Beschreibung: 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 .

Beschreibung: Recent discoveries that non–small cell lung cancer (NSCLC) can be divided into molecular subtypes based on the presence or absence of driver mutations have revolutionized the treatment of many patients with advanced disease. However, despite these advances, a majority of patients are still dependent on modestly effective cytotoxic chemotherapy to provide disease control and prolonged survival. In this article, we review the current status of attempts to target the epigenome, heritable modifications of DNA, histones, and chromatin that may act to modulate gene expression independently of DNA coding alterations, in NSCLC and the potential for combinatorial and sequential treatment strategies. Clin Cancer Res; 20(9); 2244–8. ©2014 AACR .

Beschreibung: Recent breakthroughs in translating the early development of immunomodulatory antibodies into the clinic, notably with the anti–cytotoxic T-lymphocyte antigen-4 antibody, ipilimumab, have led to durable benefits and prolonged survival for a subgroup of patients with advanced melanoma. Subsequent studies have shown that related immune checkpoint antibodies, specifically those targeting the programmed death-1 pathway, have activity in non–small cell lung cancer. Non–small cell lung cancer is the commonest cause of cancer death worldwide and this exciting avenue of clinical investigation carries with it great promise and new challenges. In this article, we discuss recent developments in lung cancer immunotherapy, reviewing recent findings from therapeutic vaccine studies and in particular we focus on the refinement of immunomodulation as a therapeutic strategy in this challenging disease. Clin Cancer Res; 20(5); 1067–73. ©2014 AACR .

Beschreibung: Purpose: Azacitidine (AZA) is a novel therapeutic option in older patients with acute myeloid leukemia (AML), but its rational utilization is compromised by the fact that neither the determinants of clinical response nor its mechanism of action are defined. Co-administration of histone deacetylase inhibitors, such as vorinostat (VOR), is reported to improve the clinical activity of AZA, but this has not been prospectively studied in patients with AML. Experimental Design: We compared outcomes in 259 adults with AML ( n = 217) and MDS ( n = 42) randomized to receive either AZA monotherapy (75 mg/m 2 x 7 days every 28 days) or AZA combined with VOR 300 mg twice a day on days 3 to 9 orally. Next-generation sequencing was performed in 250 patients on 41 genes commonly mutated in AML. Serial immunophenotyping of progenitor cells was performed in 47 patients. Results: Co-administration of VOR did not increase the overall response rate ( P = 0.84) or overall survival (OS; P = 0.32). Specifically, no benefit was identified in either de novo or relapsed AML. Mutations in the genes CDKN2A ( P = 0.0001), IDH1 ( P = 0.004), and TP53 ( P = 0.003) were associated with reduced OS. Lymphoid multipotential progenitor populations were greatly expanded at diagnosis and although reduced in size in responding patients remained detectable throughout treatment. Conclusions: This study demonstrates no benefit of concurrent administration of VOR with AZA but identifies a mutational signature predictive of outcome after AZA-based therapy. The correlation between heterozygous loss of function CDKN2A mutations and decreased OS implicates induction of cell-cycle arrest as a mechanism by which AZA exerts its clinical activity. Clin Cancer Res; 23(21); 6430–40. ©2017 AACR .