Association of Immune-Related Adverse Events With Efficacy of Atezolizumab in Patients With Non-Small Cell Lung Cancer: Pooled Analyses of the Phase 3 IMpower130, IMpower132, and IMpower150 Randomized Clinical Trials.

Importance: Immune-related adverse events (irAEs) arising from immune checkpoint inhibitor (ICI) cancer therapy may potentially predict improved outcomes. Objective: To evaluate the association between irAEs and atezolizumab efficacy in patients with advanced non-small cell lung cancer (NSCLC) using pooled data from 3 phase 3 ICI studies. Design, Setting, and Participants: IMpower130, IMpower132, and IMpower150 were phase 3, multicenter, open-label, randomized clinical trials to evaluate the efficacy and safety of chemoimmunotherapy combinations involving atezolizumab. Participants were chemotherapy-naive adults with stage IV nonsquamous NSCLC. These post hoc analyses were conducted during February 2022. Interventions: Eligible patients were randomly assigned 2:1 to receive atezolizumab with carboplatin plus nab-paclitaxel, or chemotherapy alone (IMpower130); 1:1 to receive atezolizumab with carboplatin or cisplatin plus pemetrexed, or chemotherapy alone (IMpower132); and 1:1:1 to receive atezolizumab plus bevacizumab plus carboplatin and paclitaxel, atezolizumab plus carboplatin and paclitaxel, or bevacizumab plus carboplatin and paclitaxel (IMpower150). Main Outcomes and Measures: Pooled data from IMpower130 (cutoff: March 15, 2018), IMpower132 (cutoff: May 22, 2018), and IMpower150 (cutoff: September 13, 2019) were analyzed by treatment (atezolizumab-containing vs control), irAE status (with vs without), and highest irAE grade (1-2 vs 3-5). To account for immortal bias, a time-dependent Cox model and landmark analyses of irAE occurrence at 1, 3, 6, and 12 months from baseline were used to estimate the hazard ratio (HR) of overall survival (OS). Results: Of 2503 randomized patients, 1577 were in the atezolizumab-containing arm and 926 were in the control arm. The mean (SD) age of patients was 63.1 (9.4) years and 63.0 (9.3) years, and 950 (60.2%) and 569 (61.4%) were male, respectively, in the atezolizumab arm and the control arm. Baseline characteristics were generally balanced between patients with irAEs (atezolizumab, n = 753; control, n = 289) and without (atezolizumab, n = 824; control, n = 637). In the atezolizumab arm, OS HRs (95% CI) in patients with grade 1 to 2 irAEs and grade 3 to 5 irAEs (each vs those without irAEs) in the 1-, 3-, 6-, and 12-month subgroups were 0.78 (0.65-0.94) and 1.25 (0.90-1.72), 0.74 (0.63-0.87) and 1.23 (0.93-1.64), 0.77 (0.65-0.90) and 1.1 (0.81-1.42), and 0.72 (0.59-0.89) and 0.87 (0.61-1.25), respectively. Conclusions and Relevance: In this pooled analysis of 3 randomized clinical trials, longer OS was observed in patients with vs without mild to moderate irAEs in both arms and across landmarks. These findings further support the use of first-line atezolizumab-containing regimens for advanced nonsquamous NSCLC. Trial Registration: ClinicalTrials.gov Identifiers: NCT02367781, NCT02657434, and NCT02366143.

Prognostic and predictive biomarkers for response to neoadjuvant chemoradiation in esophageal adenocarcinoma.

