Collyar, Deborah

Abstract Clinical research networks conduct important studies that would not otherwise be performed by other entities. In the case of the Antibacterial Resistance Leadership Group (ARLG), such studies include diagnostic studies using master protocols, controlled phage intervention trials, and studies that evaluate treatment strategies or dynamic interventions, such as sequences of empiric and definitive therapies. However, the value of a clinical research network lies not only in the results from these important studies but in the creation of new approaches derived from collaborative thinking, carefully examining and defining the most important research questions for clinical practice, recognizing and addressing common but suboptimal approaches, and anticipating that the standard approaches of today may be insufficient for tomorrow. This results in the development and implementation of new methodologies and tools for the design, conduct, analyses, and reporting of research studies. These new methodologies directly impact the studies conducted within the network and have a broad and long-lasting impact on the field, enhancing the scientific value and efficiency of generations of research studies. This article describes innovations from the ARLG in diagnostic studies, observational studies, and clinical trials evaluating interventions for the prevention and treatment of antibiotic-resistant bacterial infections.

PURPOSE CALGB 40603 ( NCT00861705 ), a 2 × 2 randomized phase II trial, demonstrated that adding carboplatin or bevacizumab to weekly paclitaxel (wP) followed by doxorubicin and cyclophosphamide significantly increased the pathologic complete response (pCR) rate in stage II-III triple-negative breast cancer. We now report long-term outcomes (LTOs) and correlative science end points. PATIENTS AND METHODS The Kaplan-Meier method was used to estimate LTOs in 443 patients who initiated study treatment. Log-rank tests and Cox proportional hazards models evaluated the impact of clinical characteristics, pathologic response, calculated residual cancer burden (RCB) in patients with residual disease (RD), treatment assignment, and dose delivery during wP on LTOs, including event-free survival (EFS). Genomic predictors of treatment response and outcomes were assessed on pretreatment tumor samples by mRNA sequencing. RESULTS Among baseline characteristics, only the clinical stage was associated with LTOs. At a median follow-up of 7.9 years, LTOs were not significantly improved with either carboplatin or bevacizumab, overall or in patients with basal-like subtype cancers by genomic analysis. Patients with pCR (n = 205, 46.3%) had significantly higher 5-year EFS (85.5% v 56.6%, log-rank P < .0001) and overall survival (87.9% v 63.4%, P < .0001) rates compared with patients with RD, even those with RCB class I. Among clinical and genomic features, evidence of immune activation, including tumor-infiltrating lymphocytes and low B-cell receptor evenness, was associated with pCR and improved EFS. CONCLUSION Despite higher pCR rates, neither carboplatin nor bevacizumab appeared to improve LTOs although the study was not powered to assess these secondary end points. pCR was associated with superior LTOs even when compared with minimal RD. Markers of immune activation in pretreatment tumor biopsies were independently associated with higher pCR rates and improved survival.

PURPOSE This focused update addresses the use of Onco type DX in guiding decisions on the use of adjuvant systemic therapy. METHODS ASCO uses a signals approach to facilitate guideline updating. For this focused update, the publication of the Trial Assigning Individualized Options for Treatment (TAILORx) evaluating noninferiority of endocrine therapy alone versus chemoendocrine therapy for invasive disease–free survival in women with Onco type DX scores provided a signal. An expert panel reviewed the results of TAILORx along with other published literature on the Onco type DX assay to assess for evidence of clinical utility. UPDATED RECOMMENDATIONS For patients with hormone receptor–positive, axillary node–negative breast cancer whose tumors have Onco type DX recurrence scores of less than 26, there is little to no benefit from chemotherapy, especially for patients older than age 50 years. Clinicians may recommend endocrine therapy alone for women older than age 50 years. For patients 50 years of age or younger with recurrence scores of 16 to 25, clinicians may offer chemoendocrine therapy. Patients with recurrence scores greater than 30 should be considered candidates for chemoendocrine therapy. Based on informal consensus, the panel recommends that oncologists may offer chemoendocrine therapy to these patients with recurrence scores of 26 to 30. Additional information can be found at www.asco.org/breast-cancer-guidelines .

