Background: Intravenous (IV) trastuzumab has proven clinical benefits in patients (pts) with human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). The use of pertuzumab, which targets HER2 through an independent epitope to that of trastuzumab, in combination with IV trastuzumab and docetaxel has shown improved efficacy with acceptable toxicity in metastatic (m) BC. Subcutaneous (SC) and IV trastuzumab formulations have shown comparable efficacy. This study aimed to assess the safety, tolerability, and efficacy of combining IV pertuzumab with SC trastuzumab and a taxane, as 1st-line therapy in pts with HER2+ mBC, a combination for which results have not previously been reported. Here we present demographics and interim safety data. Methods: This is an open-label, multicentre, phase IIIb study. The primary objective was the safety and tolerability of IV pertuzumab with SC trastuzumab and investigator's choice of taxane. Pts aged ≥18 years with confirmed HER2-positive [IHC3+ or ISH+] mBC with at least one measurable lesion and/or non-measurable disease according to RECIST version 1.1 and ECOG performance status (PS) 0-2 were included. Pts received IV pertuzumab every 3 weeks (loading dose=840 mg; subsequent doses=420mg) combined with SC trastuzumab at 600mg/5mL every 3 weeks and the investigator's choice of taxane (docetaxel, paclitaxel, or nab-paclitaxel). Treatment continued until disease progression, unacceptable toxicity, or consent was withdrawn, whichever occurred first. The incidence and severity of adverse events (AEs), serious (S) AEs and AEs leading to premature discontinuation of study treatment were analyzed. Results: The planned 50 pts have been recruited from 12 centres; mean age 53 (SD-12.0) years; the majority white (84%), ECOG PS 0 (n=33) and PS 1 (n=15). 98% were females; 61% post-menopausal. Taxanes of choice were nab-paclitaxel (n=36), docetaxel (n=13) and paclitaxel (n=1). Any grade AEs (n=627) were reported in 100% pts; majority grade 1-2, the most common being diarrhoea, fatigue, peripheral neuropathy, alopecia, nausea, rash, headache and vomiting. Grade 3+ AEs (n=54) were reported in 52% pts, most commonly neutropenia (10%), febrile neutropenia (8%) and diarrhoea (6%). SAEs (n=36) were reported in 48% pts; most commonly pyrexia (14%), febrile neutropenia (8%), neutropenia (4%), pulmonary embolism (4%) and cellulitis (4%). Five AEs of suspected cardiac disorders were reported in 4 pts (atrial fibrillation, cardiomyopathy, myocardial ischemia, palpitations and ejection fraction decreased). AEs leading to study drug discontinuation (n=3) were reported in 3 pts (LVEF decreased, syncope and blister). AEs leading to chemotherapy discontinuation (n=14) were reported in 20% pts. Conclusion: We report the first data on the use of pertuzumab with SC trastuzumab. The observed safety profile is consistent with that previously reported in the CLEOPATRA (Baselga, et al. NEJM 2012;366:109-19), PERUSE [Bachelot, et al. JCO 2014;32:5s(abstr#548)] and HannaH (Ismael, et al. Lancet Oncol 2012;13:869-78) studies, with no unexpected safety signals. Clinical trial information:NCT02019277. Citation Format: Woodward N, De Boer RH, Redfern A, White M, Young J, Truman M, Beith J. Interim results from the first open-label, multicenter, phase IIIb study investigating the combination of pertuzumab with subcutaneous trastuzumab and a taxane in patients with HER2-positive metastatic breast cancer (SAPPHIRE). [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 P4-14-12.
7654 Background: Vandetanib (ZD6474) is a once-daily oral anticancer drug that selectively inhibits VEGF-dependent tumor angiogenesis and EGFR- and RET-dependent tumor cell proliferation and survival. Methods: Eligible patients had locally advanced or metastatic NSCLC (stage IIIB/IV) after failure of 1st-line chemotherapy. An initial cohort of 10 patients received once- daily oral vandetanib (100 mg) with pemetrexed (500 mg/m2 i.v. infusion every 21 days). If <2 patients experienced a vandetanib- related dose-limiting toxicity (DLT), an additional cohort received vandetanib 300 mg + pemetrexed. The planned duration of treatment was =6 weeks. The primary objective of the study was to establish the safety and tolerability of vandetanib + pemetrexed. Secondary objectives included an assessment of pharmacokinetic (PK) interaction and preliminary assessment of efficacy (RECIST). Results: Twenty- one patients (14 male, 7 female; mean age 60 years, range 44–77) received vandetanib 100 mg + pemetrexed (n=10) or vandetanib 300 mg + pemetrexed (n=11). One DLT was reported in each cohort: QTc prolongation (>100 ms from baseline, but absolute QTc <500 ms) in a male patient who had electrolyte imbalance and short baseline QTc interval of 318 ms (100 mg cohort); and interstitial lung disease, which resolved after steroid therapy, in a Caucasian female patient with bronchoalveolar carcinoma and a long smoking history (300 mg cohort). The most common adverse events (AEs) were rash, anorexia, fatigue and diarrhea (all n=10; 48%). The most frequent CTC grade 3/4 AEs were increased gamma-glutamyltransferase (n=4), anorexia (n=3) and dyspnea (n=3), which are generally consistent with previous experience with vandetanib and pemetrexed as monotherapies. There was no apparent PK interaction between vandetanib and pemetrexed. In 18 patients evaluable for efficacy, there was one confirmed partial response (female; 100 mg cohort) and 13 stable disease =6 weeks. Conclusions: In patients with advanced NSCLC, vandetanib + pemetrexed was generally well tolerated, with no apparent PK interaction. A Phase III trial of vandetanib 100 mg + pemetrexed in 2nd-line NSCLC has begun. No significant financial relationships to disclose.
