First-line Chemoradiation Research Articles

A phase 1b/2 study of nanatinostat and valganciclovir in patients with advanced Epstein-Barr virus positive (EBV+) solid tumors and in combination with pembrolizumab in patients with recurrent/metastatic nasopharyngeal carcinoma (RM-NPC).

TPS6107 Background: Epstein-Barr virus (EBV) is linked to the development and pathogenesis of nasopharyngeal carcinoma (NPC). Most patients present with advanced stage disease at diagnosis (Li 2014); first-line chemoradiation is commonly followed by recurrence and poor prognosis emphasizing the need for new treatment options. Targeting EBV in NPC represents a novel therapeutic approach. EBV is predominantly latent in NPC; pre-clinical studies demonstrated that induction of the viral lytic phase by histone deacetylase inhibitors (HDACi) renders EBV+ tumor cells susceptible to the cytotoxic activity of ganciclovir (GCV) (Hui 2016). Nanatinostat (Nstat), a potent Class-I HDACi, induces the expression of the lytic BGLF4 protein kinase in EBV+ tumor cells, which activates the nucleoside analog GCV via phosphorylation. Phosphorylated GCV becomes incorporated into the cellular DNA causing chain termination and apoptosis. The all-oral combination of Nstat and valganciclovir (VGCV), a pro-drug of GCV, has demonstrated favorable safety and preliminary efficacy in a phase 1/2 study in patients with recurrent EBV+ lymphoma (NCT03397706). This phase 1b/2, open-label, multicenter study will evaluate the safety, tolerability, pharmacokinetics, and preliminary activity of Nstat + VGCV in patients with advanced EBV+ solid tumors. Additionally, the combination of pembrolizumab together with Nstat + VGCV will be evaluated in recurrent/metastatic NPC (RM-NPC) patients. NPC frequently exhibits high PD-L1 expression levels; however, PD-1 inhibitors resulted in limited response rates ranging from 20-30% in the RM-NPC setting. Methods: Phase 1b utilizes a 3+3 dose escalation design to determine the recommended Phase 2 dose (RP2D) of Nstat + VGCV in patients with EBV+ RM-NPC. In Phase 2, up to 60 patients with EBV+ RM-NPC will be randomized 1:1 to receive Nstat + VGCV at the RP2D with or without pembrolizumab to evaluate safety, tolerability, overall response rate, and potential pharmacodynamic markers of drug activity, including plasma EBV DNA levels. Additionally, patients with EBV+ solid tumors other than RM-NPC will receive Nstat + VGCV at the RP2D in a separate Phase 1b dose expansion cohort. Patients eligible for the phase 1b dose escalation and phase 2 will have EBV+ RM-NPC with 1-3 prior lines of platinum-based chemotherapy and no available curative therapies. Patients with advanced EBV+ non-NPC solid tumors (gastric cancer, lymphoepithelioma-like carcinoma, leiomyosarcoma) and no curative therapies are eligible for the phase 1b expansion cohort. All patients must have measurable disease per RECIST v1.1 and adequate bone marrow, liver, and renal function. Enrollment began in January 2022. Clinical trial information: NCT05166577.

Diagnostic efficiency of whole-body 18F-FDG PET/MRI, MRI alone, and SUV and ADC values in staging of primary uterine cervical cancer

BackgroundThe use of PET/MRI for gynecological cancers is emerging. The purpose of this study was to assess the additional diagnostic value of PET over MRI alone in local and whole-body staging of cervical cancer, and to evaluate the benefit of standardized uptake value (SUV) and apparent diffusion coefficient (ADC) in staging.MethodsPatients with histopathologically-proven cervical cancer and whole-body 18F-FDG PET/MRI obtained before definitive treatment were retrospectively registered. Local tumor spread, nodal involvement, and distant metastases were evaluated using PET/MRI or MRI dataset alone. Histopathology or clinical consensus with follow-up imaging were used as reference standard. Tumor SUVmax and ADC were measured and SUVmax/ADC ratio calculated. Area under the curve (AUC) was determined to predict diagnostic performance and Mann-Whitney U test was applied for group comparisons.ResultsIn total, 33 patients who underwent surgery (n = 23) or first-line chemoradiation (n = 10) were included. PET/MRI resulted in higher AUC compared with MRI alone in detecting parametrial (0.89 versus 0.73), vaginal (0.85 versus 0.74), and deep cervical stromal invasion (0.96 versus 0.74), respectively. PET/MRI had higher diagnostic confidence than MRI in identifying patients with radical cone biopsy and no residual at hysterectomy (sensitivity 89% versus 44%). PET/MRI and MRI showed equal AUC for pelvic nodal staging (both 0.73), whereas AUC for distant metastases was higher using PET/MRI (0.80 versus 0.67). Tumor SUVmax/ADC ratio, but not SUVmax or ADC alone, was significantly higher in the presence of metastatic pelvic lymph nodes (P < 0.05).ConclusionsPET/MRI shows higher accuracy than MRI alone for determining local tumor spread and distant metastasis emphasizing the added value of PET over MRI alone in staging of cervical cancer. Tumor SUVmax/ADC ratio may predict pelvic nodal involvement.

