Nicole Burchardi

Dual Blockade with AFatinib and Trastuzumab as NEoadjuvant Treatment for Patients with Locally Advanced or Operable Breast Cancer Receiving Taxane–Anthracycline Containing Chemotherapy—DAFNE (GBG-70)

Purpose: Dual anti-HER2 blockade with trastuzumab/pertuzumab or trastuzumab/lapatinib in combination with anthracycline/taxane–based chemotherapy can reach pathologic complete response (pCR) rates of up to 60% in HER2-positive breast cancer. The DAFNE (Dual blockade with AFatinib and trastuzumab as NEoadjuvant treatment) phase II study (NCT015591477) investigated a dual blockade with the irreversible pan-HER inhibitor afatinib and trastuzumab in this setting. Experimental Design: Participants with untreated, centrally HER2-positive breast cancer were treated for 6 weeks with afatinib (20 mg/d) and trastuzumab [(8) 6 mg/kg/3 weeks] alone; followed by 12-week treatment with paclitaxel (80 mg/m2/1 week), trastuzumab, and afatinib; followed by 12 weeks with epirubicin (90 mg/m2/3 weeks), cyclophosphamide (600 mg/m2/3 weeks), and trastuzumab before surgery. Primary objective was pCR rate, defined as ypT0/is ypN0. We expected a pCR rate of 70%; 65 patients were needed to exclude a rate of ≤55%. Results: pCR rate was 49.2% [90% confidence interval (CI), 38.5–60.1] in 65 treated patients. Patients with hormone receptor–negative (N = 19) or hormone receptor–positive (N = 46) tumors showed pCR rates of 63.2% and 43.5%, respectively (P = 0.153). Patients with (N = 9) or without (N = 56) lymphocyte predominant breast cancer (LPBC) showed pCR rates of 100% and 41.1%, respectively (P < 0.001). PCR rate was not different in patients with or without PIK3CA tumor mutations (P = 0.363). Clinical responses were seen in 96.3% of 54 evaluable patients, and breast conserving surgery was possible in 59.4% of 62 assessable patients. Most frequent nonhematologic grade 3–4 toxicities were diarrhea (7.7%), increased creatinine (4.6%), and infection (4.6%). One patient developed symptomatic congestive heart failure. Conclusions: Neoadjuvant treatment with afatinib, trastuzumab, and chemotherapy showed acceptable tolerability, and a pCR rate comparable with that of other anti-HER2 doublets but below challenging expectations. Clin Cancer Res; 21(13); 2924–31. ©2015 AACR.

Abstract OT1-03-08: DESIREE - A multicenter, randomized, double-blind, phase II study to evaluate the tolerability of an induction dose escalation of everolimus in patients with metastatic breast cancer

Background: The BOLERO-2 study demonstrated a relevant benefit for patients who received everolimus in addition to exemestane in patients who progressed during/after a non steroidal aromatase inhibitor (NSAI), which led to approval of everolimus in this indication. However, in routine use a high rate of intolerability due to side effects is reported. The most common side effect of everolimus is mucositis with a reported high rate of intolerability especially during the first 12 weeks of treatment. Mucositis is also considered to be the leading cause for treatment discontinuation not related to tumor progression. In the neoadjuvant GeparQuinto study, a dose-escalation schema was successfully used to improve tolerability of everolimus together with cytotoxic agents. Methods: DESIREE (NCT02387099) is a randomized, double-blind, phase II study of everolimus in addition to exemestane in patients who progressed during or after NSAI. Patients will be randomized in a 1:1 ratio to receive either everolimus 10 mg/day (week 1-3: 4x2.5 mg/day, blinded; week 4-24: 10mg/day, open according to label) or an escalating dose of everolimus as follows: week 1: 1x2.5 mg verum + 3x placebo/day; week 2: 2x2.5 mg verum + 2x placebo/day; week 3: 3x2.5 mg verum + 1x placebo/day; week 4-24: 10 mg/day (open according to label). The primary aim of the study is to evaluate the incidence of the first episode of mucositis grade 2-4 (WHO9s oral toxicity scale) any time during a 12 week period after start of everolimus treatment. Secondary objectives are to compare the cumulative rate of mucositis grade 2-4 at 24 weeks after start of treatment, the cumulative rate of mucositis grade 1 and any grade at 12 and 24 weeks after start of treatment, the rate of patients on 10 mg daily at 12 weeks and 24 weeks after start of treatment, the clinical benefit rate after 24 weeks, safety, time to onset of grade ≥2 mucositis, the cumulative everolimus dose at 4 weeks, the relative dose intensity for everolimus, and quality of life using the FACT-B and the QSDQ questionnaire. Biomaterial (whole blood, serum, plasma and optional primary tumor/metastasis tissue) will be collected to evaluate potential biomarkers predicting safety and compliance. Overall, 156 evaluable patients (78 in each arm) are required to detect a clinically relevant difference of 20% in the mucositis rate between treatment arms using a continuity-corrected χ2-test on a significance two sided level alpha of 0.2 and a power of 90%. The rate was estimated to be 40% and 20% in the control arm and the treatment arm, respectively. Results: The study will be conducted in up to 60 German centers. Recruitment will start in June 2015. Enrollment is planned to be completed within 24 months. Conclusion: The combination of everolimus and exemestane has shown to improve the outcome of patients with metastatic breast cancer. In the DESIREE trial a dose-escalating schema will be employed to enhance patient compliance and tolerability necessary to achieve an adequate dose-intensity. Citation Format: Loibl S, Furlanetto J, Barinoff J, Bauerschlag D, Herr D, Lubbe K, Maass N, Muller V, Mundhenke C, Schmidt M, Schwedler K, Thill M, Gkantiragas I, Burchardi N, von Minckwitz G. DESIREE - A multicenter, randomized, double-blind, phase II study to evaluate the tolerability of an induction dose escalation of everolimus in patients with metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-08.

