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3633 Background: Extensive molecular profiling in cancer regularly reveals targets for which approved drugs are available in tumor types outside the registered label. Efficacy of off-label use of these drugs is unavailable. Access to these drugs for pts is challenging. In the Drug Rediscovery Protocol (DRUP, Van der Velden et al, Nature 2019), pts are treated based on their tumor molecular profile. Here, we present the results of the successful cohort “Olaparib for tumors with BRCA1/2 alterations”. Methods: Twenty five adult cancer patients (pts) who exhausted all treatment options and had BRCA1/2 loss of function (LoF) mutations (found in routine diagnostics) were included. No pts were eligible for on-label treatment with PARP inhibitors. Pts were treated with olaparib until disease progression or unacceptable toxicity. The primary endpoint was clinical benefit (CB: objective response or stable disease (SD) ≥ 16 weeks). Pts were enrolled using a Simon-like two-stage model, with 8 pts in stage 1 and up to 24 pts in stage 2 if at least 1 pt had CB in stage 1. A fresh frozen biopsy was obtained from each pt for whole genome sequencing (WGS) and target confirmation. Results: Fourteen pts (56%) had CB. The objective response rate was 32%. Nine different cancer types were included: prostate (n=11), breast (n=4), ovarian (n=2), pancreatic (n=3), colorectal (n=2), biliary tract (n=2), kidney (n=1), adrenal gland (n=1) and endometrial (n=1). WGS could be performed on 58% of baseline tumor biopsies, confirming the original BRCA1/2 mutations in 86%. CB was observed in pts with both somatic and germline BRCA alterations and across tumor types. CB was only observed in cases with biallelic loss of BRCA1/2 in the tumor and when classified as HRD by a pan-cancer homologous recombination deficiency classifier (CHORD), which relies on genome-wide SNV, indel, and SV mutational footprints for HRD detection. No evidence of complete BRCA loss and HRD was observed in 5 pts with PD, while 4 patients with effective BRCA complete loss and HRD also had PD. WGS analysis of these pts suggested resistance mechanisms due to other oncogenic drivers (e.g FGFR1 amplification, CTNNB1 stabilization, KEAP1 inactivation). Conclusions: Olaparib seems to be an effective treatment option for pts with BRCA1/2 LoF mutated malignancies, regardless of histology, for both germline and somatic alterations, which needs confirmation in an independent cohort. CB of olaparib was observed in malignancies showing biallelic loss of BRCA1/2 and when classified as HRD, indicating the importance of the BRCA/HRD signature status. Clinical trial information: NCT02925234 .

501 Background: The multicenter phase III TRAIN-2 study showed high pathological complete response (pCR) rates after neoadjuvant chemotherapy with and without anthracylines plus dual HER2-blockade in stage II-III HER2-positive breast cancer patients (67% vs 68%, p = 0.95) (NCT01996267). Here we report 3-year efficacy and safety outcomes. Methods: Patients were randomly assigned (1:1) to receive 3 cycles 5-fluoruoracil (500mg/m2), epirubicin (90mg/m2), and cyclophosphamide (500mg/m2) followed by 6 cycles paclitaxel (80mg/m2 day 1 and 8) and carboplatin (AUC = 6mg/ml·min) (FEC-PC) or 9 cycles paclitaxel and carboplatin (PC). Both regimens were combined with trastuzumab (T; 6mg/kg, loading dose 8mg/kg) and pertuzumab (Ptz; 420mg, loading dose 840mg). Patients completed one year of trastuzumab, radiotherapy and endocrine therapy as indicated. The primary endpoint pCR was previously reported. Secondary efficacy endpoints reported here are event-free-survival (EFS) defined as time from randomization to first event (disease progression resulting in inoperability, recurrence [contralateral DCIS excluded], secondary primary malignancies, or death) and overall survival (OS), both in the intention-to-treat population. Safety endpoints are reported for patients treated with at least one dose of study medication. Results: 438 patients were randomized (219/arm) and evaluable for long-term efficacy endpoints. After a median follow-up of 48.8 months 23 EFS events occurred in the FECT-PTC-Ptz-arm and 21 in the PTC-Ptz-arm (HR 0.90; 95% CI 0.50-1.63). Three-year EFS estimates were 92.7% (95% CI: 89.3-96.2) for FECT-PTC-Ptz and 93.6% (95% CI: 90.4-96.9) for PTC-Ptz. Three-year OS estimates were 97.7% (95% CI: 95.7-99.7) for FECT-PTC-Ptz and 98.2% (95% CI: 96.4-100) for PTC-Ptz. These results were irrespective of hormone receptor and nodal status. LVEF decline ≥10% from baseline and < 50% was more common in patients who received anthracyclines than in the PTC-Ptz arm (8.6% vs. 3.2%, p = 0.021). Two patients in the FECT-PTC-Ptz arm developed acute leukemia. No other new safety concerns were seen. Conclusions: The 3-year follow-up of the TRAIN-2 study confirms the results of the primary outcome that anthracylines do not improve efficacy and are associated with clinically relevant toxicity. A neoadjuvant carboplatin-taxane based regimen with dual HER2-blockade can be considered in all stage II-III breast cancer patients, regardless of hormone receptor and nodal status. Clinical trial information: NCT01996267 .

