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Background While Programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) blockade is a potent antitumor treatment strategy, it is effective in only limited subsets of patients with cancer, emphasizing the need for the identification of additional immune checkpoints. Butyrophilin 1A1 (BTN1A1) has been reported to exhibit potential immunoregulatory activity, but its ability to function as an immune checkpoint remains to be systematically assessed, and the mechanisms underlying such activity have yet to be characterized.Methods BTN1A1 expression was evaluated in primary tumor tissue samples, and its ability to suppress T-cell activation and T cell-dependent tumor clearance was examined. The relationship between BTN1A1 and PD-L1 expression was further characterized, followed by the development of a BTN1A1-specific antibody that was administered to tumor-bearing mice to test the amenability of this target to immune checkpoint inhibition.Results BTN1A1 was confirmed to suppress T-cell activation in vitro and in vivo. Robust BTN1A1 expression was detected in a range of solid tumor tissue samples, and BTN1A1 expression was mutually exclusive with that of PD-L1 as a consequence of its inhibition of Janus-activated kinase/signal transducer and activator of transcription signaling-induced PD-L1 upregulation. Antibody-mediated BTN1A1 blockade suppressed tumor growth and enhanced immune cell infiltration in syngeneic tumor-bearing mice.Conclusion Together, these results confirm that the potential of BTN1A1 is a bona fide immune checkpoint and a viable immunotherapeutic target for the treatment of individuals with anti-PD-1/PD-L1 refractory or resistant disease, opening new avenues to improving survival outcomes for patients with a range of cancers.

Summary: Background: Only around 20–30% of patients with non-small-cell lung cancer (NCSLC) have durable benefit from immune-checkpoint inhibitors. Although tissue-based biomarkers (eg, PD-L1) are limited by suboptimal performance, tissue availability, and tumour heterogeneity, radiographic images might holistically capture the underlying cancer biology. We aimed to investigate the application of deep learning on chest CT scans to derive an imaging signature of response to immune checkpoint inhibitors and evaluate its added value in the clinical context. Methods: In this retrospective modelling study, 976 patients with metastatic, EGFR/ALK negative NSCLC treated with immune checkpoint inhibitors at MD Anderson and Stanford were enrolled from Jan 1, 2014, to Feb 29, 2020. We built and tested an ensemble deep learning model on pretreatment CTs (Deep-CT) to predict overall survival and progression-free survival after treatment with immune checkpoint inhibitors. We also evaluated the added predictive value of the Deep-CT model in the context of existing clinicopathological and radiological metrics. Findings: Our Deep-CT model demonstrated robust stratification of patient survival of the MD Anderson testing set, which was validated in the external Stanford set. The performance of the Deep-CT model remained significant on subgroup analyses stratified by PD-L1, histology, age, sex, and race. In univariate analysis, Deep-CT outperformed the conventional risk factors, including histology, smoking status, and PD-L1 expression, and remained an independent predictor after multivariate adjustment. Integrating the Deep-CT model with conventional risk factors demonstrated significantly improved prediction performance, with overall survival C-index increases from 0·70 (clinical model) to 0·75 (composite model) during testing. On the other hand, the deep learning risk scores correlated with some radiomics features, but radiomics alone could not reach the performance level of deep learning, indicating that the deep learning model effectively captured additional imaging patterns beyond known radiomics features. Interpretation: This proof-of-concept study shows that automated profiling of radiographic scans through deep learning can provide orthogonal information independent of existing clinicopathological biomarkers, bringing the goal of precision immunotherapy for patients with NSCLC closer. Funding: National Institutes of Health, Mark Foundation Damon Runyon Foundation Physician Scientist Award, MD Anderson Strategic Initiative Development Program, MD Anderson Lung Moon Shot Program, Andrea Mugnaini, and Edward L C Smith.