Abstract P1-13-05: GAIN-2: Adjuvant phase III trial to compare intense dose-dense (idd) treatment with EnPC to tailored dose-dense (dt) therapy with dtEC-dtD for patients with high-risk early breast cancer: Results of the second safety interim analyses

Background: GAIN-2 compares the effectiveness and safety of a predefined intense dose-dense regimen (EnPC) vs. a dose-dense regimen with modification of single doses depending on individual hematological and non-hematological toxicities (dtEC-dtD) (NCT01690702). Moreover, the Trastuzumab substudy compares the subcutaneous administration of the drug to the abdominal wall vs. thigh. Methods: The primary objective of the GAIN-2 trial is to compare the invasive disease-free survival (iDFS) in patients with high-risk primary breast cancer (luminal A ≥4 N+; luminal B N+; HER2+ and TNBC N0/N+). Patients are randomized between EnPC (epirubicin 150 mg/m 2 q2w x 3, nab-Paclitaxel 330 mg/m 2 q2w x 3, cyclophosphamide 2000 mg/m 2 q2w x 3) or dtEC-dtD (dd/tailored epirubicin/cyclophosphamide q2w x 4 followed by dd/tailored docetaxel q2w x 4) Two safety interim analyses after 200 (Noeding et al. Ann Oncol 2014) and 900 patients who have completed chemotherapy were planned. We present the results of the second safety analysis. In addition to the standard analyses for hematological and non-hematological toxicities, any affections of the cranial nerves as well as the rate of macula degenerations and anaphylactic reactions are of special interest. Results: Between 09/2012 and 05/2015 a total of 1473 patients have been randomized (EnPC n=734; dtEC-dtD n=739). Among those, 84 patients have been included in the trastuzumab substudy. No safety data are currently available for the substudy. Median age was 52 years and median body-mass-index 26. In terms of hematological adverse events, the rate of febrile neutropenia grade 3-4 (12% vs. 8%) and thrombopenia grade 3-4 (12% vs. 5%) was significantly increased in the EnPC arm. As for non-hematological side effects, there were significantly more patients developing an increase in alkaline phosphatase (59% vs. 40%), ALAT (69% vs. 59%), peripheral sensory neuropathy (83% vs. 68%), arthralgia (63% vs. 49%), myalgia (48% vs. 41%) and bone pain (25% vs. 17%) in the EnPC arm, whereas nosebleed (10% vs. 25%), edema (13% vs. 26%) and hand-foot syndrome (12% vs. 28%) were more common in the dtEC-dtD arm. We observed two treatment related deaths, both in the dtEC-dtD arm (cause of death: acute respiratory distress syndrome and pneumonia). There were no differences between the treatment arms for the toxicities of special interest. In the EnPC arm, overall 30% of the patients required dose-reductions due to hematological toxicities compared with only 10% in the dtEC-dtD arm (p 2 followed by docetaxel 100 mg/m 2 ) in more than one third of the patients receiving dtEC-dtD. In 9% of women a reduction was required in the 4th cycle of docetaxel. Conclusion: This interim safety analysis from a prospectively randomized trial investigating iddEnPC with predefined doses and a toxicity adapted idd/tailored strategy (dtEC-dtD) showed no additional or unexpected safety signals in the iddEnPC or dtEC-dtD arm. Therefore, no modifications in the conduction of the study are necessary and the study continues as expected. Citation Format: Mobus V, Luck H-J, Forstbauer H, Wachsmann G, Ober A, Schneeweiss A, Christensen B, von Abel E, Grischke E-M, Hoffkes H-G, Klare P, Yon-Dschun K, Schmatloch S, Furlanetto J, Burchardi N, von Minckwitz G, Loibl S. GAIN-2: Adjuvant phase III trial to compare intense dose-dense (idd) treatment with EnPC to tailored dose-dense (dt) therapy with dtEC-dtD for patients with high-risk early breast cancer: Results of the second safety interim analyses. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-13-05.

