Drilon et al. Page 2351

Substantial benefits can be achieved with crizotinib therapy in ROS1-rearranged lung cancer patients; however, acquired resistance represents an important clinical challenge. Drilon and colleagues report the discovery of a novel ROS1D2033N mutation that emerged after crizotinib therapy in a patient with CD74-ROS1-rearranged lung adenocarcinoma. ROS1D2033N confers crizotinib resistance, but remains highly sensitive to cabozantinib due to substantive differences in inhibitor binding modes. Treatment with cabozantinib resulted in significant tumor response in this patient. This is the first clinical example of overcoming acquired crizotinib-resistance with targeted therapy in a ROS1-rearranged malignancy and has immediate relevance for instructing ongoing clinical trials that are evaluating ROS1 inhibitors.

Vitale et al. Page 2359

Lenalidomide in combination with anti-CD20 monoclonal antibodies has clinical activity in lymphoproliferative disorders. In patients with chronic lymphocytic leukemia (CLL), lenalidomide also modulates T- and NK-cell function. Thirty-four patients with relapsed or refractory CLL were treated with combined lenalidomide and ofatumumab. Overall and complete response rates were 71% and 24%, respectively. The median progression-free survival was 16 months, and the estimated 5-year survival was 53%. Patients who achieved complete response had higher numbers and better-preserved function of T and NK cells before treatment. These findings emphasize the role of a competent immune system in successful cancer therapy.

Karlovich et al. Page 2386

In EGFR-mutant NSCLC, resistance to first generation EGFR-TKIs and afatinib is mediated by the T790M resistance mutation in ∼60% of cases. The authors use two plasma-testing methodologies to evaluate detection of EGFR activating and T790M resistance mutations in matched tumor and plasma samples taken mostly from a phase 1 study of the third generation EGFR inhibitor rociletinib. Plasma assays identified T790M mutations missed by biopsy because of tumor heterogeneity or lack of adequate tumor tissue. These data suggest plasma testing will be a useful complement to tumor testing, particularly in the setting of acquired resistance.

Bell et al. Page 2396

Predictive biomarkers of chemotherapy response in non-small cell lung cancer (NSCLC) are needed to better characterize patients who derive the greatest benefit. Bell and colleagues hypothesized that SMARCA4/BRG1, a gene that is commonly altered in NSCLC and other cancers, could be such a marker due to its established role in cisplatin sensitivity and DNA repair in vitro. Using mRNA expression data from patient samples enrolled in the JBR.10 randomized phase III trial, the authors were the first to demonstrate that NSCLCs harboring low SMARCA4 expression derive a large benefit from cisplatin-based adjuvant chemotherapy with a highly significant interaction test.