ABSTRACT: OBJECTIVE: This phase I trial (NCT01912625) evaluated the safety and pharmacokinetics of definitive concurrent chemoradiotherapy (cCRT) and the radiosensitizer trametinib (MEK1/2 inhibitor) for KRAS-mutated nonmetastatic non-small cell lung cancer (NSCLC). METHODS: Patients received cCRT (carboplatin/paclitaxel and 60 Gy/30 fractions radiotherapy); oral trametinib (7 days/week) commenced on day 1 and completed on the final day of radiotherapy. Dose-finding of trametinib was done using the time-to-event continual reassessment method (TiTE-CRM); dose levels were 0.5mg (level -1), 1mg (initial, level 1), 1.5mg (level 2), and 2mg (level 3). Progression-free (PFS) and overall survival (OS) times were also recorded. RESULTS: Fifteen patients (stage III, variety of KRAS mutations) were treated, with 1/5/4/5 at dose levels -1/1/2/3, respectively. Five patients received dose reductions (n=2, levels 2 and 3; n=1, level 1). Twelve patients completed the full cCRT course. One patient (following 12d trametinib) was taken off protocol for an unrelated/unresolved grade 1 event and later experienced grade 5 sepsis/respiratory failure. There was one grade 4 retinal detachment; grade 3 events included skin rash (n=2) and ventricular dysfunction, pneumonitis, pain, fatigue, and diarrhea (n=1 each). The final dose selected by the TiTE-CRM of trametinib was 1.5 mg. Pharmacokinetic profiles were elucidated and extensively described. At median follow-up of 70 months, median PFS was 11 months and median OS was 38 months. CONCLUSIONS: The MTD for trametinib when combined with cCRT is 1.5 mg, with encouraging preliminary outcomes. This combination merits further study to combine with consolidation durvalumab in non-metastatic KRAS mutant NSCLC.

Background In this phase I/II trial, we evaluated the safety and effectiveness of pembrolizumab, with or without concurrent radiotherapy (RT), for lung and liver lesions from metastatic non-small cell lung cancer (mNSCLC).Methods Patients with lung or liver lesions amenable to RT plus at least one additional non-contiguous lesion were included regardless of programmed death-ligand 1 (PD-L1) status. Pembrolizumab was given at 200 mg every 3 weeks for up to 32 cycles with or without concurrent RT. Metastatic lesions were treated with stereotactic body RT (SBRT; 50 Gy in 4 fractions) if clinically feasible or with traditionally fractionated RT (45 Gy in 15 fractions) if not. The primary end point was the best out-of-field lesion response, and a key secondary end point was progression-free survival (PFS).Results The median follow-up time was 20.4 months. One hundred patients (20 phase I, 80 phase II) were evaluable for toxicity, and 72 phase II patients were evaluable for treatment response. No patients in the phase I group experienced grade 4–5 events; in the phase II group, two had grade 4 events and nine had grade 3 events. The ORR in the combined-modality cohort (irrespective of RT schema) was 22%, vs 25% in the pembrolizumab group (irrespective of receipt of salvage RT) (p=0.99). In the concurrent pembrolizumab+RT groups, the out-of-field ORRs were 38% in the pembrolizumab+SBRT group and 10% in the pembrolizumab+traditional RT group. When examining the pembrolizumab-alone patients, the out-of-field ORRs were 33% in those designated to receive salvage SBRT (if required) and 17% for salvage traditional RT. In all patients, the median PFS for pembrolizumab alone was 5.1 months (95% CI 3.4 to 12.7 months), and pembrolizumab/RT (regardless of schema) was 9.1 months (95% CI 3.6 to 18.4 months) (p=0.52). An exploratory analysis revealed that for patients with low PD-L1 expression, the median PFS was 4.6 vs 20.8 months for pembrolizumab with and without RT, respectively (p=0.004).Conclusions Concurrent immunoradiotherapy for mNSCLC is safe, although larger trials are required to address which patients benefit most from RT.Trial registration number NCT02444741.

