A Phase II Trial of the Combination of Ixazomib, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Background: Early therapeutic intervention in high-risk SMM (HR-SMM) has demonstrated benefit based on previous studies that included treatment with lenalidomide or lenalidomide and dexamethasone (Mateos et al. N Engl J Med 2013; Lonial et al. J Clin Oncol 2020). Combination therapy with triplets has shown higher rates of deep response and improved outcomes in patients with multiple myeloma, including the combination of ixazomib, lenalidomide, and dexamethasone (Moreau et al. N Eng J Med 2016). We present our results of phase II study of ixazomib, lenalidomide and dexamethasone in HR-SMM. Methods: Patients enrolled on the study met eligibility for high-risk SMM based on the defined criteria proposed by Rajkumar et al. (Blood 2014). The treatment plan was designed to be administered on an outpatient basis where patients receive 9 cycles of induction therapy of ixazomib (4mg) at days 1, 8, and 15, in combination with lenalidomide (25mg) at days 1-21 and dexamethasone at days 1, 8, 15, and 22. The induction phase was followed by ixazomib (4mg) and lenalidomide (15mg) maintenance for another 15 cycles. A treatment cycle was defined as 28 consecutive days for a total of 24 months period. Bone marrow samples of all patients were obtained before starting therapy for baseline assessment for minimal residual disease (MRD) testing, whole-exome sequencing (WES), and RNA sequencing of plasma and bone marrow microenvironment cells. Moreover, blood samples were obtained at screening and before each cycle for isolating cell-free DNA (cfDNA) and circulating tumor cells (CTCs). Results: Sixty-one patients have been enrolled in this study from February 2017 to 2020. The median age of the patients at enrollment was 64 years (range, 40 to 84), with 33 males (54.1%). The analysis was conducted on patients who have completed at least 2 cycles of therapy (n=55). Thus far, 42 (69%) patients have completed the planned 24 cycles of therapy. High-risk cytogenetics (defined as the presence of t(4;14), 17p deletion, and 1q gain) were found in 14 patients out of the 33 evaluable (42.4%) Interphase fluorescence in situ hybridization (iFISH) results. The median number of cycles completed was 24 cycles (range: 2-24). According to the new IMWG risk stratification model (20-2-20), baseline markers showed that 32 patients (58%) were high risk, 18 (33%) were intermediate risk, and 5 (9%) were low risk. The most common grades 3 or greater toxicities were neutropenia (20%), hypophosphatemia (13%), leukopenia (11%), rash (9%), lymphocytopenia (5%), and thrombocytopenia (5%). Stem cells were collected from all eligible patients by the end of the induction phase. No patients discontinued treatment due to toxicity. At the time of data cut off, the overall response rate (partial response or better) in participants who completed at least 2 cycles of treatment was 90.9% (50 of 55), with 12 complete responses (CR, 21.8%), 10 very good partial responses (VGPR, 18.2%), 28 partial responses (50.9%), and 4 minimal responses (MR, 7.3%). ORR in patients who completed the induction phase (≥9 cycles) was 92.3% (n= 48 of 52), with 22 (40%) deep remissions including 12 (23.1%) and 10 (19.2%) having achieved a CR and VGPR, respectively. All patients who had a CR have also achieved a stringent CR. No patients developed progression to overt or active MM while on study therapy. After completion of study therapy, 4 patients progressed to active MM during follow up, 3 additional patients developed biochemical progression and started a new course of therapy but did not meet CRAB criteria and 7 patients confirmed biochemical PD and remain off therapy. Conclusions: The combination of ixazomib, lenalidomide, and dexamethasone is an effective all oral well-tolerated intervention in high-risk smoldering myeloma that demonstrated an ORR of >90% and deep remission in >40% of patients. While no patients progressed to overt MM while on therapy, some developed progression after completion of planned study therapy, indicating the possible need for higher intensification of therapy or maintenance therapy beyond 2 years in this high-risk group of patients. Longer follow-up for disease outcome is ongoing. Disclosures Nadeem: BMS: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Mo: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Eli Lilly: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; AbbVIE: Consultancy. Sperling: Adaptive: Consultancy. Richardson: AstraZeneca: Consultancy; Secura Bio: Consultancy; Regeneron: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Protocol Intelligence: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Celgene/BMS: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

Pembrolizumab (pembro) in combination with gemcitabine (Gem) and concurrent hypofractionated radiation therapy (RT) as bladder sparing treatment for muscle-invasive urothelial cancer of the bladder (MIBC): A multicenter phase 2 trial.