255ODUAL BLOCKADE WITH AFATINIB AND TRASTUZUMAB AS NEOADJUVANT TREATMENT FOR PATIENTS WITH LOCALLY ADVANCED OR OPERABLE BREAST CANCER RECEIVING TAXANE-ANTHRACYCLINE CONTAINING CHEMOTHERAPY (DAFNE)-GBG70 – EFFICACY AND SAFETY ANALYSIS

ABSTRACT Aim: Neoadjuvant chemotherapy uses anthracycline/taxane based combinations of ≥18 weeks as standard treatment. Concurrent administration of trastuzumab in HER2+ disease achieves a pCR rate (ypT0 ypN0) of approx. 40%. Dual anti-HER2 blockade can increase the rate by another 20%. DAFNE (NCT015591477) investigates the combination of afatinib (BIBW 2992), an irreversible ErbB-family blocker with trastuzumab. Methods: DAFNE is a multicenter, prospective, open-label phase II study evaluating efficacy and safety of afatinib in combination with weekly paclitaxel + trastuzumab followed by epirubicin/cyclophosphamide/trastuzumab (ECH) as neoadjuvant therapy in untreated, centrally HER2 + , operable or locally advanced breast cancer patients. All patients were treated for 30 weeks: 6 weeks with afatinib (20mg) and trastuzumab (8/6mg/kg); 12 weeks with additional weekly paclitaxel (80mg/m2); and 12 weeks with ECH according to standard. Afatinib was given every other day for the first 2 weeks to reduce the risk of diarrhea and skin toxicities. Primary prophylaxis with loperamide 2x2mg daily was mandatory for the first 4 weeks of afatinib/trastuzumab and the first 2 weeks of paclitaxel. Primary objective is pCR rate (ypT0/is ypN0). Assuming a pCR rate of 70% with a = 0.1 and 80% power, a pCR of ≤55% should be excluded. Secondary objectives are pCR by other definitions, clinical response rates, rate and type of surgery, toxicity, compliance, pCR related to skin toxicity and diarrhea and pre-specified molecular markers. Results: 65 patients were recruited (5/2012 - 7/2013) in 11 German centers. Median age was 50 years. 9.4% had T3/4, 48.5% N + , 89.2% ductal invasive, 60% G3 and 70.8% HR+ tumors. Of the 22 SAEs (in 16 patients), 27.3% were gastrointestinal, 18.2% hematologic, 13.6% infections and 9.1% related to the nervous system. pCR rate was 49.2% (90% CI: 38.5; 60.1). Conclusions: Despite a tolerable safety profile of the dual blockade with afatinib, the pCR rate was lower than expected. A subsequent phase 3 study cannot be supported. Boehringer Ingelheim, Germany supported this trial. Disclosure: G. von Minckwitz: Research Grants: Boehringer-Ingelheim. All other authors have declared no conflicts of interest.

264PDGAIN2: ADJUVANT PHASE III TRIAL COMPARING AN INTENSIFIED DOSE-DENSE ADJUVANT THERAPY WITH ENPC COMPARED WITH A DOSE-DENSE, DOSE-ADAPTED THERAPY WITH DTEC DTDOCETAXEL IN PATIENTS WITH PRIMARY BREAST CANCER AND A HIGH RISK OF RECURRENCE

ABSTRACT Aim: Combined chemotherapy requires compromises in terms of dosage and treatment interval due to toxicities. The sequential administration of monotherapies allows high doses of single substances and dose-dense intervals. So far, such regimens have proved to be very effective in early breast cancer with high risk of recurrence. Nab-paclitaxel (nP) leads to a more favorable toxicity profile and greater efficacy compared with solvent-based taxanes. Methods: The GAIN2 study compares toxicity and efficacy of a pre-defined dose-dense high-dose regimen (EnPC) with a dose-dense regimen, where single doses are adjusted depending on individual haematological and non-haematological toxicities (dtEC-dtD). Primary endpoint is the invasive disease-free survival in patients with primary node-positive or high-risk node-negative breast cancer. Two safety interim analyses after 200 and 900 patients who have completed chemotherapy are planned. The results of the first safety analysis will be presented. In addition to the standard analyses for haematological and non-haematological toxicities, any affections of the cranial nerves as well as the rate of macular degeneration and anaphylactic reactions are of special interest. Results: In terms of hematological adverse events, the rate of febrile neutropenia grade 3-4 (14% vs. 5%) and thrombocytopenia grade 3-4 (14% vs. 5%) was significantly increased in the EnPC arm. As for the non-haematological side effects, there were significantly more patients developing anorexia (grade 1-4) in the EnPC arm. There were no differences between the treatment arms for the toxicities of special interest. In the EnPC arm, 28% required dose-reductions due to hematological toxicities compared with only 11% in the dtEC dtD arm (p = 0.002). The dose could be escalated to the maximum in half of the patients receiving dtEC dtD. In 7% of women a reduction was required in the 4th cycle of docetaxel. Conclusions: Due to similar toxicity profiles, the study will be continued without changes. Disclosure: A. Schneeweiss: Honoraria, Research Funding and Advisory Role: Celgene and Roche; G. von Minckwitz: Honoraria and Research Funding: Amgen, Celgene and Roche; V. Mobus: Honoraria and Research Funding: Amgen, GSK, Sanofi-Aventis, Pfizer, Roche. All other authors have declared no conflicts of interest.