The aim of this international phase II trial was to determine the efficacy and safety profile of weekly vinorelbine plus trastuzumab as first-line chemotherapy for women with HER 2-overexpressing metastatic breast cancer. Sixty-nine patients with tumours overexpressing HER 2 received vinorelbine: 30 mg m À2 week À1 and trastuzumab: 4 mg kg À1 on day 1 as a loading dose followed by 2 mg kg À1 week À1 starting on day 8. Sixty-two patients were evaluable for response and 69 patients were evaluable for toxicity. The overall response rate was 62.9%. The median time to response was 8.4 weeks, the median duration of response was 17.5 months, the median progression-free survival was 9.9 months (95% CI, 5.6 -12.1) and the one-year progression-free survival was 39.1%. The median survival for all patients was 23.7 months (95% CI, 18.4 -32.6). This regimen was safe: grade 3 -4 neutropenia were observed over 17.7% of courses in 83.8% of patients, with only two episodes of febrile neutropenia (0.1%) in two patients (2.9%). Only one patient discontinued treatment due to grade 3 symptomatic cardiac dysfunction that resolved with therapy. Vinorelbine plus trastuzumab is one of the most active treatment regimens for patients with HER 2-positive metastatic breast cancer and demonstrates a very favourable safety profile allowing prolonged treatment with long-term survival. This study has been presented in

Background: Neratinib (N), an irreversible pan-tyrosine kinase inhibitor (TKI), with activity against HER1, -2 and -4, has shown antitumor activity in patients (pts) with HER2+ breast cancer (BC). Lapatinib (L), a reversible HER1 and -2 TKI is approved in combination with capecitabine (C) for treatment of pts with HER2+ advanced or metastatic BC who had prior therapy. Materials and Methods: This phase 2, randomized, open-label study evaluated safety and efficacy of N 240 mg/day vs L 1,250 mg/day plus C 2,000 mg/m2/day (14 days/21 day cycle) in pts with HER2+ locally advanced or metastatic BC. Eligible pts had: ≤2 prior trastuzumab regimens, prior taxane treatment, and no prior anthracycline treatment with cumulative dose >400 mg/m2 doxorubicin, >800 mg/m2 epirubicin, or >equivalent dose of other anthracycline. Primary endpoint was progression-free survival (PFS; investigator-assessed); secondary endpoints included safety, overall survival (OS), objective response rate (ORR), and clinical benefit rate (CBR;% pts with complete response, partial response, or stable disease ≥24 wks). Tumor assessments were every 6 wks for the first 48 wks, then every 12 wks until progressive disease (PD; RECIST 1.0) or initiation of new anticancer therapy. Results: Overall, 117 pts were randomized to N and 116 to L plus C (LC). Mean age (SD; range) was 53.9 y (10.3; 28–79); 60% were White, 34% Asian, and 6% other. Prior treatments included: trastuzumab (229 pts: 168 metastatic or locally advanced, 51 adjuvant, 10 neoadjuvant), taxanes (230 pts), and anthracycline (156 pts). Median treatment duration (range) was 126.5 days (1-636) for N and 201 days (13-622) for LC. Median relative dose intensity (actual/expected exposure) for N was 100%. As of data cutoff, 84% had discontinued treatment; 65% from PD (N 63%, LC 67%), 9% for adverse events (AEs; N 7%, LC 11%). In the ITT cohort, for N and LC, respectively, median PFS (95% CI) was 4.5 mo (3.1−5.7) and 6.8 mo (5.9−8.2; P = 0.091; hazard ratio = 1.3 [95% CI, 1.0−1.8]); median OS (95% CI) was 19.4 mo (19.4−22.2; 41 deaths) and 19.0 mo (16.9-NA; 35 deaths; P = 0.180); ORR (95% CI) was 29% (21-38) and 41% (32-50; P = 0.067); CBR (95% CI) was 44% (35-54) and 64% (54-73; P = 0.003). Most common drug-related treatment-emergent AEs (TEAEs; any grade) were diarrhea (N 84%, LC 67%), nausea (34%, 38%), palmar-plantar erythrodysesthesia (PPE; 5%, 63%), and rash (18%, 34%); for grade ≥3, diarrhea (28%, 10%) and PPE (0, 14%). Dose reductions/discontinuations from diarrhea occurred in 13/3 pts on N, and 15/7 pts on LC. Study deaths for N and LC, respectively, included: 36 pts (31%) and 32 pts (28%) from PD; 5 pts (4%) and 3 pts (3%) from AEs unrelated to study drug. Discussion: In this setting of pts less heavily pre-treated than in the pivotal LC trial, single agent N demonstrated high anti-tumor activity (ORR 29%), confirming results from prior N phase 2 trials. N alone did not appear to be as effective as LC. No unexpected TEAEs were observed; N was well tolerated in pts with HER2+ locally advanced or metastatic BC; while diarrhea was more frequent on N than LC, it was manageable with antidiarrheals and did not lead to more treatment discontinuations. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S5-7.