4504 Background: Trimodality bladder preservation therapy (TMT) is a standard treatment option for clinically localized MIBC with curative intent. Pembro has shown activity in MIBC in the neoadjuvant setting and may combine well with TMT to improve outcomes. This trial evaluated the safety and efficacy of pembro added to TMT in MIBC. Methods: This multicenter phase 2 trial included pts with cT2 – T4aN0M0 MIBC who declined or were ineligible for cystectomy (RC), ECOG PS 0/1, eGFR > 30 cc/min, and no contraindications to pelvic RT or pembro. No perioperative chemotx for MIBC was permitted. Pts received pembro 200 mg x 1 followed 2-3 weeks by maximal TURBT and then whole bladder RT (52 Gy/20 fx; IMRT preferred) with twice wkly gem 27 mg/m2 and pembro Q3 wks x 3 treatments. 12 wks post-RT, CT/MR AP, TUR of tumor bed and cytology were performed to document response. Up to 6 pts were enrolled to a safety cohort (SC) followed by 48 pts in efficacy cohort (EC). The primary endpt is 2-yr bladder-intact disease-free survival (BIDFS: first of MIBC or regional nodal recurrence, distant metastases, or death) assessed by serial cysto/cytology and CT/MRI. EC had 85% power to detect a 20% absolute improvement in 2-yr BIDFS rate over 60% historical rate (RTOG Pooled analysis; Mak JCO 2014). Key secondary endpts were safety, 12 wks CR rate, metastases-free survival and overall survival. Tumor tissue was collected at study entry, maximal TURBT and post-treatment TUR of tumor bed with serial PBMCs for correlative analyses. Results: From 5/2016 to 10/2020, 54 pts (6 SC, 48 EC; 72% M) enrolled at 5 centers; Median age 67 (65-89) for SC and 74 (51-97) for EC. C-stage (74% cT2, 22% cT3, and 4% cT4). 39 (72%) declined RC. All 6 pts in SC and 42/48 (88%) of EC pts completed all study therapy; 1/48 (2%), 2/48 (4%), and 4/48 (8%) discontinued RT/Gem, Gem or Pembro, respectively, most often due to toxicity. As of 1/2021 (median F/U 40.9 mos (38.6-50.8) SC and 11.7 mos (0.6 – 32.2) EC), no recurrences in SC, and 12/48 EC pts had any recurrence (6 NMIBC, 0 MIBC, 2 regional and 4 distant). The estimated 1 yr BIDFS rate is 77% (95% CI: 0.60-0.87). 12 wks CR rate was 100% in SC and 83% for EC (1 PR, 3 NR, 1 Progression, 11 NE; 2 still on active study). In the EC, 35% of pts had a Gr ≥3 TEAE (Gr 3 events included UTI 8%, diarrhea 4%, colitis 4%, bladder pain/obstruction 4%, neutropenia 2%, thrombocytopenia 2%). Notable Pembro Gr ≥3 TRAE included 3 pts (6%) Gr 3 GI toxicity and 1 pt Gr 4 colonic perforation. 1 patient died due to fungemia, unrelated to study therapy. Conclusions: Pembro added to hypofractionated RT and twice weekly gem was well-tolerated with promising efficacy in this early analysis. Pembro-related toxicity was consistent with prior monotherapy trials. Selected correlative analyses from serially collected blood and tissue specimens will be presented. Clinical trial information: NCT02621151.