Abstract IA05: Signaling networks in small-cell lung cancer

Abstract SCLC is a lethal neuroendocrine (NE) cancer that accounts for ~15% of all lung cancers and causes ~250,000 deaths worldwide each year. SCLC is linked to heavy cigarette smoking and exposure to carcinogens. Unfortunately, the number of SCLC-related deaths continues to rise. A major clinical challenge is that ~70% of SCLC patients have disseminated disease at the time of diagnosis; these patients have a 5-year survival of &amp;lt;1%. Even patients with localized disease at diagnosis have dismal survival rates. A second major challenge is that treatments for SCLC are inefficient and have remained mostly unchanged for the past 30 years, with no new approved treatments since 1996 and no approved targeted therapies. SCLC is managed with first-line chemoradiation. Patients usually respond well initially, but almost all relapse within months. There is a need to better understand the mechanisms underlying the aggressive growth and spread of SCLC and its rapid chemoresistance. At a gross level, SCLC tumors are quite “homogeneous” histologically (with fields of similar-looking small, blue, round cancer cells) and genetically (with near-ubiquitous loss of the Rb and p53 tumor suppressors). However, accumulating evidence has recently highlighted several levels of heterogeneity, and it has become clear that a better characterization and understanding of both genetic and epigenetic heterogeneity during SCLC progression will be critical to identify new therapeutic options. We have used mouse genetics combined with genomic and proteomic approaches to identify key signaling pathways that are implicated in the expansion of SCLC cell populations. In particular, we have recently identified kinases and phosphatases that control the expansion of long-term propagating cells (aka cancer stem cells) in SCLC. Citation Format: Julien Sage. Signaling networks in small-cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA05.

First-line chemotherapy versus chemoradiation for resectable distal esophageal adenocarcinoma.

331 Background: Multiple randomized controlled trials have shown that both neoadjuvant chemotherapy (CT) and chemoradiation (CRT) convey survival benefit as compared to upfront surgery in patients with esophageal adenocarcinoma. However, international practice remains variable. Therefore, the present study compares the outcomes of first-line CT to CRT for patients with adenocarcinoma arising from the distal esophagus. Methods: Patients with clinical stage T2-T3, N0-N+ esophageal adenocarcinoma originating from the distal esophagus who received first-line CT or CRT were identified from the National Cancer Data Base (2006-2014). Propensity-score were created for the odds of receiving CRT. Patients were matched 1:1 based on propensity score. Subset analysis was performed in patients who underwent esophagectomy. Pathological complete response was defined as ypT0N0M0. Results: In total, 709 and 8,877 patients who received first-line CT and CRT were identified, respectively. CT was associated with stage cT2 (27.2% vs. 23.3%; p = 0.017), and treatment at a high-volume center (27.2% vs. 20.2%; p &lt; 0.001). After matching, resection rates were comparable for patients who received first-line CT and CRT (62.2% vs. 63.7%; p = 0.545). However, median overall survival was slightly lower for patients who receive CT compared to CRT (23.7 vs. 28.4 months; p = 0.044). Among patients who underwent esophagectomy, time to surgery (135 vs. 134 days; p = 0.689) and median overall survival (37.0 vs. 40.5 months; p = 0.630) was similar between matched cohorts. However, complete response (15.8% vs. 25.8%; p &lt; 0.001) and negative margin (94.3% vs. 88.9%; p = 0.004) rates were significantly lower after CT compared to CRT. Conclusions: In patients with esophageal adenocarcinoma, first-line CRT results in significantly higher pathological complete response rates, negative resection margins rates, and improved survival. These findings suggest that first-line CRT is preferable over CT when tolerated in patients with esophageal adenocarcinoma.