BACKGROUND: Esophageal adenocarcinoma is a lethal disease. For locally advanced patients, neoadjuvant chemoradiotherapy followed by surgery is the standard of care. Risk stratification relies heavily on clinicopathologic features, particularly pathologic response, which is inadequate, therefore establishing the need for new and reliable biomarkers for risk stratification. METHODS: Thirty four patients with locally advanced esophageal adenocarcinoma were analyzed, of which 21 received a CROSS regimen with carboplatin, paclitaxel, and radiation. Capture-based targeted sequencing was performed on the paired baseline and post-treatment samples. Differentially mutated gene analysis between responders and non-responders of treatment was performed to determine predictors of response. A univariate Cox proportional hazard regression was used to examine associations between gene mutation status and overall survival. RESULTS: A 3-gene signature, based on mutations in EPHA5, BCL6, and ERBB2, was identified that robustly predicts response to the CROSS regimen. For this model, sensitivity was 84.6% and specificity was 100%. Independently, a 9 gene signature was created using APC, MAP3K6, ETS1, CSF3R, PDGFRB, GATA2, ARID1A, PML, and FGF6, which significantly stratifies patients into risk categories, prognosticating for improved relapse-free (p = 4.73E-03) and overall survival (p = 3.325E-06). The sensitivity for this model was 73.33% and the specificity was 94.74%. CONCLUSION: We have identified a 3-gene signature (EPHA5, BCL6, and ERBB2) that is predictive of response to neoadjuvant chemoradiotherapy and a separate prognostic 9-gene classifier that predicts survival outcomes. These panels provide significant potential for personalized management of locally advanced esophageal cancer.

Chemotherapy use in early stage anal canal squamous cell carcinoma and its impact on long-term overall survival,,.

BACKGROUND: The standard of care for non-metastatic squamous cell carcinoma of the anal canal (SCCA) is concurrent chemoradiotherapy. It is postulated that chemotherapy could be omitted for the earliest stages without worsening outcomes. METHODS: We queried the NCDB from 2004-2016 for patients with cT1N0M0 SCCA treated non-operatively with radiation, with and without chemotherapy, and at least two months of follow-up. Of the 2,959 patients meeting eligibility, 92% received chemotherapy (n = 2722) and 8% (n = 237) did not. Most patients were white (n = 2676), female (n = 2019), had private insurance (n = 1507) and were treated in a comprehensive cancer center (n = 1389). Average age was 58.5 years. RESULTS: Predictors of chemotherapy omission were age > 58 years (OR 0.66, 95% CI [0.49-0.90], P = 0.0087), higher comorbidity score (OR 0.62, 95% CI [0.38-0.99], P = 0.0442), African American race (OR 0.57, 95% CI [0.36-0.90], P = 0.0156) and treatment at the start of the study period (OR 1 for years 2004-2006). HR for single-agent chemotherapy was 0.70 (95% CI [0.50-0.96], P = 0.0288) and 0.48 for multi-agent (95% CI [0.38-0.62], P <0.0001). Overall survival was 86% in those that received chemotherapy vs 65% in those who did not (P <0.0001). CONCLUSIONS: In conclusion, patients with early-stage squamous cell cancer of the anus who are treated with combination chemoradiation continue to demonstrate better overall survival than those who undergo radiotherapy alone.

Intratumoral immunotherapy with STING agonist, ADU-S100, induces CD8+ T-cell mediated anti-tumor immunity in an esophageal adenocarcinoma model.

BACKGROUND: Esophageal adenocarcinoma (EAC) is a deadly disease with limited treatment options. STING is a transmembrane protein that activates transcription of interferon genes, resulting in stimulation of APCs and enhanced CD8+ T-cell infiltration. The present study evaluates STING agonists, alone and in combination with radiation to determine durable anticancer activity in solid tumors. MATERIALS AND METHODS: Esophagojejunostomy was performed on rats to induce reflux leading to the development of EAC. At 32 weeks post operatively, rats received intratumorally either 50 µg STING (ADU-S100) or placebo (PBS), +/- 16Gy radiation. Drug activity was evaluated by pre- and post- treatment MRI, histology, immunofluorescence and RT-PCR. RESULTS: Mean MRI tumor volume decreased by 30.1% and 50.8% in ADU-S100 and ADU-S100 + radiation animals and increased by 76.7% and 152.4% in placebo and placebo + radiation animals, respectively (P < 0.0001). Downstream gene expression, pre- to on- and post- treatment, demonstrated significant upregulation of IFNß, TNFα, IL-6, and CCL-2 in the treatment groups vs. placebo. On- or post- treatment, radiation alone, ADU-S100 alone, and ADU-S100 + radiation groups demonstrated enhanced PD-LI expression, induced by upregulation of CD8+ T-cells (p < 0.01). CONCLUSIONS: ADU-S100 +/- radiation exhibits potent antitumor activity and a promising immunomodulatory profile in a de novo EAC.