Nivolumab and stereotactic radiosurgery for patients with breast cancer brain metastases: A non-randomized, open-label phase Ib study.

e14010 Background: There may be a potential synergy intracranially between stereotactic radiation and immune checkpoint inhibition in brain metastases management. We hypothesize treatment with nivolumab and stereotactic radiosurgery (SRS) will be feasible and well tolerated and may improve intracranial tumor control rates compared to SRS alone in the management of breast cancer brain metastases. Methods: The study was designed as a prospective, single-arm, nonrandomized, open-label, phase Ib trial of nivolumab and SRS among patients with metastatic breast cancer brain metastases. Key eligibility criteria included patients with breast cancer brain metastases of all subtypes, age ≥ 18, ECOG ≤ 2 with ≤ 10 brain metastases. The primary objective was to evaluate the safety and feasibility of study therapy. Secondary objectives included evaluation of local brain metastasis control, distant brain metastasis control, progression free survival (PFS), and overall survival following study therapy. Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) and immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) criteria were used to assess intracranial and extracranial disease, respectively. Treatment was initiated with a dose of nivolumab (480 mg IV) that was repeated every 4 weeks. The initial dose of nivolumab was followed 1 week later by SRS. This study is closed to accrual and is registered with ClinicalTrials.gov, NCT03807765. Results: Between February 2019 and July 2020, a total of 12 patients were treated to 17 lesions. Median follow-up from start of protocol therapy is currently 9.6 months (range: 2.8-18.7 months). No dose limiting toxicities (DLTs) were noted in our patient population. The most common neurologic adverse events included grade 1-2 headaches and dizziness occurring in 5 (42%) of patients. Median intracranial control was 6.2 months (95% CI 3.0 -14) with 6 and 12 month control rates of 55% and 22%, respectively. A total of 4 patients had systemic progression during the study. Median time to systemic PFS has not been reached with 6 and 12 month rates of 63% and 51%, respectively. Conclusions: Nivolumab and SRS is a safe and feasible treatment option in breast cancer brain metastases. Preliminary studies reveal activity in certain breast cancer patients to study therapy. Clinical trial information: NCT03807765.

Outcomes for patients in the pembrolizumab+axitinib arm with advanced renal cell carcinoma (RCC) who completed two years of treatment in the phase III KEYNOTE-426 study.

327 Background: In the randomized, open-label, phase III KEYNOTE-426 study (NCT02853331), pembrolizumab + axitinib significantly improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) versus sunitinib as first-line therapy for advanced RCC. Per protocol, patients could discontinue pembrolizumab or axitinib and continue the other agent. Pembrolizumab was stopped for all patients at 2 years. Axitinib could be continued until progression or toxicity. This exploratory subgroup analysis of KEYNOTE-426 describes outcomes of patients who completed 2 years of pembrolizumab. Methods: Patients included in KEYNOTE-426 were treatment naive, with clear cell RCC, KPS ≥70%, and measurable disease (RECIST v1.1). Patients were randomly assigned 1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks for up to 35 doses + axitinib 5 mg orally twice daily or sunitinib 50 mg once daily (4 weeks on/2 weeks off) until progression, toxicity, or withdrawal. Primary end points of the original analysis were OS and PFS. Key secondary end points were ORR and safety. Results: Of 432 patients treated with pembrolizumab + axitinib, 129 (29.9%) completed 2 years of study therapy. Median (range) age of these patients was 61 (36-82) years, and 72.1% were male; 42 (32.6%) and 87 (67.4%) patients had International mRCC Database Consortium favorable and intermediate/poor risk, respectively, consistent with the intention-to-treat population (31.9% vs 68.1%). Median (range) follow-up (time from randomization to data cutoff) was 31.1 (24.0-37.7) months. For patients who completed 2 years of study therapy, the OS rates at 36 months was 93.8% (95% CI, 85.5%-97.4%). The PFS rates at 24 and 36 months were 72.7% (95% CI, 64.0%-79.7%) and 57.7% (95% CI, 46.3%-67.5%), respectively. The ORR was 85.3%, and the CR rate was 14.0%. 59.7% of patients experienced grade 3-5 treatment-related adverse events and 8.5% experienced grade 3-5 immune-mediated adverse events. Conclusions: In this exploratory analysis, a significant proportion of patients in the pembrolizumab + axitinib arm completed 2 years of pembrolizumab with ongoing clinical benefit. Clinical trial information: NCT02853331 .