7037 Background: Fluoropyrimidines (FP) are the cornerstone of chemotherapy in many solid tumors and linked to cardiotoxicity (CarTx) in about 5% (Polk, Cancer Treat Rev 2013), often leading to FP discontinuation. CarTx may be less common with S-1 and successful switch from other FP has been reported (Kwakman, EJC 2017). Methods: This 6-country, 12-center, cohort study included patients with solid tumors (ICD10 C15-C21, C24-25, C50, C80) who experienced FP-related CarTx. Primary endpoint was recurrent (R) CarTx during S-1 therapy after switch from any other FP. Results: CarTx during capecitabine (n = 124), continuous (n = 13) or bolus 5-fluorouracil (n = 4) was reported for 141 patients who switched to S-1 therapy. CarTx was chest pain including vasospasm without cardiac findings (55%), acute coronary syndrome or myocardial infarction (32%), atrial fibrillation (4%), heart failure/cardiomyopathy (4%), tachy-/bradycardia (3%), and/or other (15%). CarTx was grade 3-4 in 55%, appeared on cycle 1-2 in 89%, and at median 4 days (range 0-466) from FP initiation (Table). Causality was judged related in 26%, probable in 60%, and possible in 14%. Action with FP causing CarTx was permanent discontinuation in 91%. Treatment intent was curative in 70%. Cumulative incidence of RCarTx with S-1 was 3.5% (CI95%, 1.2-8.4%) and median time to R-CarTx was 11 (range 6-195) days. Four (out of 141) had grade 1 and one grade 2 R-CarTx. Three were judged possibly related to S-1 and 2 not related. S-1 was discontinued in one patient and continued in 4 (for 63-252 days) without action (n = 2), with dose reduction (n = 1), or delay (n = 1). There were no differences in demographic or risk factors regarding R-CarTx on S-1 (Table). Conclusions: FP-related CarTx is often severe, occurs early, and leads to permanent FP discontinuation. Switching to S-1-based therapy is safe, with, at the most, grade 1-2 R-CarTx in only 3.5%, and rarely leads to treatment discontinuation (0.7%), allowing patients to continue on an FP-based regimen. Clinical trial information: NCT04260269 . [Table: see text]

536 Background: International guidelines differ in their recommendation for adjuvant chemotherapy in small node negative TNBC. We evaluated associations of chemotherapy with long-term outcome in a large population-based TNBC cohort. Methods: All patients diagnosed with pT1N0M0 TNBC between 2005 and 2015 were identified from the Netherlands Cancer Registry. Patient, tumor and therapy characteristics were recorded. Date and cause of death were obtained from Statistics Netherlands. We used multivariable cox regression models to evaluate associations of chemotherapy with overall survival (OS) and breast-cancer specific survival (BCSS), adjusted for baseline characteristics. Subgroup analyses were performed by tumor size and grade. Results: We identified 4393 patients: 284 with T1a, 924 with T1b, and 3185 with T1c tumors. Chemotherapy was administered in 53% of patients: 6% with T1a, 17% with T1b and 67% with T1c. Chemotherapy use increased over time and varied by geographic region. Patients receiving chemotherapy were younger, had larger tumors, higher tumor grade, and more often isolated tumor cells (itc) in the lymph nodes. At a median follow-up of 7 years (IQR 5-10 years), 611 patients had died, of whom 287 due to breast cancer. Chemotherapy was associated with improved OS in the whole group (adjusted hazard ratio [aHR] 0.55; 95% CI 0.44–0.69), in the pT1c subgroup (aHR 0.53, 95% CI 0.41-0.67), and in grade 3 tumors (aHR 0.50, 95% CI 0.39-0.65). Associations were not significant for pT1ab or grade 1-2 tumors (table). Findings for BCSS were in line with OS results (table). To illustrate the absolute difference we estimated 10-year OS and BCSS for a 60-year old woman with a pT1cN0(itc+) grade 3 TNBC. The predicted 10-year OS was 67% with chemotherapy and 49% without; predictions for 10-year BCSS were 80% and 66%, respectively. Conclusions: Adjuvant chemotherapy is associated with higher OS and BCSS in small node negative TNBC. Benefit is most evident in grade 3 tumors and tumors > 1cm and not evident in tumors ≤1cm and grade 1-2.[Table: see text]