638 Background: Head-to-head comparison of a steroidal aromatase inhibitor (AI) (E) vs. a non-steroidal AI (A) with crossover at the time of progression to evaluate the sequence of administration. Principal and secondary objectives were overall response rate (ORR), clinical benefit (CB) and time to progression (TTP). Methods: Postmenopausal pt with measurable ABC and positive HR, were stratified [previous tamoxifen (tam) (yes vs. no), previous chemotherapy (ct) (yes vs. no) and stage (IIIb vs. IV)], and randomized to E (25mg/day), or A (1mg/day) until progression. As per Simon’s test, with a p1 of 25% ORR and a p0 of 10% ORR, α and β errors 0.05 and 10%, 50 pt per arm were needed. Results: 103 (51 vs. 52) pt were recruited between 2002 and 2004. Main pt characteristics: median age 70 and 73 years, 82 vs. 88% stage IV, 12 vs. 17% previous ct, 51 vs. 50% previous tam, median size of lesions of 5 vs. 4 cm, mean number of lesions of 1.4 in both arms. Most frequent site of lesions were breast (33 vs. 35%), lymph nodes (22% vs. 25%) and connective tissue (27% vs. 23%). Efficacy: For initial treatment ORR was 37% (CI95% 24–51) in arm E vs. 52% (CI95% 38–66) in arm A (p= 0.151). 47% of pt in E vs. 60% in A presented CB (p=0.202). Mean TTP for arm E was 8.1 months (m) (1.1–15.2) and for arm A was 12.1 m (6.6–17.6) (p=0.4716). 11 pt (arm E) and 12 (arm A) crossed-over after progression. Following crossover mean TTP for E was 4.4 m (3.7–5.1) and for second line A was 1.9 m (0.1–3.7) (p=0.0172). Conclusions: E and A seem to be equivalent in terms of efficacy as first treatment for postmenopausal pt with ABC and positive HR. We suggest a possible advantage of the steroidal AI, exemestane, following disease progression on the non-steroid AI anastrozole. [Table: see text]

Background: Abemaciclib, an oral drug administered twice daily on a continuous schedule, is a specific inhibitor of both CDK4 and CDK6. In MONARCH 1, abemaciclib demonstrated evidence of single-agent activity and an acceptable safety profile in patients with heavily pretreated HR+, HER2- metastatic breast cancer (MBC) whose disease progressed on or after endocrine therapy and chemotherapy; with a confirmed objective response rate of 19.7% and a median duration of response of 8.6 months (Dickler, M. et al. American Society of Clinical Oncology (ASCO), abstr #510 (2016)). This Phase 2 study I3Y-MC-JPCG will evaluate the potential to enhance the risk/benefit profile of abemaciclib in women with previously treated HR+, HER2- MBC, either administered in combination with endocrine therapy or as monotherapy (at the maximum recommended single-agent dose with primary prophylactic antidiarrheal medication or at a lower dose of abemaciclib monotherapy). Such intervention with prophylactic loperamide may increase dose intensity and further optimize the clinical benefit for patients. Trial design: Study JPCG (NCT02747004) is a Phase 2 multicenter, randomized, open-label trial with 3 separate treatment arms in patients with HR+, HER2- MBC who have progressed on or after prior endocrine therapy and have received prior treatment with chemotherapy. Patients will be stratified based on presence of liver metastases and prior use of tamoxifen in the advanced/metastatic setting and will be randomized in a 1:1:1 ratio to receive abemaciclib 150 mg Q12H plus tamoxifen 20 mg every day (Arm A) or abemaciclib 150 mg Q12H monotherapy (Arm B); or abemaciclib 200 mg Q12H monotherapy plus primary prophylactic loperamide (Arm C). Eligibility criteria: Eligible patients include women with HR+, HER2- MBC with evidence of relapse or disease progression following endocrine therapy who have received prior treatment with