Research Spotlight

Twelves, C., J. Cortes, P. A. Kaufman, L. Yelle, A. Awada, T. A. Binder, M. Olivo, J. Song, J. A. O’Shaughnessy, M. Jove and E. A. Perez (2015). “New” metastases are associated with a poorer prognosis than growth of pre-existing metastases in patients with metastatic breast cancer treated with chemotherapy. Breast Cancer Research : BCR, 17, 150.

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Introduction: Progression-free survival (PFS) and overall survival (OS) endpoints often only weakly correlate. This analysis investigates how different progression events impact on OS, using data from two phase 3 studies with eribulin in women with advanced/metastatic breast cancer (MBC). Methods: In Study 301, 1102 women with <= 2 prior chemotherapies for advanced/MBC were randomized to eribulin mesylate (1.4 mg/m(2) on days 1 and 8 every 21 days) or capecitabine (1.25 g/m(2) twice daily on days 1-14 every 21 days). Study 305/EMBRACE enrolled 762 patients following two to five prior chemotherapies for advanced/MBC, randomized to eribulin (as above) or treatment of physician's choice. We analyzed OS and PFS post hoc for patients whose disease progressed due to development of "new" metastases, growth of pre-existing lesions, and patients with no reported disease progression. Results: In both clinical studies, development of new metastases was associated with an increased risk of death (p < 0.0001). The time to development of new metastasis or death was significantly longer with eribulin than the comparator in Study 305 (p = 0.0017), but not in Study 301 (p = 0.46). Significantly longer OS was observed in the eribulin compared with the comparator arm for the new metastases subgroup in Study 301 (p = 0.008), but not in Study 305 (p = 0.16), compared with other progression subgroups. Conclusions: Patients with MBC progressing with new metastases have a worse prognosis than those whose disease progresses due to growth of existing lesions or patients with no reported disease progression. These findings have potentially important implications for the interpretation of clinical study data and clinical practice.

Yardley, D. A., A. Brufsky, R. E. Coleman, P. F. Conte, J. Cortes, S. Gluck, J. M. Nabholtz, J. O’Shaughnessy, R. M. Beck, A. Ko, M. F. Renschler, D. Barton and N. Harbeck (2015). “Phase II/III weekly nab-paclitaxel plus gemcitabine or carboplatin versus gemcitabine/carboplatin as first-line treatment of patients with metastatic triple-negative breast cancer (the tnAcity study): study protocol for a randomized controlled trial.” Trials 16(1): 575.

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BACKGROUND: Triple-negative breast cancer is an aggressive disease with unmet clinical needs. In a phase III study of patients with metastatic triple-negative breast cancer, first-line gemcitabine/carboplatin resulted in a median progression-free survival of 4.6 months. nab-paclitaxel-based regimens (with gemcitabine or carboplatin +/- bevacizumab) also demonstrated efficacy and safety in first-line phase II trials of human epidermal growth factor receptor 2-negative metastatic breast cancer. TRIAL DESIGN: In this international, multicenter, open-label, randomized phase II/III trial, the efficacy and safety of first-line nab-paclitaxel with gemcitabine or with carboplatin will be compared with gemcitabine/carboplatin (control arm) for metastatic triple-negative breast cancer. METHODS: In the phase II portion, 240 patients with measurable metastatic triple-negative breast cancer and treatment-naive for metastatic disease will be randomized 1:1:1 (stratified by disease-free interval: 1 year) to nab-paclitaxel 125 mg/m(2) plus gemcitabine 1000 mg/m(2), nab-paclitaxel 125 mg/m(2) plus carboplatin area under the curve 2 mg x min/mL, or gemcitabine 1000 mg/m(2) plus carboplatin area under the curve 2 mg x min/mL, all given on days 1 and 8 of a 21-day cycle. Investigator-assessed progression-free survival (primary endpoint), overall response rate, overall survival, and safety will be assessed. A ranking algorithm of five efficacy and safety parameters will be used to pick the “winner” of the nab-paclitaxel regimens. In the phase III portion, 550 patients will be randomized 1:1 (stratified by disease-free interval: 1 year, and prior adjuvant/neoadjuvant taxane use) to the nab-paclitaxel combination arm selected from the phase II portion or to the control arm. Patients in phase II will not be part of the phase III population. The phase III primary endpoint is blinded, independently-assessed progression-free survival; secondary endpoints include blinded, independently-assessed overall response rate, overall survival, disease control rate, duration of response, and safety. Biomarker and circulating tumor-cell exploratory analyses and quality-of-life assessments will also be performed. A list of approving ethical bodies was provided in Additional file 1. DISCUSSION: The tnAcity trial aims to identify a new standard cytotoxic chemotherapy regimen for first-line treatment of metastatic triple-negative breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01881230 . Date of registration: 17 June 2013.

