A Phase I, Dose Escalation Study of Oral ASP8273 in Patients with Non-small Cell Lung Cancers with Epidermal Growth Factor Receptor Mutations.

Purpose: Acquired EGFR T790M mutations are the most frequently identified resistance mechanism to EGFR tyrosine kinase inhibitors (TKI) in patients with EGFR-mutant lung cancers. ASP8273 is a third-generation EGFR TKI with antitumor activity in preclinical models of EGFR-mutant lung cancer that targets mutant EGFR, including EGFR T790M.Experimental Design: In this multicohort, phase I study (NCT02113813), escalating doses of ASP8273 (25-500 mg) were administered once daily to non-small cell lung cancer (NSCLC) patients with disease progression after prior treatment with an EGFR TKI. EGFR T790M was required for all cohorts, except the dose escalation cohort. Primary endpoints were safety/tolerability; secondary endpoints were determination of the RP2D, pharmacokinetic profile, and preliminary antitumor activity of ASP8273. Evaluation of the use of EGFR mutations in circulating free DNA (cfDNA) as a biomarker of ASP8273 treatment effects was an exploratory endpoint.Results: A total of 110 patients were treated with ASP8273 across dose escalation (n = 36), response-expansion (n = 36), RP2D (300 mg; n = 19) and food-effect (n = 19) cohorts. The most common treatment-emergent adverse events included diarrhea, nausea, fatigue, constipation, vomiting, and hyponatremia. Across all doses, in patients with EGFR T790M, the response rate was 30.7% (n = 27/88; 95% CI, 19.5%-44.5%), and median progression-free survival was 6.8 months (95% CI, 5.5-10.1 months). EGFR mutations in cfDNA, both the activating mutation and EGFR T790M, became undetectable in most patients in the setting of clinical response and reemerged upon disease progression.Conclusions: ASP8273 was well tolerated and promoted antitumor activity in patients with EGFR-mutant lung cancer with disease progression on prior EGFR TKI therapy. Clin Cancer Res; 23(24); 7467-73. ©2017 AACR.

Rituximab in the treatment of follicular lymphoma: the future of biosimilars in the evolving therapeutic landscape.

Follicular lymphoma (FL) is the second most common type of non-Hodgkin's lymphoma. FL is an incurable disease with treatment options ranging from a "watch-and-wait" approach to localized therapy with radiation or systemic therapy with rituximab in combination with chemotherapy regimens. This review summarizes the role of rituximab across the spectrum of FL treatment and the evolving therapeutic landscape with the emergence of novel agents currently in clinical development. Despite the prospect of new agents on the horizon, it is widely accepted that rituximab will remain as the cornerstone of therapy because of its established long-term efficacy. Many biologics, including rituximab, have lost exclusivity of composition-of-matter patent or will do so in the next few years, which is a concern for patients and physicians alike. Moreover, access to rituximab is challenging, particularly in countries with restricted resources. Together, these concerns have fueled the development of safe and effective biosimilars. The term "biosimilar" refers to a biologic product that is highly similar to an approved reference (or originator) product, notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences in purity, potency, or safety. Biosimilars are developed to treat the same condition(s) using the same treatment regimens as an approved reference biologic, and have the potential to increase access to more affordable treatment of FL. Herein, we also discuss the potential benefits of eagerly awaited rituximab biosimilars, which may mitigate the impact of the lack of access to rituximab.