637 Background: Cross-sectional imaging (CSI) has emerged as preferred imaging modality for staging and follow-up (FU). Moreover, the 2017 EAU RCC guidelines discourage the use of Chest X-Ray (CXR). In an international database (RECUR) data were collected to compare imaging modalities in contemporary FU, and to explore if more frequent use of CSI translates into improved overall survival (OS) after recurrence. Methods: Consecutive non-metastatic RCC patients treated with curative intent at 12 institutes across 8 European countries between 2006 and 2011, with at least 4 years of FU were included. Leibovich or UICC risk group (RG) (low, intermediate, high), recurrence characteristics, type of FU imaging (CSI (CT or MRI) vs. Conventional (CXR or Ultrasound)) and survival data were recorded. Isolated local, solitary and oligometastatic recurrences were considered potentially curable (PC) while all others were considered probably incurable (PI). Patients were analysed according to type of imaging that resulted in detection of recurrence (CSI vs. conventional) and if > or < 50% of all FU imaging were CSI based. Landmark analysis of OS after recurrence was performed for CSI and conventional imaging. Results: In 1612 patients, 336 (21%) had a recurrence. Of these, 122 were PC and 213 PI. Of the 17333 FU imaging procedures performed, 7953 were CT (46%), 6540 (38%) were CXR, 183 (1%) were MRI and 2651 (15%) were Ultrasound (US) investigations. The overall CT thorax/CXR- ratio decreased significantly across the risk groups, being 1.0, 0.46 and 0.35 in the high, intermediate and low RG, respectively (p < 0.001). Moreover, between the high RG and the other RG`s the overall CT Abd/US-ratio also decreased (3.2, 1.7 and 1.7, respectively)(p < 0.001). There was no significant difference in OS between patients with PC or PI recurrences based on type of imaging with which the recurrence was detected, nor on the ratio of CSI ( > / < 50%) during FU. Conclusions: More than 50% of FU imaging was conventional, with CSI more often used in high risk groups. The present study suggests that the type of imaging (conventional vs. CSI) for detection of recurrence does not affect subsequent OS.

507 Background: Neoadjuvant chemotherapy with dual HER2 blockade boosts pathologic complete response (pCR) rates in HER2+ breast cancer. The optimal chemotherapy backbone in this setting is unknown. We conducted a multicenter phase III trial to study whether anthracyclines would improve outcome compared to a carboplatin-taxane regimen (NCT01996267). Methods: We randomly assigned (1:1) patients with stage II-III HER2+ breast cancer to receive 9 cycles paclitaxel (80mg/m2 day 1 and 8) and carboplatin (AUC = 6mg/ml·min) (arm A) or 3 cycles 5-fluoruoracil (500mg/m2), epirubicin (90mg/m2), and cyclophosphamide (500mg/m2) followed by 6 cycles paclitaxel and carboplatin (arm B). Both arms received trastuzumab (6mg/kg, loading dose 8mg/kg) and pertuzumab (420mg, loading dose 840mg) concurrent with all chemotherapy cycles, and cycles were repeated every 3 weeks. The primary endpoint was pCR in breast and axilla (ypT0/is,ypN0). Results: 438 patients were included and 418 (arm A 206 vs arm B 212) were evaluable for the primary endpoint. The pCR rate did not differ between arms (arm A 68% [95% CI 61-74] vs arm B 67% [95% CI 60-73], p = 0.75). Hormone receptor (HR) negative tumors had significantly higher pCR rates (87% vs 54%, p < 0.0001), but we found no evidence for treatment-by-HR interaction (p = 0.23). Common adverse events grade ≥3 were neutropenia (arm A 53% vs arm B 57%, p = 0.34), febrile neutropenia (arm A 2% vs arm B 11%, p = 0.0001), and diarrhea (arm A 17% vs arm B 12%, p = 0.14). Neuropathy grade ≥2 was common in both arms (arm A 31% vs arm B 29%, p = 0.83), while left ventricular ejection fraction (LVEF) decline grade ≥2 (defined as ≥10% decline from baseline or LVEF < 50%) was more common in arm B (arm A 18% vs arm B 29%, p = 0.007). Symptomatic left ventricular systolic dysfunction was rare ( < 1%) in both arms. Conclusions: Anthracyclines increase the incidence of febrile neutropenia and grade ≥2 LVEF decline, but do not improve pCR rate in the contemporary neoadjuvant treatment of HER2+ breast cancer with dual HER2 blockade. Therefore, we currently favor a carboplatin-taxane based regimen. Follow-up is required to confirm these results with regard to long-term outcome. Clinical trial information: NCT01996267.