591 Background: Both Cb and Bev demonstrate activity when combined with standard chemotherapy in TNBC. CALGB 40603 is a 2x2 randomized trial that previously demonstrated that adding Cb to NACT significantly increased pathologic complete responses in the breast/axilla (pCR), while adding Bev did not (Sikov, JCO 2015). Here we report 5-year LTOs and assess factors that influenced them. Methods: 443 patients with clinical stage II-III previously untreated TNBC received 12 weeks of paclitaxel (wP) +/- Cb then dose-dense AC, +/- Bev before surgery. The primary endpoint was pCR. Analyses of LTOs (event-free survival (EFS), distant recurrence-free interval (DRFI) and overall survival (OS)), impact of residual cancer burden and other variables were secondary. Results: Median follow-up was 5.7 years (y); 5y EFS was 70.9% (95% CI; 66.7%-75.4%), DRFI 76.3% (72.3%-80.5%) and OS 76.9% (72.9%-81.2%). Pretreatment clinical stage and achieving pCR correlated with LTOs, while age, race, subtype (basal-like vs. not) and tumor grade did not. Among pCR 5y EFS was 86.4% vs. 57.5% for non-pCR (HR 0.28, 0.19-0.43), OS was 88.7% vs 66.5% (HR = 0.28, 0.17-0.44). This relationship was similar in all trial arms. Any residual disease conferred poorer outcome; compared with pCR/Residual Cancer Burden (RCB) 0, EFS HRs were 2.29 (1.32-3.97), 3.01 (1.90-4.74), and 9.67 (5.66-16.51) for RCBI, II and III, respectively. There were no improvements in LTOs with Cb (EFS HR 0.99, 0.70-1.40) or Bev (EFS HR 0.91, 0.64-1.29). In an exploratory analysis, receipt of ≥11 doses of wP was associated with better EFS (HR 1.92, 1.33-2.77); this was particularly notable in Cb-treated arms. Conclusions: As expected, regardless of treatment arm pCR was associated with markedly better LTOs, and pts with any residual disease had significantly worse outcomes. The addition of Cb or Bev to standard NACT for TNBC did not improve LTOs in this trial, although it should be noted that the trial was not powered for this endpoint. Omission of chemotherapy doses may result in poorer outcomes, especially among Cb-treated pts, which may warrant further evaluation. Support: U10CA180821; U10CA180882; Genentech; https://acknowledgments.alliancefound.org ; NCT00861705 Clinical trial information: NCT00861705.

Abstract Anticancer drugs are combined in an effort to treat a heterogeneous tumor or to maximize the pharmacodynamic effect. The development of combination regimens, while desirable, poses unique challenges. These include the selection of agents for combination therapy that may lead to improved efficacy while maintaining acceptable toxicity, the design of clinical trials that provide informative results for individual agents and combinations, and logistic and regulatory challenges. The phase I trial is often the initial step in the clinical evaluation of a combination regimen. In view of the importance of combination regimens and the challenges associated with developing them, the Clinical Trial Design (CTD) Task Force of the National Cancer Institute Investigational Drug Steering Committee developed a set of recommendations for the phase I development of a combination regimen. The first two recommendations focus on the scientific rationale and development plans for the combination regimen; subsequent recommendations encompass clinical design aspects. The CTD Task Force recommends that selection of the proposed regimens be based on a biologic or pharmacologic rationale supported by clinical and/or robust and validated preclinical evidence, and accompanied by a plan for subsequent development of the combination. The design of the phase I clinical trial should take into consideration the potential pharmacokinetic and pharmacodynamic interactions as well as overlapping toxicity. Depending on the specific hypothesized interaction, the primary endpoint may be dose optimization, pharmacokinetics, and/or pharmacodynamics (i.e., biomarker). Clin Cancer Res; 20(16); 4210–7. ©2014 AACR.