In the PACIFIC trial, durvalumab significantly improved progression-free and overall survival (PFS/OS) versus placebo, with manageable safety, in unresectable, stage III non-small-cell lung cancer (NSCLC) patients without progression after chemoradiotherapy (CRT). We report exploratory analyses of outcomes by tumour cell (TC) programmed death-ligand 1 (PD-L1) expression. Patients and methods: Patients were randomly assigned (2:1) to intravenous durvalumab 10 mg/kg every 2 weeks or placebo 12 months, stratified by age, sex, and smoking history, but not PD-L1 status. Where available, pre-CRT samples were tested for PD-L1 expression (immunohistochemistry) and scored at pre-specified (25%) and post hoc (1%) TC cut-offs. Treatment-effect hazard ratios (HRs) were estimated from unstratified Cox proportional hazards models (KaplaneMeier-estimated medians). Results: In total, 713 patients were randomly assigned, 709 of whom received at least 1 dose of study treatment durvalumab (n ¼ 473) or placebo (n ¼ 236). Some 451 (63%) were PD-L1-assessable: 35%, 65%, 67%, 33%, and 32% had TC !25%, <25%, !1%, <1%, and 1%e24%, respectively. As of 31 January 2019, median follow-up was 33.3 months. Durvalumab improved PFS versus placebo (primary-analysis data cut-off, 13 February 2017) across all subgroups [HR, 95% confidence interval (CI); medians]: TC !25% (0.41, 0.26e0.65; 17.8 versus 3.7 months), <25% (0.59, 0.43e0.82; 16.9 versus 6.9 months), !1% (0.46, 0.33e0.64; 17.8 versus 5.6 months), <1% (0.73, 0.48e1.11; 10.7 versus 5.6 months), 1%e24% [0.49, 0.30e0.80; not reached (NR) versus 9.0 months], and unknown (0.59, 0.42 e0.83; 14.0 versus 6.4 months). Durvalumab improved OS across most subgroups (31 January 2019 data cut-off; HR, 95% CI; medians): TC ! 25% (0.50, 0.30e0.83; NR versus 21.1 months), <25% (0.89, 0.63e1.25; 39.7 versus 37.4 months), !1% (0.59, 0.41e0.83; NR versus 29.6 months), 1%e24% (0.67, 0.41e1.10; 43.3 versus 30.5 months), and unknown (0.60, 0.43e0.84; 44.2 versus 23.5 months), but not <1% (1.14, 0.71e1.84; 33.1 versus 45.6 months). Safety was similar across subgroups. Conclusions: PFS benefit with durvalumab was observed across all subgroups, and OS benefit across all but TC <1%, for which limitations and wide HR CI preclude robust conclusions.

Anti-PD-1/PD-L1 therapies have demonstrated activity in patients with advanced stage non-small cell lung cancer (NSCLC). However, little is known about the safety and feasibility of patients receiving anti-PD-1/PD-L1 therapy and stereotactic radiation for the treatment of brain metastases. Data were analyzed retrospectively from NSCLC patients treated with stereotactic radiation either before, during or after anti-PD-1/PD-L1 therapy with nivolumab (anti-PD-1) or durvalumab (anti-PD-L1). Seventeen patients treated with stereotactic radiosurgery (SRS) or fractionated stereotactic radiation therapy (FSRT) to 49 brain metastases over 21 sessions were identified. Radiation was administered prior to, during and after anti-PD-1/PD-L1 therapy in 22 lesions (45%), 13 lesions (27%), and 14 lesions (29%), respectively. The 6 months Kaplan-Meier (KM) distant brain control rate was 48% following stereotactic radiation. Six and 12 month KM rates of OS from the date of stereotactic radiation and the date of cranial metastases diagnosis were 48/41% and 81/51%, respectively. The 6 month rate of distant brain control following stereotactic radiation for patients treated with stereotactic radiation during or prior to anti-PD-1/PD-L1 therapy was 57% compared to 0% among patients who received anti-PD-1/PD-L1 therapy before stereotactic radiation (p = 0.05). A Karnofsky Performance Status (KPS) of <90 was found to be predictive of worse OS following radiation treatment on both univariate and multivariate analyses (MVA, p = 0.01). In our series, stereotactic radiation to NSCLC brain metastases was well tolerated in patients who received anti-PD-1/PD-L1 therapy. Prospective evaluation to determine how these two modalities can be used synergistically to improve distant brain control and OS is warranted.

