% Bayesian predictive probability of success (i.e. demonstrating superiority to control) in a future 300-patient phase 3 neoadjuvant trial with a pCR endpoint within signatures defined by HR & HER2 status & MP result. This investigational arm was eligible for graduation in 3 of 10 pre-defined signatures: HER2-, HR+HER2- and HR-HER2-. Regimens may also leave the trial for futility (&lt; 10% probability of success), maximum sample size accrual (10% &lt; probability of success &lt;85%), maximum time in trial (2 years) or for safety as recommended by the independent DSMB. Results: Sixty patients were randomized and evaluable to SGN-LIV1A. The study arm was stopped due to reaching the predetermined time limit for patient accrual of 2 yrs. Final estimated pCR rates are below. The estimated pCR rates were similar between the SGN-LIV1A and control arms for any tumor subtype. Preliminary safety events for SGN-LIV1A include increased rates of transaminitis and hyperglycemia and reduced rates of peripheral neuropathy compared to control. One patient was removed from the analysis as she was determined to have angiosarcoma of the breast. Notably, this patient had a dramatic early response and subsequent pCR to SGN-LIV1A treatment. Conclusion: The value of I-SPY 2 is to give insight about the performance of an investigational agent’s likelihood of achieving pCR. SGN-LIV1A delivered every 3 weeks was comparable to paclitaxel for the primary endpoint of pCR in I-SPY2 and may have a similar side effect profile, however, with less peripheral neuropathy. Clinical trials evaluating weekly dosing of SGN-LIV1A are ongoing. A trial of SGN-LIV1A in the treatment of angiosarcoma is under consideration at this time. Final Estimated pCR Rates and Predictive ProbabilitiesEstimated pCR rate(95% prob interval)SignatureSGN-LIV1AControlProbability SGNLIV1A Superior to ControlPredictive Probability of Success in Phase 3HER2-0.16 (0.08-0.24) N= 600.20 (0.16-0.25) N= 3270.180.02HR-/HER2-0.25 (0.12-0.37) N=360.28 (0.21-0.35) N=1460.310.06HR+/HER2-0.09 (0-0.18) N=240.14 (0.09-0.19) N=1810.150.03 Citation Format: Heather Beckwith, Richard Schwab, Christina Yau, Erica Stringer-Reasor, Shi Wei, A. Jo Chien, Kathy S Albain, Kevin Kalinsky, Anne Wallace, Anthony Elias, Douglas Yee, Amy S Clark, Judy C Boughey, Heather Han, Rita Nanda, Claudine Isaacs, Zahi Mitri, Julie E Lang, Alexandra Thomas, Tara Sanft, Angela DeMichele, Jane Perlmutter, Hope S Rugo, Nola M Hylton, W. Fraser Symmans, Michelle E Melisko, Laura J van't Veer, I-SPY 2 Consortium, Amy Wilson, Smita M Asare, Ashish Sanil, Donald A Berry, Laura J Esserman. Evaluation of SGN-LIV1a followed by AC in high-risk HER2 negative stage II/III breast cancer: Results from the I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-10.

Abstract Background: Chest wall recurrence may occur in up to 30% of patients with breast cancer, and is associated with a high morbidity and mortality. We hypothesized that immunotherapy may be beneficial in this setting because of the inflammatory nature of this disease, and the association of chest wall disease with lymphovascular invasion. Combination immunotherapy and chemotherapy may have a synergistic effect. In this study, we combined pembrolizumab, an anti-programmed cell death 1 (PD-1) antibody with carboplatin, in patients with chest wall disease. This combination has previously been shown to be effective in advanced lung cancer. Trial design: This is a 2:1 randomized phase II study of pembrolizumab and carboplatin (Arm A) versus carboplatin alone (Arm B) in patients with chest wall involvement from breast cancer. Pembrolizumab is dosed at 200 mg IV every 3 weeks, and carboplatin is dosed at AUC 5 IV every 3 weeks. Patients on Arm A have the option to continue on pembrolizumab alone after 6 cycles of combination treatment (Arm Ax). Patients on Arm B have the option to cross-over to pembrolizumab (+/- carboplatin) after 6 cycles of carboplatin alone (Arm Bx). Patients with HER2 positive disease may continue trastuzumab in addition to the study treatment. Patients undergo chest wall biopsies and peripheral blood collection for correlative studies at enrollment and after 2 cycles of treatment, and also imaging with CT chest, abdomen, and pelvis, and bone scan every 3 cycles. Eligibility criteria: Patients must have chest wall involvement from breast cancer, with or without distant metastases. Patients may have triple-negative breast cancer, hormone receptor positive, HER2- disease (after two prior lines of hormone therapy), or refractory HER2 positive disease. Patients may have received any number of lines of prior chemotherapy. A prior platinum is allowed as long as there was not disease progression on this agent. Specific Aims: 1. (Primary aim) Disease control rate in the chest wall and other distant sites at 18 weeks of treatment using RECIST 1.1 criteria, 2. progression-free survival, 3. toxicity, 4. response based on tumor PD-L1 expression, and 5. response based on irRECIST. Exploratory aims include evaluating: 1. Soluble PD-L1 expression, 2. changes in tumor and peripheral blood immune composition, 3. peripheral blood circulating tumor cells, 4. peripheral blood cell-free DNA, and 5. the association of MYC with PD-1 and TIM-3 on tumor cells, based on preclinical data to suggest that MYC may upregulate these inflammatory markers. Statistical Methods: 84 patients (56 in Arm A and 28 in Arm B) are being enrolled at 7 sites in the Translational Breast Cancer Research Consortium. The study is powered to determine a 20% difference in disease control rates between arms (HR 0.52, α= 0.10, ß=0.20). A futility analysis was originally planned to occur for Arm B after 18 patients are enrolled, but a subsequent amendment has enabled an earlier assessment after 14 patients were enrolled. Accrual: Present accrual is 40 patients. (NCT03095352). This trial is funded in part by Merck and a Development Program Grant from the University of California San Francisco. Contact information: Neelima Vidula, MD, Massachusetts General Hospital, nvidula@mgh.harvard.edu Citation Format: Neelima Vidula, Rita Nanda, Kathy Miller, Paula Pohlmann, Vandana Abramson, Leisha A. Emens, Ben H. Park, Minetta C. Liu, Andrei Goga, Hope S. Rugo. Translational breast cancer research consortium 044 trial: Randomized phase 2 study of pembrolizumab and carboplatin versus carboplatin alone for chest wall recurrence of breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-13-09.