Manoj Prahladan

Abstract Trastuzumab deruxtecan (T-DXd) intracranial activity has been observed in small or retrospective patient cohorts with human epidermal growth factor receptor 2–positive (HER2 + ) advanced/metastatic breast cancer (mBC) and stable or active (untreated/previously treated and progressing) brain metastases (BMs). The phase 3b/4 DESTINY-Breast12 study investigated T-DXd in patients with HER2 + mBC and is, to our knowledge, the largest prospective study of T-DXd in patients with BMs in this setting. Patients (stable/active BMs ( n = 263) and no BMs ( n = 241)) treated with one or more prior anti-HER2–based regimens received T-DXd (5.4 mg per kg). Primary endpoints were progression-free survival (PFS; BMs cohort) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (non-BMs cohort). Additional endpoints included central nervous system (CNS) PFS, ORR, time to second progression, CNS ORR (BMs cohort), incidence of new symptomatic CNS metastases (non-BMs cohort), time to progression, duration of response, overall survival and safety (both cohorts). No formal hypothesis testing was conducted for this single-arm, open-label study. In the BMs cohort, 12-month PFS was 61.6% (95% confidence interval (CI): 54.9–67.6), and 12-month CNS PFS was 58.9% (95% CI: 51.9–65.3). In the non-BMs cohort, ORR was 62.7% (95% CI: 56.5–68.8). Grade 3 or higher adverse events occurred in 51% (BMs cohort) and 49% (non-BMs cohort) of patients. Investigator-reported interstitial lung disease/pneumonitis occurred in 16% (grade ≥3: 3%) of patients with BMs and 13% (grade ≥3: 1%) of patients without BMs. These data show substantial and durable overall and intracranial activity for T-DXd, supporting its use in previously treated patients with HER2 + mBC irrespective of stable/active baseline BMs. ClinicalTrials.gov identifier: NCT04739761 .

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Background: Mantle cell lymphoma (MCL) is a B cell malignancy accounting for 3-10% of all Non-Hodgkin Lymphomas and arises mainly in older adults with a male predominance (McKey et al). Historically, median survival was 4–5 years (Herrmann et al, 2009) however this is now in the order of 8–12 years in younger fitter patients who are able to tolerate intensive therapies (Eskelund et al, 2016). The current standard treatment is chemoimmunotherapy with or without autologous stem cell transplantation (ASCT). Although intensive therapy can achieve durable responses most patients eventually succumb to their disease. Novel therapeutic agents have shown efficacy in relapsed/refractory disease and are now being tested as frontline treatment (Sharma et al., 2018). Aims: We report a single centre experience of MCL and its treatment. Methods: Retrospective data was collected on all patients diagnosed with MCL at Ipswich Hospital NHS Trust over a nine year period between January 2010 and January 2019. Results: Forty-two patients were included in the analysis. Median age was 68yrs with a male to female ratio of 5:1. Eastern Co-operative Oncology Group (ECOG) performance status ranged from 0-1 in 66%, ≥2 in 14% and 19% had no status documented. Twenty-four patients (57%) received a non-intensive chemoimmunotherapy regimen; rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or rituximab-bendamustine (BR) as first line treatment with twenty of these patients receiving rituximab maintenance. Thirteen patients (31%) were fit enough to receive an intensive chemoimmunotherapy regimen with all but one consolidated with an ASCT. Of those transplanted five went on to receive rituximab maintenance. The remaining 12% of patients received either R-Chlorambucil, palliative radiotherapy, FCR or supportive care. The median Kaplan-Meier overall survival (OS) for all patients had not been reached. Median progression free survival (PFS) was 48 months. Comparing first line therapies, the median OS for those that received RCHOP/BR was 60 months with a median PFS of 35 months vs. not reached for both OS and PFS with intensive chemoimmunotherapy followed by ASCT. Eighteen patients had relapsed during the nine year period. There was no standard second line treatment. Eight patients received further chemoimmunotherapy including BR, R-cytarabine and FCR, one PEP-C, three ibrutinib, four palliative radiotherapy and two received supportive care only. After first relapse median PFS was 6 months and median OS was only 10 months. Nine patients received a third line treatment, of which 3 received ibrutinib and one venetoclax and the median OS was 9 months. The six relapsed/refractory patients that received Ibrutinib at either first or second relapse had a median OS of 8 months vs. 12 months in those that received other forms of therapy. Summary/Conclusion: As expected the best outcomes were with high intensity regimens consolidated by ASCT. Our data period was not long enough to show the continuous pattern of relapse despite durable responses that have now been shown by long term follow up data (Eskelund et al, 2016). The outlook was poor for relapsed/refractory disease with a median OS of 10 months. Rule et al analysed data from 370 patients receiving ibrutinib for relapsed/refractory MCL, enrolled across three different studies (PCYC-1104, SPARK, and RAY), and demonstrated an excellent outcome, with a median PFS of 13 months and median OS of 26.7 months. We did not see a beneficial effect on OS with the use of novel therapies in our patients (8 months vs. 12 months) although our study numbers were small.