Claggett, B., M. Packer, J. J. V. McMurray, K. Swedberg, J. Rouleau, M. R. Zile, P. Jhund, M. Lefkowitz, V. Shi, S. D. Solomon and P.-H. Investigators (2015). “Estimating the Long-Term Treatment Benefits of Sacubitril-Valsartan.” New England Journal of Medicine 373(23): 2289-2290.

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Although data from clinical trials can be used to estimate the effectiveness of a new therapy as compared with a control during the study follow-up, estimating long-term treatment effects is often difficult. The PARADIGM-HF trial showed that sacubitril–valsartan was superior to enalapril in reducing the rates of death from cardiovascular causes or hospitalization for heart failure (the composite primary end point) and death from any cause among patients with heart failure and a reduced ejection fraction. To estimate the long-term treatment effects of sacubitril–valsartan versus enalapril, we derived actuarial estimates of age-specific event rates and expected survival times using data regarding the age at randomization and the age at the time of an outcome event from the PARADIGM-HF trial (Table S1 and Fig. S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). We estimated Kaplan–Meier survival curves for any given age for each treatment group, using age (rather than the time from randomization) as the time scale. We also estimated the average duration of event-free survival according to the area under the survival curve (see the Methods section in the Supplementary Appendix). We then validated our methods by comparing similar long-term survival estimates from the SOLVD-Treatment trial with long-term follow-up data, which showed concordant results (see the Validation of Methods section in the Supplementary Appendix).

Tran, C., E. Wilder and J. R. Griffin (2015). “Stomatitis, Cutaneous Bullae, and Renal Failure.” JAMA-Journal of the American Medical Association 314(21): 2296-2297.

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A 64-year-old African American woman presented to the emergency department for evaluation of bleeding mouth sores, tender crusted plaques on her scalp, and blisters on her skin. Three weeks previously, she noticed painful erosions throughout her mouth. A week later, painful blisters appeared on her upper extremities, trunk, and thighs. She also reported 2 pruritic and painful lesions on her scalp that had appeared 6 months prior, shortly after a chemical hair treatment. She had a history of alcohol, tobacco, cocaine, and marijuana use but denied current illicit drug use. She had not taken any medications prior to the appearance of the lesions. The patient reported a 2.25-kg weight loss, subjective fevers, and chills but no urinary symptoms. On admission, the patient was tachycardic (113/min), but she was afebrile and other vital signs were normal. Physical examination revealed crusted plaques on her scalp bilaterally (Figure). Erosive stomatitis involving the lower lip, buccal mucosa, hard palate, soft palate, and tongue was noted (Figure). Multiple well-circumscribed, round-to-oval bullae, erosions, and hyperpigmented patches were noted on her upper extremities, trunk, and thighs (Figure). Laboratory evaluation revealed a serum creatinine level of 7.1 mg/dL (627.6 μmol/L), up from a baseline (10 days prior) level of 0.9 mg/dL (79.6 μmol/L). Urinalysis revealed a specific gravity of 1.015 and was positive for hyaline casts and protein but negative for white blood cells, red blood cells, and bacteria. A complete blood cell count was unremarkable. Results of human immunodeficiency virus screen and urine drug screen were normal . . . A shave biopsy from a back lesion showed suprabasal acantholysis and bulla. Direct immunofluorescence testing of punch biopsies from the edges of lesions on the back and scalp showed intercellular deposition of IgG and C3 in the lower epidermis. Indirect immunofluorescence on monkey esophagus substrate revealed serum cell surface IgG antibodies. Testing with ELISA revealed elevated anti–Dsg 1 and anti–Dsg 3 antibodies (132 U and 187 U, respectively). Therapy was initiated with an oral anesthetic rinse, oral prednisone (60 mg daily), and topical corticosteroids. With intravenous fluid administration, the patient’s creatinine level corrected to 0.7 mg/dL (61.9 μmol/L), suggesting acute renal failure most likely attributable to decreased oral intake secondary to pain. The patient was discharged with follow-up in dermatology clinic to initiate azathioprine as an outpatient. (Excerpts from text; no abstract.)