at least 2 chemotherapy regimens, of which at least 1 but not more than 2 regimens have been administered in the metastatic setting. Patients are required to have measurable disease, adequate organ function, an ECOG PS of ≤1, and no prior treatment with any CDK4 and CDK6 inhibitor. Specific aims: The primary objective of JPCG is to evaluate the progression-free survival per RECIST v1.1, of abemaciclib 150 mg Q12H plus tamoxifen 20 mg QD, abemaciclib 150 mg Q12H monotherapy, and abemaciclib 200 mg Q12H plus prophylactic loperamide in women with HR+, HER2- MBC who have progressed on or after prior endocrine therapy and received prior chemotherapy. Secondary objectives are to evaluate response rates, overall survival, safety, pharmacokinetics, and quality of life. Exploratory objectives include evaluation of the associations between biomarkers relevant to abemaciclib and clinical outcomes. Statistical methods: Assuming a hazard ratio of 0.667, the study yields approximately 80% statistical power to detect superiority of Arm A over Arm C at a 1-sided alpha level of 0.10 using a log-rank test. Arms B and C will be compared using an informal non-inferiority rule. Target accrual: Approximately 225 patients. Contact information: For further information, please contact 1-877-CTLILLY (1-877-285-4559). Citation Format: Diéras V, Hamilton E, Johnston EL, Forrester T, Martín M. Phase 2 study of abemaciclib plus tamoxifen or abemaciclib alone in women with previously treated hormone receptor-positive (HR+), HER2- metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-08.

TPS606 Background: The standard of care for clinically localized muscle-invasive bladder cancer (MIBC) is neoadjuvant platinum-based combination chemotherapy followed by radical cystectomy (RC). Up to 40% of patients (pts) are ineligible to receive cisplatin and proceed to RC without any neoadjuvant therapy. We and others have demonstrated enrichment of molecular alterations in cell cycle genes in MIBC, including copy number losses of CDKN2A in 41% of pts. Abemaciclib is a unique CDK4/6 inhibitor with single agent activity and a target kinome distinct from other CDK4/6 inhibitors. We have demonstrated that CRISPR knockout of CDKN2A increases susceptibility to abemaciclib in bladder cancer cell lines. Beyond tumor-intrinsic effects, abemaciclib also modulates the tumor microenvironment (TME) via upregulating human endogenous retroviral elements and increasing T cell infiltration. Methods: Cell cycLe inhibitiON to target the EVolution of urOthelial cancer (CLONEVO) is a single arm, window-of-opportunity trial of neoadjuvant abemaciclib which will evaluate tumor cell and TME changes in response to abemaciclib. Enrolled pts must be ineligible for platinum-based neoadjuvant therapy for resectable MIBC. Pts receive abemaciclib (200 mg BID PO) for 4 weeks prior to RC. Tumor tissue collected via transurethral resection of bladder tumor (TURBT) and residual tumor at RC undergo single cell RNA sequencing and whole-exome sequencing. Patient-derived organoids and xenografts are generated for a co-clinical trial of abemaciclib alone or in combination. The primary endpoint is the measurement of changes in cell cycle dynamics. Secondary objectives are assessment of toxicity via NCI CTCAE v 5.0 and pathologic downstaging of MIBC. We will perform targeted sequencing of a panel of cell cycle genes in serial plasma and urine cell free DNA to evaluate changes in the variant allele fractions of somatic alterations. The novel design of this trial allows dynamic in vivo assessment of tumor changes and creates a new paradigm for studying tumor evolution in real time. Clinical trial information: NCT03837821.