Abstract As the NRG GI006 and PROTECT trials seek to confirm results of the first randomized trial supporting the utility of proton beam therapy for esophageal cancer, several outstanding questions are discussed in this review. First, the applicability/extrapolation of the existing randomized trial is mentioned. This includes a potentially larger benefit of PBT at non‐high‐volume centers with less surgical expertise, along with the emerging use of active scanning PBT approaches that could further improve toxicity profiles. Patient selection for PBT is then discussed, including differential utility for patients based on the degree of baseline comorbidities, the extent/location of disease, and the surgical case volume at the treating institution. PBT in the setting of emerging techniques, such as minimally invasive esophagectomy, is also mentioned. Next, costs of PBT and insurance coverage hurdles are described, especially regarding pre‐specified agreements between providers/institutions and payors, the need for cost‐effectiveness analyses for PBT in this population, and effects of the new radiation oncology alternative payment model. Finally, immunotherapy has now become a standard option for esophageal cancer (resected or unresected/recurrent/metastatic cases). Therefore, in the context of immunotherapy for these patients, revisiting the role of radiation dose‐escalation and elective nodal irradiation may be required.

Introduction: Durvalumab after concurrent chemoradiation (CCRT) for NSCLC improves survival, but only in a subset of patients. We investigated the effect of severe radiation-induced lymphopenia (sRIL) on survival in these patients. Methods: Outcomes after CCRT (2010–2019) or CCRT followed by durvalumab (2018–2019) were reviewed. RIL was defined by absolute lymphocyte count (ALC) nadir in samples collected at end of CCRT; sRIL was defined as nadir ALC less than 0.23 × 109/L (the lowest tertile). Progression-free survival (PFS) and overall survival (OS) were calculated by the Kaplan-Meier method. Cox proportional hazard modeling evaluated associations between clinical variables and survival. Results: Of 309 patients, 192 (62%) received CCRT only and 117 (38%) CCRT plus durvalumab. Multivariable logistic regression analysis indicated that sRIL was associated with planning target volume (OR = 1.002, p = 0.001), stage IIIB disease (OR = 2.77, p = 0.04), and baseline ALC (OR = 0.36, p < 0.01). Durvalumab extended median PFS (23.3 versus 14.1 mo, p = 0.003) and OS (not reached versus 30.8 mo, p < 0.01). sRIL predicted poorer PFS and OS in both treatment groups. Among patients with sRIL, durvalumab did not improve survival (median = 24.6 mo versus 18.1 mo CCRT only, p = 0.079). On multivariable analyses, sRIL (OR = 1.81, p < 0.01) independently predicted poor survival. Conclusions: Severe RIL compromises survival benefits from durvalumab after CCRT for NSCLC. Measures to mitigate RIL after CCRT may be warranted to enhance the benefit of consolidation durvalumab.

Abstract Background Cancer Associated Macrophage-Like cells (CAMLs) are polynucleated circulating stromal cells found in the bloodstream of numerous solid-tumor malignancies. Variations within CAML size have been associated with poorer progression free survival (PFS) and overall survival (OS) in a variety of cancers; however, no study has evaluated their clinical significance in esophageal cancer (EC). Methods To examine this significance, we ran a 2 year prospective pilot study consisting of newly diagnosed stage I-III EC patients (n = 32) receiving chemoradiotherapy (CRT). CAML sizes were sequentially monitored prior to CRT (BL), ~ 2 weeks into treatment (T1), and at the first available sample after the completion of CRT (T2). Results We found CAMLs in 88% (n = 28/32) of all patient samples throughout the trial, with a sensitivity of 76% (n = 22/29) in pre-treatment screening samples. Improved 2 year PFS and OS was found in patients with CAMLs

Purpose: To evaluate the safety and efficacy of definitive chemoradiotherapy (CRT) for patients with clinical T1N0M0 esophageal adenocarcinoma. Methods and Materials: This was a retrospective study of patients with clinical T1N0 adenocarcinoma of the esophagus treated with curative-intent CRT between 2004 and 2017 at 2 tertiary care centers. Patients received CRT instead of esophagectomy owing to medical comorbidities or patient preference. Toxicities were evaluated according to Common Terminology Criteria for Adverse Events version 4.03. The Kaplan-Meier method was used to estimate overall, progression-free, and disease-specific survivals. Results: Twenty-eight patients were included for analysis. Median age was 76 years (range 55-90). The majority of patients were male (93%) and had a history of Barrett’s esophagus (71%). Tumor characteristics included distal esophagus location (93%), clinical stage T1b (86%), and median length of 2 cm (range, 1-9). Prior endoscopic resection was performed in 57%.The median follow-up was 44 months (range, 4-146). The acute grade 3 adverse events were observed in 7 patients (25%). One patient died of complications potentially related to chemoradiation. Eight patients (29%) had disease progression at a median of 7.6 months after CRT. First site of progression was local only (14%), local and regional (11%), or distant (4%). Salvage locally directed treatment was performed in 3 of 4 patients with local-only recurrence. The 3-year overall survival, progression-free, and disease-specific rates were 78%, 62%, and 81%, respectively. Conclusion: CRT is a safe and effective curative treatment strategy for select patients with clinical T1N0M0 esophageal adenocarcinoma.