Factors associated with treatment receipt and overall survival for patients with locally advanced large cell neuroendocrine carcinoma of the lung: A National Cancer Database analysis.

PURPOSE: Large cell neuroendocrine carcinoma (LCNEC) is a rare pulmonary malignancy with clinicopathologic features of both non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Given the paucity of available data regarding LCNEC management, we queried the National Cancer Database (NCDB) to describe trends in management, identify predictors of treatment receipt, and compare outcomes in patients receiving chemotherapy (ChT) and chemoradiotherapy (CRT). METHODS: We identified patients with locally advanced (Stage III) LCNEC of the lung treated with definitive ChT or CRT between the years of 2004-2015. Odds ratios were calculated to determine predictors of CRT receipt. Multivariable cox regression was used to determine predictors of overall survival. RESULTS: Using the above criteria, 5797 patients were identified, 54 % of whom received CRT (n = 3153) while 46 % (n = 2644) received ChT alone. Most patients had T4 (35 %) and N2 (59 %) disease. Median overall survival was 11.9 months (11.3-12.6) in patients receiving ChT compared to 16.1 months (15.4-16.9) in patients receiving CRT (p < 0.0001). Overall survival at 1, 3, and 5 years was 50 %, 20 %, and 13 % versus 60 %, 27 %, and 18 %, in patients receiving ChT and CRT, respectively. Older patients and those with higher comorbidity scores were less likely to receive CRT; whereas patients with higher education level, treatment receipt at an academic/research program facility, N2 disease, and later treatment year were more likely to receive CRT. On multivariable analysis, older age, greater comorbidity score, presence of N2 disease, and presence of T4 disease were all associated with decreased OS. CRT receipt was an independent predictor of increased overall survival. CONCLUSIONS: Definitive CRT was an independent predictor of increased overall survival in patients with locally advanced LCNEC of the lung. Findings from our study may help guide potential areas of future investigation to help define an ideal treatment approach for LCNEC.

Definitive Chemoradiation for Rectal Cancer: Is There a Role for Dose Escalation? A National Cancer Database Study.

