Kumthekar et al. Page 2789

Leptomeningeal carcinomatosis (LC) from breast cancer is a disabling condition resulting from rapid and expansive tumor growth along the meningeal membranes. ANG1005 consists of three paclitaxel molecules covalently linked to Angiopep-2, designed to cross the blood-brain and blood-cerebrospinal barriers. Kumthekar and colleagues performed a phase II study of ANG1005 in breast cancer patients with brain metastases with or without LC. ANG1005 was observed to cross the blood-brain barrier to reach tumor cells. Stable disease or better was seen in the majority of the evaluable patients, with iORR of 15% (investigator) or 8% (independent radiology review). In the LC subset, 79% of the patients had intracranial disease control with an estimated median overall survival of 8.0 months (95% CI, 5.4–9.4). A randomized phase III trial of this agent is currently underway to further assess its efficacy in patients with LC.

Alsadhan et al. Page 2800

Covalent inhibitors of Bruton's tyrosine kinase (BTK) are effective across multiple B-cell malignancies. Alsadhan and colleagues assessed the pharmacodynamics of acalabrutinib in patients with chronic lymphocytic leukemia dosed either 200 mg once daily or 100 mg twice daily with a 48-hour drug withdrawal at day 3. Free BTK levels were higher in patients treated once daily than those treated twice daily. Furthermore, superior inhibition of BTK and NFkB signaling was observed with twice daily compared to once daily dosing during the drug withdrawal. This work provides important insights for determining optimal dosing of BTK inhibitors in CLL.

Algazi et al. Page 2827

Converting “cold” nonimmune infiltrated cancers into “hot” immune infiltrated ones is a critical need in oncology. Algazi and colleagues selected patients with “cold” melanoma as defined by low numbers of exhausted T cells by flow cytometry in tumor-infiltrating lymphocytes (TILs) and treated them with intratumoral IL-12 and pembrolizumab in a prospective phase II trial. The RECIST ORR was 41% with a CR rate of 36%. The combination enhanced immune infiltration and sustained IL-12/IFN-g feed forward signaling, driving cross-presenting DCs with increased TILs, as well as systemic immunity. Responding patients had higher ratios of Teff/Tregs and CD8+/M2 macrophages than nonresponders, perhap. reflecting competing immune mechanisms. These results demonstrate the promotion of a systemic antitumor immune response, although further study is necessary to elucidate mechanisms of resistance in nonresponding patients.

Sato et al. Page 2932

The identification of mechanisms of resistance to anti-ROS1 treatment in ROS1 fusion-driven lung cancers is an urgent need for this patient population. Sato and colleagues assessed MSK-IMPACT data from patients with ROS1 fusion-driven lung cancers to identify genomic alterations that affect responses to therapy. Mutations in MAPK pathway components were identified in 11% (8/75) of patients with a ROS1 fusion; these mutations included novel in-frame deletions in MEK1 and MEKK1 and loss-of-function mutations in NF1. MAPK pathway mutations correlated with poor survival in this cohort. Expression of the identified MEK1 or MEKK1 deletions or knockdown of NF1 resulted in conferred resistance to ROS1 tyrosine kinase inhibitors, while combination treatment with ROS1 and MEK inhibitors inhibited the growth of cells expressing both ROS1 fusions and MEK1delE41_L54. These results illuminate a novel treatment strategy to combat resistance in ROS1-fusion positive lung cancer.