Abstract Background Small cell lung cancer (SCLC) can recur in the brain after whole-brain irradiation (WBI). We documented outcomes after treatment of such recurrences and sought predictors of local control and overall survival (OS). Materials and methods Eighty-five patients with SCLC and brain recurrence after prophylactic or therapeutic WBI in 1998–2015 were identified and data were extracted from the medical records. Survival was estimated with the Kaplan-Meier method, and univariate and multivariate Cox proportional hazards modeling was used to identify factors associated with OS or further brain progression. Results Brain recurrence was treated by stereotactic radiosurgery (SRS) in 33 patients (39%), repeat WBI in 14 (16%), chemotherapy-only in 16 (19%), and observation in 22 (26%). Median OS time after brain recurrence (OSrec) was 4.3 months for all patients; 6-month OSrec rates were 58% after SRS, 21% after repeat WBI, 50% after chemotherapy-only, and 5% after observation (P

Mouse models of gastroesophageal junction (GEJ) cancer strive to recapitulate the intratumoral heterogeneity and cellular crosstalk within patient tumors to improve clinical translation. GEJ cancers remain a therapeutic challenge due to the lack of a reliable mouse model for preclinical drug testing. In this study, a novel patient-derived orthotopic xenograft (PDOX) was established from GEJ cancer via transabdominal surgical implantation. Patient tumor was compared to subcutaneously implanted patient-derived tumor xenograft (PDX) and PDOX by Hematoxylin and Eosin staining, immunohistochemistry and next-generation sequencing. Treatment efficacy studies of radiotherapy were performed. We observed that mechanical abrasion of mouse GEJ prior to surgical implantation of a patient-derived tumor in situ promotes tumor engraftment (100%, n=6). Complete PDOX engraftment was observed with rapid intra- and extraluminal tumor growth, as evidenced by magnetic resonance imaging. PDOXs contain fibroblasts, tumor-associated macrophages, immune and inflammatory cells, vascular and lymphatic vessels. Stromal hallmarks of aggressive GEJ cancers are recapitulated in a GEJ PDOX mouse model. PDOXs demonstrate tumor invasion into vasculature and perineural space. Next-generation sequencing revealed loss of heterozygosity with very high allelic frequency in NOTCH3, TGFB1, EZH2 and KMT2C in the patient tumor, the subcutaneous PDX and the PDOX. Immunohistochemical analysis of Her2/neu (also known as ERBB2), p53 (also known as TP53) and p16 (also known as CDKN2A) in PDX and PDOX revealed maintenance of expression of proteins found in patient tumors, but membranous EGFR overexpression in patient tumor cells was absent in both xenografts. Targeted radiotherapy in this model suggested a decrease in size by 61% according to Response Evaluation Criteria in Solid Tumors (RECIST), indicating a partial response to radiation therapy. Our GEJ PDOX model exhibits remarkable fidelity to human disease and captures the precise tissue microenvironment present within the local GEJ architecture, providing a novel tool for translating findings from studies on human GEJ cancer. This model can be applied to study metastatic progression and to develop novel therapeutic approaches for the treatment of GEJ cancer. This article has an associated First Person interview with the first author of the paper.