ACTR-59. A PHASE 1 STUDY OF BPM31510 PLUS VITAMIN K IN SUBJECTS WITH HIGH-GRADE GLIOMA THAT HAS RECURRED ON A BEVACIZUMAB-CONTAINING REGIMEN

Abstract BACKGROUND High-grade gliomas (HGG) are characterized by dysregulated metabolism, utilizing glycolysis for energy production to support unrestricted growth. BPM 31510, an ubidecarenone (coenzyme Q10) containing lipid nanodispersion, causes a switch in cancer energy sourcing from glycolysis towards mitochondrial oxidative phosphorylation in vitro, reversing the Warburg effect and suggesting potential as an anti-tumor agent. The current study is a phase I study of BPM31510 + vitamin K in GB with tumor growth after bevacizumab (BEV). METHODS This is an open-label phase I study of BPM31510 continuous infusion with weekly vitamin K (10mg IM) in HGG patients using an mTPI design, starting at 110mg/kg, allowing for a single dose de-escalation and 2 dose-escalations. Patients had received first-line ChemoRadiation and were in recurrence following a BEV containing regimen. RESULTS 9 eligible and evaluable patients completed the 28 day DLT period. 8 patients had primary GB, 1 had anaplastic astrocytoma with confirmed pathologic transformation to GB. Median age was 55 years (27–67) and median KPS 70 (60–90) at enrollment. 4 patients were treated at the highest dose 171mg/kg, where there was a single DLT: Grade 3 AST &amp; ALT. The most common grade 1–2 AEs possibly, probably or definitely related to drug were elevated AST, rash, and fatigue, each occurring in 3 patients. Median OS for 9 eligible/evaluable patients was 128 days (95% CI: 48–209) while PFS was 34 days (CI of mean 8.9). 3 patients are currently alive; 2 patients have survived &gt;1 year. PK/PD data are being processed and will be presented. CONCLUSION This study confirms that BPM 31510 + vitamin K is safe and feasible in treatment-refractory HGG patients. Though this study demonstrates safety at 171mg/kg, the proposed dose for future studies in GB, based on additional pre-clinical and non-GB clinical data is 88mg/kg.

Ipilimumab and Bevacizumab in Glioblastoma

The median survival in glioblastoma is just over a year, with no standard second-line therapy. Ipilimumab is an immune checkpoint inhibitor that activates the anti-tumour immune response by cytotoxic T-lymphocyte antigen-4 blockade. There is significant evidence supporting its role in the treatment of malignant melanoma, including in patients with brain metastases. The addition of the anti-angiogenesis agent, bevacizumab, seems to offer additional benefit and limit the immune-related side-effects of ipilimumab in melanoma. To date there have been no clinical trials investigating this combination in glioblastoma. In this single practice case series, 20 patients with glioblastoma were consented for and treated with ipilimumab and bevacizumab in combination. Safety, tolerability and the response to treatment were reviewed for all patients. Three patients were treated after palliative first-line radiotherapy, one patient after first-line chemoradiation and 16 patients were treated with recurrent disease. Sixty-five per cent of patients completed four cycles of 3 weekly ipilimumab therapy, administered with 2 weekly bevacizumab. Radiographic responses for patients with recurrent disease were evaluated by Response Assessment in Neuro-oncology (RANO) criteria; 31% of patients showed a partial response, 31% had stable disease and 38% had disease progression. The treatment combination was well tolerated, with treatment terminated before completion due to adverse events in two patients. Autoimmune toxicity was manageable with systemic corticosteroid therapy. Ipilimumab and bevacizumab in combination show promising activity with a predictable and manageable toxicity profile, warranting further clinical studies.

Clinical effectiveness of first-line chemoradiation for adult patients with locally advanced non-small cell lung cancer: a systematic review

Clinical effectiveness of first-line chemoradiation for adult patients with locally advanced non-small cell lung cancer: a systematic review

Clinical effectiveness of first-line chemoradiation for adult patients with locally advanced non-small cell lung cancer: a systematic review.