Ixazomib with or without Rituximab Following Immunochemotherapy and Autologous Stem Cell Transplant in Mantle Cell Lymphoma

Background: Maintenance rituximab administered post autologous stem cell transplant (ASCT) in mantle cell lymphoma (MCL) is associated with improved overall survival (OS). Maintenance approaches with the proteasome inhibitor, bortezomib, are associated with improved progression-free survival (PFS), although its use is limited by peripheral neuropathy (Kaplan et al, 2020). We conducted a phase 1 study to evaluate the safety of maintenance therapy with ixazomib, an oral proteasome inhibitor, alone and in combination with rituximab for patients with MCL completing ASCT in first remission. Methods: Adult patients with MCL completing an ASCT in first partial or complete remission and who remained progression-free were enrolled between days 70-180 post-ASCT. Initially, patients received ixazomib monotherapy in cohorts of three using a standard 3+3 design. Patients self-administered ixazomib on days 1, 8, and 15 of each 28-day cycle at one of 3 dose levels: 2.3mg, 3mg, or 4mg. Patients continued therapy until disease progression, intolerance, or completion of 10 cycles. While we were enrolling to the 4mg dose level, the LYMA trial reported an OS benefit associated with maintenance rituximab (Le Gouill et al, 2017), so the protocol was amended to explore the combination of ixazomib and rituximab. Combination therapy consisted of ixazomib 4mg (given at the same schedule) and rituximab 375 mg/m2 given on day 1 of cycles 1, 3, 5, 7, and 9. The primary objective of the study was to evaluate the safety of this treatment and determine the maximum tolerated dose (MTD) while secondary objectives included efficacy. Results Twelve patients enrolled in the trial and received at least one dose of study therapy. Seven patients received ixazomib monotherapy (3mg = 3 patients, 4mg= 4 patients), and 5 patients received combination with rituximab and 4mg ixazomib. In all patients, the median age was 58 years (range 42-73 years) and 75% of the patients were male. Five patients had a high risk MIPI score. All patients entered the study in complete remission. Pre-transplant induction was R-HyperCVAD (n=6), VR-CAP/R-DHAP (n=2), NORDIC regimen (n=2), R-CHOP/R-DHAP (n=1), and R-DHAX (n=1). Transplant conditioning regimens were BEAM (n=7) or Bu/Cy/VP-16 (n=5). In the monotherapy group, 6 patients completed all 10 cycles of therapy. One patient experienced a dose limiting toxicity (DLT) which consisted of grade 3 neutropenia following cycle 1. In addition to the patient who experienced a DLT, one patient discontinued therapy early due to persistent abdominal pain that was ultimately determined to be unrelated to study therapy after an extensive evaluation. Two patients required dose reductions due to grade 3 hematologic toxicities. Two patients in the combination therapy group completed 10 cycles of therapy. Two patients experienced DLTs which consisted of grade 4 neutropenia, and 1 patient opted to discontinue therapy early due to persistent grade 2 peripheral neuropathy. In all patients, common adverse events (AEs) regardless of attribution were abdominal pain (n=6), leukopenia (n=5), nausea (n=4), thrombocytopenia (n=4), and peripheral neuropathy (n=3). Grade 3/4 AEs were thrombocytopenia (n=1) and neutropenia (n=4). No grade 3/4 peripheral neuropathy was observed. With a median follow up of 29.6 months, no patients experienced disease progression and all are alive. Due to the myelosuppression-related DLT's encountered in the combination arm, the study was closed to further accrual. Conclusions Our findings suggest adding rituximab to ixazomib at the evaluated dose and schedule as post-ASCT maintenance is associated with myelosuppression, and we would suggest future studies evaluate an alternative dose/schedule to mitigate this risk. The lack of early progressions is encouraging, confirming the findings from CALGB50403 that proteasome inhibition may provide therapeutic benefit in this setting. Further evaluation of rituximab-containing post-induction combination therapies may identify a safer dosing strategy while improving long-term remission rates. Disclosures Allen: Bayer: Consultancy, Other; Curio Sciences: Honoraria; Clinical Care Options: Speakers Bureau; Research to Practice: Speakers Bureau; Imbrium: Consultancy, Other. Waller:Verastem Oncology, Inc: Consultancy, Research Funding. Flowers:Bayer: Consultancy; Denovo Biopharma: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; BeiGene: Consultancy; Celgene: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Karyopharm: Consultancy; OptumRx: Consultancy; Pharmacyclics/Janssen: Consultancy; Spectrum: Consultancy; Acerta: Research Funding; Millennium/Takeda: Consultancy, Research Funding; TG Therapeutics: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; Kite: Research Funding; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees. Cohen:Genentech, BMS, Novartis, LAM, BioInvent, LRF, ASH, Astra Zeneca, Seattle Genetics: Research Funding; Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo: Consultancy.