18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is widely used for cancer staging before treatment and detection of recurrence during post-treatment surveillance. It is increasingly being recognised that tumour FDG uptake values may not only be prognostic, but could have predictive value to assess for treatment response during and after neoadjuvant therapy in oesophageal cancer (OC). This review focusses on the available evidence concerning the prognostic or predictive role of FDG-PET and evaluates the potential value of FDG-PET in guiding treatment decisions in OC. The correlation between pretreatment maximum standardised uptake value (SUVmax) and prognosis has been demonstrated by multiple studies, although the results are inconsistent and sometimes conflicting. With regard to the predictive value for FDG-PET, post-SUVmax after neoadjuvant chemotherapy appears to hold better promise compared to chemoradiotherapy due to the confounding effect of radiation oesophagitis. Since a number of studies have demonstrated that FDG-PET can discriminate responders from non-responders to induction chemotherapy, the predictive value of FDG-PET imaging was evaluated prospectively and the initial results of CALGB 80803 suggested that changing chemotherapy regimen based on FDG-PET response to induction chemotherapy may improve pathologic complete response rate in PET non-responders when an alternative chemotherapy is used. Furthermore, additional research has suggested that FDG-PET response after induction chemotherapy or neoadjuvant chemotherapy may enrich a patient subset who may potentially avoid subsequent surgery after chemoradiotherapy. However, the majority of reports published on FDG-PET in OC are limited to small, retrospective, and single-institutional studies. Therefore, much of the current evidence-to-date is still hypothesis-generating and would require vigorous validation before FDG-PET could become part of routine clinical practice to direct treatment decisions.

Purpose: In patients with esophageal cancer (EC), intensity modulated radiation therapy (IMRT) improves dose sparing to the heart and lung, with some evidence showing clinical benefit. Herein, we report our cumulative clinical experience with the use of IMRT for EC. Methods and materials: This is a retrospective analysis of 587 patients with nonmetastatic EC who were treated consecutively with IMRT from January 2004 to June 30, 2013. All patients with stage I-IVA (American Joint Committee on Cancer 2002) received concurrent chemoradiation therapy either preoperatively or definitively. The Kaplan-Meier method was used to compute overall survival (OS) and locoregional recurrence-free survival and disease-free survival. The Common Terminology Criteria for Adverse Events, Version 4.0 were used to grade acute and subacute complications. Results: The median radiation dose was 50.4 Gy in 28 daily fractions. As of July 2015, the median follow-up was 31.4 months (range, 2.9-130.7 months) for all patients and 61.8 months (range, 7.7-130.7 months) for survivors. The median OS was 38.9 months, and the 1-, 3-, and 5-year OS rates were 86.7%, 51.8%, and 41.2%, respectively. The 1-, 3-, and 5-year locoregional recurrence-free survival rates were 77.6%, 68.2%, and 66.1%, respectively, and the 1-, 3-, and 5-year disease-free survival rates were 58.6%, 43.7%, and 41.4%, respectively. Outcomes for both trimodality and bimodality treated patients were better than the outcomes reported in the literature. Eight patients (1.4%) experienced grade ≥3 pneumonitis, and 74 patients (13%) developed grade ≥3 esophagitis. For patients who underwent surgery, the most common postoperative complications were pneumonia (9.6%), anastomotic leakage (11.1%), and atrial fibrillation (12.5%). Conclusions: This is the largest, single institutional study to date on the long-term outcomes of treatment with IMRT for EC. For photon-based radiation therapy, IMRT yields excellent outcomes and should be considered for the treatment of EC.

Purpose: Intensity-modulated proton therapy (IMPT) is an emerging advanced radiation technique. Although dosimetric studies demonstrate the superiority of IMPT for improving target conformity and reducing unnecessary dose to critical normal tissues, clinical experience is limited. We aim to describe our preliminary experience implementing IMPT concurrently with chemotherapy in esophageal carcinoma (EC). Methods and materials: From May 2011 through February 2016, 19 patients with EC (median age, 73 years) were treated with IMPT using 180 to 250 MV protons with a median dose of 50.4 Gy relative biological effectiveness in 28 fractions concurrently with chemotherapy. Beam arrangement was most commonly in the posteroanterior and bilateral posterior oblique beams. The Kaplan-Meier method was used to assess survival outcomes. Treatment-related toxicities were evaluated using the Common Terminology Criteria for Adverse Events, version 4.0. Results: Single-field and multifield optimization was performed in 13 and 6 patients, respectively. The average gross tumor volume was 69.1 cm3; mean lung and heart dose delivered were 4.94 and 7.86 Gy, respectively; and the maximal spinal cord dose was 32.81 Gy. Clinical complete response was achieved in 84%. Only 4 patients underwent surgery. The most common grade 3 acute toxicities were esophagitis and fatigue (3 patients). Grade 3 esophageal stricture occurred in 1 patient. With a median follow-up time of 17 months, overall survival was 39.2 months, with 1-year overall survival, locoregional recurrence-free survival, and distant metastasis-free survival rates of 100%, 88.8%, and 72.9%, respectively. Locoregional and distant failures occurred in 3 and 5 patients, respectively. Conclusions: IMPT is an effective treatment for EC, with high tumor response, good local control, and acceptable acute toxicity.