Cancer clinics currently use high-dose stereotactic body radiation therapy as a curative treatment for several kinds of cancers. However, the contribution of vascular endothelial cells to tumor response to radiation remains controversial. Using dual-recombinase technology, we generated primary sarcomas in mice with targeted genetic mutations specifically in tumor cells or endothelial cells. We selectively mutated the proapoptotic gene Bax or the DNA damage–response gene Atm to genetically manipulate the radiosensitivity of endothelial cells in primary soft tissue sarcomas. Bax deletion from endothelial cells did not affect radiation-induced cell death in tumor endothelial cells or sarcoma response to radiation therapy. Although Atm deletion increased endothelial cell death after radiation therapy, deletion of Atm from endothelial cells failed to enhance sarcoma eradication. In contrast, deletion of Atm from tumor cells increased sarcoma eradication by radiation therapy. These results demonstrate that tumor cells, rather than endothelial cells, are critical targets that regulate sarcoma eradication by radiation therapy. Treatment with BEZ235, a small-molecule protein kinase inhibitor, radiosensitized primary sarcomas more than hearts. These results suggest that inhibiting ATM kinase during radiation therapy is a viable strategy for radiosensitization of some tumors.

Purpose-To image a genetically engineered mouse model of non-small cell lung cancer with micro-CT to measure tumor response to radiation therapy. Methods and Materials-TheCre-loxP system was utilized to generate primary lung cancers in mice with mutation in K-ras alone or in combination with p53 mutation. Mice were serially imaged by micro-CT and tumor volumes were determined. A comparison of tumor volume by micro-CT and tumor histology was performed. Tumor response to radiation therapy (15.5 Gy) was assessed with micro-CT.Results-The tumor volume measured with free-breathing micro-CT scans was greater than the volume calculated by histology. Nevertheless, this imaging approach demonstrated that lung cancers with mutant p53 grew more rapidly than lung tumors with wild-type p53 and also showed that radiation therapy increased the doubling time of p53 mutant lung cancers five-fold. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Conflicts of Interest: none. Conclusions-Micro-CT is an effective tool to noninvasively measure the growth of primary lung cancers in genetically engineered mice and assess tumor response to radiation therapy. This imaging approach will be useful to study the radiation biology of lung cancer. NIH Public Access

PURPOSE In the treatment of uveal melanomas, the optimal prescribed dose to maximize disease control, but minimize radiation-related complications is unknown. Historically our institution has treated uveal melanomas to doses less than 85 Gy to the tumor apex even if the apex was less than 5mm in height. Here, we investigate how tumor control and visual outcomes are affected by the radiation dose at the tumor apex. METHODS AND MATERIALS A retrospective review was performed to evaluate patients treated for uveal melanoma with Iodine-125 plaques between 1988 and 2010. Radiation dose is reported as dose to tumor apex and dose to 5 mm. Primary end points included time to local failure, distant failure, and death. Secondary end points included eye preservation, visual acuity, and radiation-related complications. Univariate and multivariate analyses were performed to determine association between radiation dose and the end point variables. RESULTS One hundred ninety patients with sufficient data to evaluate the end points were included. The 5 year local control (LC) rate was 91%. The 5 year distant metastases (DM) rate was 10%. The 5 year overall survival (OS) rate was 84%. There were no differences in outcome (LC, DM, OS) when dose was stratified by apex dose quartile (<69 Gy, 69–81 Gy, 81–89 Gy, >89 Gy). However, increasing apex dose and dose to 5 mm depth were correlated with greater visual acuity loss (p=0.02, p=0.0006), worse final visual acuity (p=0.02, p<0.0001) and radiation complications (p<0.0001, p=0.0009). In addition, enucleation rates were worse with increasing quartiles of dose to 5 mm (p=0.0001). CONCLUSIONS Doses at least as low as 69 Gy prescribed to the tumor apex achieve rates of local control, distant metastasis free survival, and overall survival that are similar to radiation doses of 85 Gy to the tumor apex, but with improved visual outcomes.