53. TUCATINIB VS PLACEBO ADDED TO TRASTUZUMAB AND CAPECITABINE FOR PATIENTS WITH PREVIOUSLY TREATED HER2+ METASTATIC BREAST CANCER (MBC) WITH BRAIN METASTASES (BM) (HER2CLIMB)

BACKGROUND HER2CLIMB (NCT02614794) primary results have been reported previously (Murthy, NEJM 2019). We report results of exploratory efficacy analyses in pts with brain metastases (BM). METHODS All HER2+ MBC pts enrolled had a baseline brain MRI. Pts with BM were eligible and randomized 2:1 to receive tucatinib (TUC) or placebo, in combination with trastuzumab and capecitabine. Efficacy analyses were performed by applying RECIST 1.1 to the brain based on investigator evaluation. CNS-PFS and OS were evaluated in BM pts overall. Intracranial (IC) confirmed ORR-IC and DOR-IC were evaluated in BM pts with measurable IC disease. After isolated brain progression, pts could continue study therapy until second progression, and time from randomization to second progression or death was evaluated. RESULTS Overall, 291 pts (48%) had BM at baseline: 198 (48%) in the TUC arm and 93 (46%) in the control arm. There was a 68% reduction in risk of CNS-PFS in the TUC arm (HR: 0.32; P<0.0001). Median CNS-PFS was 9.9 mo in the TUC arm vs 4.2 mo in the control arm. Risk of overall death was reduced by 42% in the TUC arm (OS HR: 0.58; P=0.005). Median OS was 18.1 mo vs 12.0 mo. ORR-IC was higher in the TUC arm (47.3%) vs the control arm (20.0%). Median DOR-IC was 6.8 mo vs 3.0 mo. In pts with isolated brain progression who continued study therapy after local treatment (n=30), risk of second progression or death was reduced by 71% (HR: 0.29), and median time from randomization to second progression or death was 15.9 mo vs 9.7 mo, favoring the TUC arm. CONCLUSIONS In pts with previously treated HER2+ MBC with BM, TUC in combination with trastuzumab and capecitabine doubled the ORR-IC, reduced risk of IC progression or death by two-thirds and reduced risk of death by nearly half.

FLT3 ligand (CDX-301) and stereotactic radiotherapy for advanced non-small cell lung cancer.