Purpose: The efficiency of radiation delivery via volumetric modulated arc therapy (VMAT) is indisputable, but outcomes after VMAT for thoracic esophageal carcinoma are largely unknown. Methods and materials: We retrospectively analyzed 65 patients with thoracic esophageal cancer who received VMAT to 50.4 Gy (range, 45-50.4 Gy) with concurrent chemotherapy from November 2012 to March 2016 at a single tertiary cancer center. We then used propensity score matching to match these 65 patients with 130 other patients treated with step-and-shoot intensity modulated radiation therapy (ssIMRT) and concurrent chemotherapy. Differences in continuous and categorical variables were examined with independent-sample t or Wilcoxon tests and χ2 tests. Results: Dosimetrically, VMAT had a higher conformity index (87.75 ± 10.70 VMAT vs 83.20 ± 9.42 ssIMRT, P = .003), a higher heart V5, and a lower V50 than ssIMRT, but lung V5-20, heart V30, heart V40, cordmax, and homogeneity index were similar. At median follow-up intervals of 14.3 months (range, 3.8-34.5 months) for VMAT and 31.8 months (range, 1.8-117.2 months) for ssIMRT, overall survival rates were similar between the treatments (93.5% VMAT vs 91.5% ssIMRT at 1 year; 60.0% VMAT and 61.4% ssIMRT at 2 years; P = .868). Recurrence-free survival rates were similar (73.3% VMAT vs 79.5% ssIMRT at 1 year, 59.9% VMAT and 61.8% ssIMRT at 2 years; P = .614), as were pathologic complete response rates (31.2% VMAT vs 23.3% ssIMRT; P = .41) and toxicity and postoperative complications (radiation pneumonitis 9% VMAT vs 15.4% ssIMRT; pericardial effusion 2% VMAT vs 7% ssIMRT; esophageal fistula and stricture 9% VMAT vs 13% ssIMRT; all P > .05). Conclusion: Compared with ssIMRT, VMAT had better target conformity with similar organ sparing and comparable rates of survival, recurrence, and toxicity. These results suggest that VMAT can be safe and effective for esophageal cancer.

Background: CDK9 inhibitors are antitumorigenic against solid tumors, including esophageal adenocarcinoma (EAC). However, efficacy of a CDK9 inhibitor combined with 5-fluorouracil (5-FU) and target proteins that are targeted by these agents in EAC are unknown. Methods: The anti-EAC efficacy of a new CDK9 inhibitor, BAY1143572, with and without 5-FU was assessed in vitro and in xenograft models in athymic nu/nu mice. Synergy between BAY1143572 and 5-FU in inhibiting cell proliferation was analyzed by calculating the combination index using CompuSyn software. Potential targets of BAY1143572 and 5-FU were identified by reverse-phase protein array. The effects of BAY1143572 and 5-FU on MCL-1 in vitro were analyzed by Western blotting, quantitative real-time polymerase chain reaction, and chromatin immunoprecipitation assay. MCL-1 protein expression in tumors from patients with locoregional EAC treated with chemoradiation and surgery was assessed by immunohistochemistry. Results: BAY1143572 had dose-dependent antiproliferative and proapoptotic effects and demonstrated synergy with 5-FU against EAC in vitro . The median volumes of FLO-1 and ESO-26 xenografts treated with 5-FU plus BAY114352 were significantly smaller than those of xenografts treated with either agent alone ( p