BACKGROUND: Surgery remains the standard of care in rectal cancer. Select patients will not undergo surgery for reasons such as medical inoperability or a watch-and-wait approach and instead are managed with definitive chemoradiation. OBJECTIVE: We used the National Cancer Database to identify overall survival and predictors thereof in the nonoperative management of patients with rectal cancer. DESIGN: This was a retrospective review. SETTINGS: This study used deidentified data from the National Cancer Database. PATIENTS: We queried the national cancer database from 2004 to 2014 for stage 1 to 3 rectal adenocarcinoma treated with only chemotherapy and radiation to definitive doses. Dose escalated therapy was defined as >54 Gy. MAIN OUTCOME MEASURES: Univariable and multivariable analyses were performed to identify sociodemographic, treatment, and tumor characteristics predictive of dose escalation and overall survival. Propensity-adjusted Cox proportional hazard ratios for survival were used to account for indication bias. RESULTS: Among the 6311 patients eligible for the study, 11% were treated with doses >54 Gy. Earlier stage and increased age/comorbidity patients were more likely to receive dose escalation, and patients with more recent treatment and treatment at an academic facility were less likely. The median follow-up time was 31 months (range, 2-154 mo). Three- and 5-year overall survival rates for all patients were 60% and 46%. Patients treated with dose escalation had a median survival of 33 months compared with 56 months for those treated with ≤54 Gy (p < 0.0001). LIMITATIONS: The main limitation is the inherent selection bias present in National Cancer Database studies. Important treatment details and outcomes as they relate to a definitive chemoradiation approach in rectal cancer are lacking. Salvage therapy was also not recorded, which in this population could be surgery. CONCLUSIONS: In this analysis, dose escalation in the nonoperative management of rectal cancer was associated with a lower overall survival compared with more conventional doses. Careful patient selection and enrollment on appropriate clinical trials may be warranted in the nonoperative setting. See Video Abstract at http://links.lww.com/DCR/B15. LA QUIMIORRADIACIÓN DEFINITIVA PARA EL CÁNCER RECTAL: ¿HAY LUGAR PARA EL AUMENTO DE LA DOSIS? UN ESTUDIO DE BASE DE DATOS NACIONAL DEL CÁNCER:: La cirugía sigue siendo el estándar en el tratamiento del cáncer rectal. Algunos pacientes no son quirúrgicos por razones como, no ser operables o con el enfoque de ver y esperar, y en su lugar son tratados con la quimiorradiación definitiva.Utilizamos la base de datos nacional del cáncer para identificar la supervivencia general y los factores predictivos de la misma, en el tratamiento no quirúrgico de pacientes con cáncer rectal.Esta fue una revisión retrospectiva.Utilizamos los datos identificados en la base de datos nacional del cáncer.Se consultó la base de datos nacional del cáncer del 2004-2014, para adenocarcinoma rectal en estadio 1-3, tratada únicamente con quimioterapia y radiación hasta la dosis definitiva. La terapia de aumento de la dosis se definió como >54 Gy.Se realizaron análisis univariables y multivariables para identificar características sociodemográficas, de tratamiento y predictivas del aumento de la dosis y supervivencia en general. Los índices de riesgo proporcionales de Cox ajustados a la propensión para la supervivencia, se utilizaron para tener en cuenta el sesgo de indicación.Entre los 6311 pacientes elegibles para el estudio, el 11% fue tratado con dosis >54 Gy. Los pacientes en estadios tempranos y con mayor edad/comorbilidad, tenían más probabilidades de recibir aumento de la dosis, y menos propensos los pacientes con tratamientos recientes y de centros académicos. El tiempo medio de seguimiento fue de 31 meses (2-154 meses). Las tasas de supervivencia global de tres y cinco años para todos los pacientes, fueron respectivamente del 60% y 46%. Los pacientes tratados con aumento de la dosis, tuvieron una supervivencia media de 33 meses, en comparación con los 56 meses para los pacientes tratados con ≤54 Gy (p < 0,0001).La principal limitación es el inherente sesgo en la selección, presente en los estudios de la base de datos nacional del cáncer. Faltan los detalles importantes del tratamiento y los resultados en relación con el enfoque definitivo de quimiorradiación en cáncer rectal. Tampoco se registró la terapia de rescate, que en esta población podría ser la cirugía.En este análisis, el aumento de la dosis en el manejo no quirúrgico del cáncer rectal, se asoció con una menor supervivencia global, en comparación con la dosis más convencional. La cuidadosa selección del paciente y la inscripción en los apropiados ensayos clínicos, pueden estar justificados en el entorno no quirúrgico. Vea el Resumen del Video en http://links.lww.com/DCR/B15.

Chemotherapy Versus Supportive Care for Unresected Malignant Pleural Mesothelioma.

BACKGROUND: Management options for unresected malignant pleural mesothelioma (MPM) are largely limited to palliative chemotherapy and best supportive care. This study sought to delineate subgroups most likely to benefit from chemotherapy. PATIENTS AND METHODS: The National Cancer Database was queried for newly-diagnosed unresected sarcomatoid, biphasic, and/or metastatic (M1) MPM. Statistics included Kaplan-Meier overall survival (OS) analysis with and without propensity matching, landmark Kaplan-Meier analysis to address immortal time bias, and multivariable Cox proportional hazards modeling in all patients as well as within histologic/M-classification-based subcohorts. RESULTS: Of 4655 patients (48% chemotherapy, 52% best supportive care), 15%, 27%, and 40% had epithelioid, biphasic, and sarcomatoid disease, respectively; 41% had M1 disease. The median OS in the chemotherapy and BSC cohorts was 10.4 versus 4.8 months (P < .001). OS differences persisted following landmark analysis (P = .038) and propensity matching (P < .001). Chemotherapy was associated with higher OS in M1 cases with unknown histology and M1 epithelioid patients (P < .001 for both). For non-epithelioid cases, chemotherapy was associated with higher OS for M0 (P < .001 for sarcomatoid and biphasic) but not M1 (P > .05 for both) disease. CONCLUSIONS: Chemotherapy may benefit metastatic epithelioid and non-metastatic non-epithelioid MPM to a greater degree than metastatic non-epithelioid disease. Causation, however, is not implied, and careful patient selection in this population cannot be understated.