The National Institute for Health and Clinical Excellence has issued guidelines on the treatment of non-small cell lung cancer (NSCLC) and recommends that patients with stage IIIA-IIIB disease who are not amenable to surgery be treated with potentially curative chemoradiation (CTX-RT). This review was conducted as part of a larger systematic review of all first-line chemotherapy (CTX) and CTX-RT treatments for patients with locally advanced or metastatic NSCLC. However, it was considered that patients with potentially curable disease (e.g. stage IIIA) are different from those with advanced disease, who are suitable for palliative treatment only, and therefore the results should be reported separately. To evaluate the clinical effectiveness of first-line CTX in addition to radiotherapy (RT) (CTX-RT vs CTX-RT) for adult patients with locally advanced NSCLC who are suitable for potentially curative treatment. Three electronic databases (MEDLINE, EMBASE and The Cochrane Library) were searched from January 1990 to September 2010. Inclusion criteria comprised adult patients with locally advanced NSCLC, trials that compared any first-line CTX-RT therapy (induction, sequential, concurrent and consolidation) and outcomes of overall survival (OS) and/or progression-free survival (PFS). The results of clinical data extraction and quality assessment were summarised in tables and with narrative description. Direct meta-analyses using OS data were undertaken where possible: sequential CTX-RT compared with concurrent CTX-RT; sequential CTX-RT compared with concurrent/consolidation CTX-RT; and sequential CTX-RT compared with concurrent CTX-RT with or without consolidation. There were not sufficient data to perform meta-analysis on PFS. Of the 240 potentially relevant studies that were published post 2000, 19 met the inclusion criteria and compared CTX-RT with CTX-RT. The results from the OS meta-analysis comparing sequential CTX-RT with concurrent CTX-RT appear to show an OS advantage for concurrent CTX-RT arms over sequential arms; this result is not statistically significant [hazard ratio (HR) 0.79; 95% confidence interval (CI) 0.50 to 1.25)]. The results from the OS meta-analysis comparing sequential CTX-RT with concurrent/consolidation CTX-RT appear to show a statistically significant OS advantage for concurrent/consolidation CTX-RT treatment over sequential treatment (HR 0.68; 95% CI 0.55 to 0.83). The results from the OS meta-analysis comparing sequential CTX-RT with concurrent CTX-RT with or without consolidation appear to show a statistically significant OS advantage for concurrent CTX-RT with or without consolidation over sequential treatment (HR 0.72; 95% CI 0.61 to 0.84). This report provides a summary and critical appraisal of a comprehensive evidence base of CTX-RT trials; however, it is possible that additional trials have been reported since our last literature search. It is disappointing that the quality of the research in this area does not meet the accepted quality standards regarding trial design and reporting. This review identified that the research conducted in the area of CTX-RT was generally of poor quality and suffered from a lack of reporting of all important clinical findings, including OS. The 19 trials included in the systematic review were too disparate to form any conclusions as to the effectiveness of individual CTX agents or types of RT. The focus of primary research should be good methodological quality; appropriate allocation of concealment and randomisation, and comprehensive reporting of key outcomes, will enable meaningful synthesis and conclusions to be drawn. The National Institute for Health Research Health Technology Assessment programme.

Phase II trial of first-line chemoradiotherapy with intensity-modulated radiation therapy followed by chemotherapy for synchronous unresectable distant metastases rectal adenocarcinoma

AimsBased on the hypothesis that first-line chemoradiation followed by chemotherapy was superior for primary tumor and non-inferior for distant lesions compared to chemotherapy alone in synchronous unresectable distant metastases rectal adenocarcinoma, this study was designed to assess the efficacy and safety of this strategy.Materials and methodsThirty two eligible patients received intensity modulated radiation therapy (45 Gy to the pelvis and a concomitant 10 Gy boost to the gross tumor), along with concurrent weekly capecitabine and oxaliplatin. Patients underwent radical surgery if all lesions were visually evaluated as resectable and received chemotherapy for a total of 6 months, whether pre- or post-operatively (definitive therapy group). The remaining patients received 6 months of consolidation chemotherapy followed by maintenance chemotherapy (non-definitive therapy group).ResultsThe toxicities were acceptable, with radiation-induced dermatitis around the anal verge being the most common (18.8%). Fourteen patients underwent surgical resection of the rectal tumor, with 5 (35.7%) experiencing a pathological complete response. Nine out of 14 received definitive treatment, defined as R0 resections of all visible tumors. At a median follow-up of 12 months (range, 4–23 months), 2 cases were evaluated as local failure, and the median overall survival (OS) and progression free survival (PFS) for all 32 patients were 17.5 and 12 months, respectively. OS differed significantly in the definitive and non-definitive therapy groups (p=0.045), and PFS tended to differ (p=0.274).ConclusionIt was demonstrated that the strategy of first-line chemoradiation followed by chemotherapy was effective and tolerable, especially for local control. OS and PFS were superior in patients who did than did not undergo curative therapy.