9618 Background: In a murine non-small cell lung cancer (NSCLC) model, we demonstrated synergy between localized radiotherapy and the dendritic cell growth factor fms-like tyrosine kinase 3 (FLT3) ligand. We now present results from a phase II study testing this combination in patients with advanced and treatment-refractory NSCLC. Methods: Advanced NSCLC patients with multifocal active disease after at least one line of systemic therapy and ECOG performance status 0-2 received 5 daily subcutaneous injections of CDX-301 (75 µg/kg) concurrent with stereotactic body radiotherapy (SBRT, 30-54 Gy in 1-5 fractions based on target size and location) directed at a single site of disease. Additional “cycles” of SBRT and CDX-301 could be administered at least four months after the initial study treatment, at the discretion of the treating physicians. The primary endpoint was progression-free survival four months after treatment initiation (PFS4), with a hypothesis that the PFS4 rate would exceed 40%. Secondary endpoints included overall survival (OS) duration, responses on PET (PERCIST criteria) and CT (RECIST criteria), and dose-limiting toxicities (grade ≥3 adverse events within 30 days). Lesions targeted with SBRT were excluded from response assessments. The intended sample size was 29 subjects. Blood samples were obtained for flow cytometry and other analyses of immune activation. Results: Twenty-nine subjects received study therapy between October 2016 and January 2020. Subjects received a median of 3 lines (range: 1-5) of systemic therapy prior to study enrollment, including immune checkpoint inhibitors targeting the PD-1/PD-L1 axis in 26 subjects (90%). At the time of this analysis, the actuarial PFS4 rate is 60%, which exceeds our pre-specified efficacy objective. With a median follow-up duration for living patients of 12 months, the actuarial 12-month OS rate is 55%. Partial response of lesions not targeted with SBRT (“abscopal effect”) was observed in 9 subjects (31%) using PET criteria and in 4 subjects (14%) using CT criteria. Seven subjects (24%) received a second course of SBRT and CDX-301 after initial study therapy. No dose-limiting toxicities have been observed. Only six subjects (21%) have received additional chemotherapy or immunotherapy after study treatment. Conclusions: The combination of CDX-301 and SBRT is well-tolerated and has activity as systemic therapy for advanced NSCLC. Additional studies to maximize the efficacy of this in situ vaccination approach with the addition of an agonist anti-CD40 antibody (CDX-1140) are planned. Clinical trial information: NCT02839265 .

Tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB).

1005 Background: Tucatinib (TUC) is an investigational, highly selective HER2 kinase inhibitor. HER2CLIMB (NCT02614794) showed clinically meaningful and statistically significant improvements in overall survival (OS) and progression free survival (PFS) in all pts, prolongation of PFS in pts with brain metastases (BM), and objective response rate (ORR) when TUC was added to trastuzumab (T) and capecitabine (C). Primary methods and outcomes have been reported previously (Murthy NEJM 2019). We report the results of exploratory efficacy analyses in pts with BM. Methods: All pts with HER2+ metastatic breast cancer (MBC) enrolled in HER2CLIMB had a baseline brain MRI. Pts with BM were eligible and classified as untreated, treated stable, or treated and progressing. Pts were randomized 2:1 to receive TUC or placebo, in combination with T and C. Efficacy analyses in pts with BM at baseline were performed by applying RECIST 1.1 to the brain based on investigator evaluation. CNS-PFS (progression in the brain or death) and OS were evaluated in BM pts overall. Intracranial (IC) confirmed ORR (ORR-IC) and IC duration of response (DOR-IC) were evaluated in BM pts with measurable IC disease. After isolated brain progression, pts could continue study therapy after local treatment until second progression, and time from randomization to second progression or death was evaluated. Results: Overall, 291 pts (48%) had BM at baseline: 198 (48%) in the TUC arm and 93 (46%) in the control arm. There was a 68% reduction in risk of CNS-PFS in the TUC arm (HR: 0.32; 95% CI: 0.22, 0.48; P < 0.0001). Median CNS-PFS was 9.9 mo in the TUC arm vs 4.2 mo in the control arm. Risk of death overall was reduced by 42% in the TUC arm (OS HR: 0.58; 95% CI: 0.40, 0.85; P = 0.005). Median OS was 18.1 mo vs 12.0 mo. ORR-IC was higher in the TUC arm (47.3%; 95% CI: 33.7, 61.2) vs the control arm (20.0%; 95% CI: 5.7, 43.7). Median DOR-IC was 6.8 mo (95% CI: 5.5, 16.4) vs 3.0 mo (95% CI: 3.0, 10.3). In pts with isolated brain progression who continued study therapy after local treatment (n = 30), risk of second progression or death was reduced by 67% (HR: 0.33; 95% CI: 0.11, 1.02), and median PFS from randomization was 15.9 mo vs 9.7 mo, favoring the TUC arm. Conclusions: In pts with heavily previously treated HER2+ MBC with BM, TUC in combination with T and C doubled the ORR-IC, reduced risk of IC progression or death by two thirds and reduced risk of death by nearly half. If approved, TUC in combination with T and C has the potential to become a new standard of care in pts with HER2+ MBC with and without BM. Clinical trial information: NCT02614794 .