#2078 Background: Tumour size (T) and nodal status (N) have traditionally been regarded as the most important prognostic factors which determine individual recommendations for adjuvant treatment. Early trials of adjuvant systemic therapy relied on nodal status as the key determinant of recurrence risk, with node negative patients (pts) often excluded due to their 'low risk' classification. With greater understanding that predominant growth signalling pathways in a given tumour may be of greater importance than size and nodal spread, current clinical practice places greater emphasis on high risk biological factors. Factors include young age (<35y), HER2 positivity (pos), grade III status, absence of hormone receptors (HR), and triple negative (TN) phenotype. Presence of these features will likely influence systemic treatment recommendations. With this in mind we examined data which has been prospectively collected to determine the outcomes of pts with high risk T1N0 tumours and compared them to pts with lower risk biological profiles.
 Methods: Data on 2285 pts with early breast cancer were analysed. Comparisons were made between T1N0 high risk pts (defined as having one or more of the following features: age<35, grade III, HER2 pos, or TN) and pts with good biological prognostic features (defined as the absence of all the above factors) in the following subgroups: 1) T1N0, 2) T1N1-2, and 3) T2-3N0. In addition outcomes were specifically assessed in T1N0 pts with Her2 pos vs negative disease; TN vs non-TN.
 Results: 401 pts with T1N0 high risk tumours were identified (T1N0HR). In the low risk group there were 330 pts with T0 tumours (T1N0LR), 286 pts with T1Npositive tumours (T1NposLR) and 154 pts with T2/T3N0 tumours (T2/3N0LR). There were 137 pts T1N0 Her2 pos (T1N0H2). The median follow up for all pts was 3.4 yrs (0.5-36). Treatment given and clinical outcome for each pt group are shown in the table.
 
 The majority of DFS events in the T1N0H2 pts occurred in those not receiving adjuvant trastuzumab (12.4% vs 2.2%). TN tumours were seen in 12.5% of pts studied. Despite the use of systemic therapy in 97.5% of TN pts (vs 64% in non-TN) , there was a higher DFS event and death rate (18% vs 15%; and 13% vs 6% respectively)
 Conclusions: Outcomes for T1N0HR pts were similar to that of T1N0LR and T2/3N0LR pts, possibly related to the greater use of systemic therapies in the T1N0HR pts (89% vs 50% vs 79%). Despite the high rate of adjuvant systemic therapy, the outcomes for the T1N0HR group were inferior to the outcomes for pts in the T1NposLR group (DFS 15.7% vs 9.8%) supporting the view that biological factors may be a more important determinant of outcome than nodal status. Similarly, even in pts with small tumour size, triple negative phenotype had worse outcome. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2078.
631 Background: We designed a vaccine to induce T cells able to recognize epitopes from HER2 and to engender a polyclonal antibody reponse. Methods: The vaccine is a recombinant HER2 protein, including its extra and part of its intra-cellular domains (ECD/ICD), combined with a potent immunologic adjuvant. Cohorts of patients with Stage II/III breast cancer (BC) received 20, 100 or 500 μg in the adjuvant setting. Treatment comprised of six vaccinations over 14 weeks, for the 500-μg dose, recall injections were given on weeks 34 and 38. The trial was extended to include an alternative vaccination schedule: 500 μg on days 0, 28 and 98. In an on-going trial, patients with metastatic BC treated in the first line setting are receiving the 500-μg treatment and being assessed for clinical response. Results: The vaccine was well tolerated, with no symptomatic cardiotoxicity. Antibody (Ab) response against ECD was dose-dependent, with 2/12, 9/14 and 14/15 immune responders in the respective cohorts after four vaccinations. Response was dose-related. Ab isotypes were analyzed in the 500 μg cohort: in 50% of patients, high levels of IgM (30–60%) against ECD were found after four vaccinations. The switch towards IgG was complete in all patients after six vaccinations. The efficacy of booster vaccinations was observed mainly in patients with low IgM after eight weeks. After two vaccinations, Ab titers on the alternative 500 μg vaccination schedule were as high as after four vaccinations utilizing the initial schedule. The anti-ECD antibodies in 11/15 patients (500 μg level) bound HER2-overexpressing breast-cancer cell lines. In sera from 2 patients tested thus far, the gene-expression resembled that of trastuzumab. Assays show that specific T cells were obtained; detailed analysis is continuing. Among metastatic patients, two showed evidence of tumor regression after vaccination. Conclusions: The HER2 vaccine was well tolerated and induced (dose-dependently) anti-ECD Ab that bound the HER2 receptor. Data suggest that the vaccine also induced specific T-cell immunity. The alternative vaccination schedule may increase the Ab titers. This data justifies further evaluation of this vaccine in the phase II/III setting. [Table: see text]
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