Burke et al. Page 2297

Treatment failure from drug resistance is the primary reason for relapse in acute lymphoblastic leukemia (ALL). Burke and colleagues conducted a pilot clinical trial in patients with ALL using two classes of epigenetic modifying agents (decitabine and vorinostat) with the goal of synergistically targeting epigenetic alterations before and during chemotherap. that included UK ALLR3 re-induction. On this regimen, nine subjects (39%) achieved a complete response and five had stable disease (22%). Modulation of epigenetic marks was observed. However, the toxicity profile of the combination assessed was not acceptable. Therefore, future studies are necessary to determine if epigenetic modifying therapies can be successfully combined with chemotherapeutics for children with relapsed leukemia.

Xie et al. Page 2318

Metastatic pancreatic ductal adenocarcinoma (PDAC) carries a dismal prognosis and is refractory to conventional chemotherapy. Although immunotherapy has been safe and effective in multiple tumor types, the utility of immunotherapy is limited in PDAC. In a phase I study of patients with metastatic PDAC, Xie and colleagues investigated the tolerability and clinical efficacy of darmalumab with or without tremelimumab in combination with stereotactic body radiation therapy (SBRT). The combination of checkpoint inhibitors with SBRT was well tolerated and showed moderate efficacy, with an overall response rate of 5.1%. These findings reinforce the need for optimization of immunotherapeutic strategies in metastatic PDAC.

Aggarwal et al. Page 2354

Pembrolizumab-based therap. is currently the standard of care for patients with metastatic non-small cell lung cancer (mNSCLC) lacking actionable mutations. High tumor mutation burden (TMB) is associated with response to pembrolizumab, but current protocols for measuring TMB require obtaining sufficient tissue for analysis, which can be a challenge. Aggarwal and colleagues measured the plasma TMB (pTMB) of 66 patients with mNSCLC who received pembrolizumab monotherapy with or without chemotherapy. High baseline pTMB (greater than 16 mut/Mb) correlated with improved PFS after pembrolizumab-based therapy in mNSCLC. In addition, mutations in STK11, KEAP1, PTEN, and ERBB2 were identified in pTMB-high patients who did not respond. Although a larger validation study is needed, these results show the potential clinical utility of a plasma based TMB test to help inform therapy selection.

Ivanova et al. Page 2393

The development of anti-cancer therapies requires appropriate preclinical models in which to test treatments. Roughly three percent of non-small cell lung cancers (NSCLC) harbor mutations in HER2, but there are limited models of HER2 mutant NSCLC available for preclinical study. Ivanova and colleagues assessed drug combinations in HER2-mutant (NSCLC) patient xenograft-derived organotypic spheroids (XDOTS) using a short-term ex vivo system. Two such models were generated, and successful drug combinations were identified for both. Therefore, the XDOTS platform can be used to evaluate therapies and therapeutic combinations ex vivo using PDX tumors, further enhancing precision medicine possibilities in NSCLC.