PI3K/mTOR Dual Inhibitor, LY3023414, Demonstrates Potent Antitumor Efficacy Against Esophageal Adenocarcinoma in a Rat Model.

OBJECTIVE: The purpose of the current study is to determine the efficacy of a PI3K/mTOR dual inhibitor, LY3023414, on established EAC in an in vivo model. BACKGROUND: Esophageal adenocarcinoma (EAC) is a highly lethal cancer with limited treatment options. The PI3K/mTOR pathway is upregulated in EAC and may be a target for novel therapies. METHODS: Esophagojejunostomy was performed on Sprague-Dawley rats to induce carcinogenesis, and LY3023414 was cyclically administered intraperitoneally between 32 and 40 weeks postsurgery to treatment animals. Magnetic resonance imaging (MRI) and histology were used to determine clinical response. Immunohistochemistry, immunofluorescence, and Western blot were used to validate apoptosis by cleaved caspase-3, proliferation by Ki67, and pathway inhibition, respectively. RESULTS: Mean MRI tumor volume increased by 109.2% in controls (n = 32) and decreased by 56.8% in treatment animals (n=17) (P < 0.01). Treatment with LY3023414 demonstrated tumor volume increase in 0% (control = 46.4%) (P < 0.01), decrease in 58.8% (control = 7.1%) (P < 0.01), and stable volume in 41.2% (control = 46.4%) (P = 0.77). EAC prevalence in controls increased by 25%; whereas, prevalence in treatment animals decreased by 29.4% (P < 0.01). Approximately, 75% of treatment animals presenting with residual masses on MRI had a histological response >50%. Increased apoptosis by cleaved caspase-3 (P = 0.03) and decreased proliferation by Ki67 (P < 0.01) were demonstrated in the treatment arm, when compared with the control arm. On Western blot analysis of pathway checkpoints, p-mTOR (p=0.03) and PI3K-α (P = 0.04) were downregulated in treatment responsive residual tumors, when compared with controls. CONCLUSIONS: LY3023414 demonstrates efficacy against EAC in a preclinical model, establishing the rationale for clinical testing.

Primary tumor microRNA signature predicts recurrence and survival in patients with locally advanced esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) is an aggressive cancer necessitating the development of improved risk stratification tools for personalized care. Previously, microRNAs have been shown to correlate with the progression and prognosis of various cancer types; however, the value in EAC remains largely unexplored. We performed global microRNA profiling on 32 formalin-fixed, paraffin-embedded EAC specimens to identify microRNAs associated with progression. Literature search and pathway analysis further refined output to five significantly deregulated candidate biomarkers. Four of the five microRNAs (miR-652-5p, miR-7-2-3p, miR-3925-3p, and miR-219-3p) were validated by qRT-PCR. Survival outcomes were evaluated in testing set of 26 stage II/III EAC patients to determine the prognostic relevance of the selected microRNAs. In the testing set, miR-652-5p and miR-7-2-3p expressions were significantly associated with progression-free survival (p-value = .00771 and p-value = .00293). The highest area under receiver operating characteristic (ROC) curve was 0.8212 for the combination of miR-652-5p and miR-7-2-3p. Collectively, our findings demonstrated that the miR-652-5p/miR-7-2-3p signature may serve as a promising prognostic marker in patients with locally advanced EAC.