2520Background: Endocrine therapy resistance remains a major challenge in the treatment of HR-positive breast cancer. The strategy of combining PI3K-AKT-mTOR pathway inhibitors with endocrine therapy can improve clinical outcomes (eg. BOLERO-2, BELLE-2) but at the cost of increased toxicity. Taselisib is a potent, selective, beta-isoform sparing inhibitor of PI3K designed to have a better therapeutic index than first-generation pan-PI3K inhibitors. Methods: Pts with prior exposure to endocrine therapy were enrolled using a 3+3 design, testing taselisib in combination with tamoxifen 20mg qd. A (21 day on / 7 day off) intermittent schedule was also compared with daily continuous dosing (28/28). The primary objective was to determine the recommended phase II dose and schedule. Other objectives included: pharmacokinetics (PK), pharmacodynamics (PD) and serial monitoring of plasma ctDNA using digital PCR / tagged amplicon deep-sequencing. Results: 30 pts were enrolled in 3 cohorts: taselisib 2mg (21/7), 4mg (2...

3640Background: Hand-foot syndrome (HFS) is a common side effect of capecitabine. S-1 is an oral fluoropyrimidine with comparable efficacy to capecitabine in gastrointestinal cancers but associated...

556 Background: In 2013 a model to predict cancer-specific survival (CSS) after CN was published (Eur Urol 63:947-52, 2013), consisting of a preoperative nomogram to predict 6-month (mo) probability of death (PoD) based on serum albumin and serum lactate dehydrogenase and a postoperative nomogram (12-mo PoD) to which were added pathologic primary tumour stage, nodal stage and intraoperative blood transfusion. We externally validated the model with a contemporary European dataset of patients treated in the VEGF-targeted therapy era. Methods: After having received the original calibration indices, data from 205 mRCC patients who underwent CN between 2006 and 2013 at 3 European centres in Amsterdam, Edinburgh and Munich were used for external validation. Next to the variables for the nomogram, age, MSKCC, IMDC, number and metastatic sites and subtype were collected. Both nomograms were used to obtain predictions for the subjects. Based on the quantiles of the distribution of predictions subjects were grouped into 4 categories and Kaplan-Meier estimates calculated as were calibration plots of observed versus predicted PoD. Since all subjects had follow-up for > 1.25 years CSS at 6 and 12 mo as a dichotomous outcome and the ROC curves were plotted. Results: With a median follow-up of 29 mo and a median OS of 15 (95% CI 12-22) mo for the entire cohort, 32 and 82 patients died from RCC at 6 and 12 mo after CN respectively. For the pre- and postoperative nomogram the respective ROC curve had an AUC of 0.667 and 0.712. In the preoperative calibration plot the observed PoD at 6 mo was higher than the predicted, resulting in a lower discrimination when compared to the original validation (0.76 and 0.74 for pre- and postoperative nomograms respectively). Conclusions: In external validation the pre- and postoperative nomograms perform well in patients with primary mRCC. Their discrimination is in the reported range of MSKCC and IMDC risk scores, which were not developed to address the decision of CN (concordance index 0.657 and 0.71, Lancet Oncol 14:141-8, 2013). Although discrimination of the preoperative nomogram was lower in external validation, it retains ability to predict early death after CN.

2507 Background: AZD1775 (formerly MK-1775) is a potent and selective inhibitor of Wee1, a kinase that phosphorylates CDC2. Phosphorylation of CDC2 inactivates the CDC2/cyclin B complex and is ther...