Stupp, R., S. Taillibert, A. A. Kanner, S. Kesari, D. M. Steinberg, S. A. Toms, L. P. Taylor, F. Lieberman, A. Silvani, K. L. Fink, G. H. Barnett, J. J. Zhu, J. W. Henson, H. H. Engelhard, T. C. Chen, D. D. Tran, J. Sroubek, N. D. Tran, A. F. Hottinger, J. Landolfi, R. Desai, M. Caroli, Y. Kew, J. Honnorat, A. Idbaih, E. D. Kirson, U. Weinberg, Y. Palti, M. E. Hegi and Z. Ram (2015). “Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial.” JAMA 314(23): 2535-2543.

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IMPORTANCE: Glioblastoma is the most devastating primary malignancy of the central nervous system in adults. Most patients die within 1 to 2 years of diagnosis. Tumor-treating fields (TTFields) are a locoregionally delivered antimitotic treatment that interferes with cell division and organelle assembly. OBJECTIVE: To evaluate the efficacy and safety of TTFields used in combination with temozolomide maintenance treatment after chemoradiation therapy for patients with glioblastoma. DESIGN, SETTING, AND PARTICIPANTS: After completion of chemoradiotherapy, patients with glioblastoma were randomized (2:1) to receive maintenance treatment with either TTFields plus temozolomide (n = 466) or temozolomide alone (n = 229) (median time from diagnosis to randomization, 3.8 months in both groups). The study enrolled 695 of the planned 700 patients between July 2009 and November 2014 at 83 centers in the United States, Canada, Europe, Israel, and South Korea. The trial was terminated based on the results of this planned interim analysis. INTERVENTIONS: Treatment with TTFields was delivered continuously (>18 hours/day) via 4 transducer arrays placed on the shaved scalp and connected to a portable medical device. Temozolomide (150-200 mg/m2/d) was given for 5 days of each 28-day cycle. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival in the intent-to-treat population (significance threshold of .01) with overall survival in the per-protocol population (n = 280) as a powered secondary end point (significance threshold of .006). This prespecified interim analysis was to be conducted on the first 315 patients after at least 18 months of follow-up. RESULTS: The interim analysis included 210 patients randomized to TTFields plus temozolomide and 105 randomized to temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18-60 months). Median progression-free survival in the intent-to-treat population was 7.1 months (95% CI, 5.9-8.2 months) in the TTFields plus temozolomide group and 4.0 months (95% CI, 3.3-5.2 months) in the temozolomide alone group (hazard ratio [HR], 0.62 [98.7% CI, 0.43-0.89]; P = .001). Median overall survival in the per-protocol population was 20.5 months (95% CI, 16.7-25.0 months) in the TTFields plus temozolomide group (n = 196) and 15.6 months (95% CI, 13.3-19.1 months) in the temozolomide alone group (n = 84) (HR, 0.64 [99.4% CI, 0.42-0.98]; P = .004). CONCLUSIONS AND RELEVANCE: In this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00916409.