Abstract Background: Patients (pts) with human epidermal growth factor receptor 2–positive breast cancer (HER2+ BC) have a high incidence (up to 50%) of brain metastasis (BM) despite advances in treatment (Zimmer AS et al. Cancer Rep (Hoboken). 2020;e1274; Hurvitz SA et al. Clin Cancer Res. 2019;25:2433-2441). Although several agents have been studied in pts with HER2+ BC with BM, an unmet medical need remains. In DESTINY-Breast01, T-DXd demonstrated efficacy in the overall population and preliminary efficacy in a pt subgroup with stable BM (n=24), with a confirmed objective response rate (ORR) of 61.4%, an extracranial confirmed ORR by independent central review (ICR) of 58.3%, respectively, and median progression-free survival (PFS) of 19.4 and 18.1 months, respectively (Modi S et al. Cancer Res. 2021. Abst PD3-06; Jerusalem G et al. Ann Oncol. 2020. Abst 138O). T-DXd also demonstrated preliminary efficacy in a subgroup of pts with BM in the DESTINY-Breast03 trial, with an extracranial ORR of 67.4%, intracranial ORR of 63.9%, and median PFS of 15.0 months (Hurvitz S et al. SABCS 2021. Abst GS3-01). However, both trials excluded pts with active/progressive BM. Here we describe a trial evaluating T-DXd in a real-world setting in pts with stable or active BM and pts without BM with previously treated advanced/metastatic HER2+ BC. The data generated by this study will complement previous and ongoing studies, providing a more robust understanding of T-DXd treatment in patients with and without BM. Trial design: DESTINY-Breast12 (NCT04739761) is an open-label, multicenter, international (91 sites in the US, Europe, Australia, Canada, and Japan), phase 3b/4 study assessing the efficacy and safety of T-DXd 5.4 mg/kg every 3 weeks in pts with HER2+ BC ± BM. As part of prescreening, all pts will provide informed consent for tumor tissue samples (archival tumor tissue or fresh biopsy) to be collected and tested for HER2 status. Pts will be enrolled in 1 of 2 cohorts (250 pts each): cohort 1 (no BM at baseline) and cohort 2 (BM at baseline). Pts must have previously treated HER2-positive BC that has progressed on or after ≥1 prior anti-HER2–based regimen (including disease progression ≤6 months after adjuvant treatment with HER2-targeted therapies) and received ≤2 lines of therapy in the metastatic setting (excluding pts with prior tucatinib). Cohort 1 will be limited to include ≤25% third-line pts. Pts with BM must have untreated BM not needing immediate local therapy or previously treated stable or progressing BM. Primary endpoints are ORR in cohort 1 and PFS in cohort 2 (both by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1 per ICR). Secondary endpoints in both cohorts are overall survival, DOR, time to progression, duration of subsequent therapy, PFS2, safety, and changes in symptoms, functioning, and quality of life. Incidence of new symptomatic central nervous system (CNS) metastasis is a secondary endpoint in cohort 1, and ORR and CNS ORR by RECIST 1.1 per ICR, CNS PFS and DOR, and time to new CNS metastasis are secondary endpoints in cohort 2. Citation Format: Nancy U. Lin, Eva Ciruelos, Guy Jerusalem, Volkmar Müller, Naoki Niikura, Giuseppe Viale, Emma Oscroft, Shawn Anand, Manoj Prahladan, Nadia Harbeck. Open-label, phase 3b/4 study of trastuzumab deruxtecan (T-DXd) in patients with or without baseline brain metastasis with advanced/metastatic human epidermal growth factor receptor 2–positive breast cancer: DESTINY-Breast12 [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 OT2-16-02.