M. van den Heuvel

A phase III study of belagenpumatucel-L, an allogeneic tumour cell vaccine, as maintenance therapy for non-small cell lung cancer

BACKGROUND Treatment options after first-line chemotherapy are limited in non-small cell lung cancer (NSCLC). Belagenpumatucel-L is a therapeutic vaccine comprised of 4 transforming growth factor (TGF)-β2-antisense gene-modified, irradiated, allogeneic NSCLC cell lines that may be useful for maintenance after initial treatment. METHODS Stage III/IV NSCLC patients who did not progress after platinum-based chemotherapy were randomised 1:1 to receive maintenance belagenpumatucel-L or placebo. Patients were eligible for randomisation between one and four months from the end of induction chemotherapy. The primary endpoint was overall survival. RESULTS This phase III trial enrolled 270 patients in the belagenpumatucel-L arm and 262 in the control arm. Belagenpumatucel-L was well tolerated with no serious safety concerns. There was no difference in survival between the arms (median survival 20.3 versus 17.8months with belagenpumatucel-L versus placebo, respectively; hazard ratio (HR) 0.94, p=0.594). There were also no differences in progression-free survival (4.3months versus 4.0 for belagenpumatucel-L vs placebo, respectively; HR 0.99, p=0.947). A prespecified Cox regression analysis demonstrated that the time elapsed between randomisation and the end of induction chemotherapy had a significant impact on survival (p=0.002) and that prior radiation was a positive prognostic factor (median survival 28.4months with belagenpumatucel-L versus 16.0months with placebo; HR 0.61, p=0.032). CONCLUSIONS Although the overall trial did not meet its survival endpoint, improved survival for belagenpumatucel-L is suggested in patients who were randomised within 12weeks of completion of chemotherapy and in those who had received prior radiation. Further studies of belagenpumatucel-L in NSCLC are warranted.

Immune checkpoint inhibition-related colitis: symptoms, endoscopic features, histology and response to management

Background Immune checkpoint inhibitors are successfully introduced as anticancer treatment. However, they may induce severe immune-related adverse events (irAEs). One of the most frequent irAEs is diarrhoea. The main objective of this study was to analyse symptoms (ie, grade of diarrhoea), endoscopic and histological features and response to management in immune checkpoint inhibition-related colitis (IRC). Patients and methods We retrospectively analysed patients who developed diarrhoea on checkpoint inhibition and therefore underwent an endoscopy and/or were treated with corticosteroids. Patients were treated between August 2010 and March 2016 for metastatic melanoma or non-small cell lung cancer. Severity of IRC was scored using the endoscopic Mayo score and the van der Heide score. Results Out of a cohort of 781 patients, 92 patients were identified who developed diarrhoea and therefore underwent an endoscopy and/or were treated with corticosteroids. Patients were treated with monotherapy anticytotoxic T-lymphocyte antigen-4, antiprogrammed death receptor-1 or a combination of both. All patients had symptoms of diarrhoea (grade 1: 16%; grade 2: 39% and grade 3: 44%). A complete colonoscopy was performed in 62 (67%) patients, of whom 42 (68%) had a pancolitis (≥3 affected segments). Ulcers were seen in 32% of endoscopies. There was no significant correlation between the grade of diarrhoea at presentation and endoscopic severity scores, the presence of ulcers or histological features. In 54 episodes of diarrhoea (56%), patients received one or more cycles infliximab for steroid-refractory colitis. Patients with higher endoscopic severity scores, ulcers and/or a pancolitis needed infliximab more often. Conclusions The correlation between grade of diarrhoea and endoscopic or histological features for severity of colitis is poor. Patients with higher endoscopic severity scores, ulcers or a pancolitis needed the addition of infliximab more often. Therefore, endoscopy may have value in the evaluation of the severity of IRC and may help in decision making for optimal management.

A randomized controlled trial comparing indwelling pleural catheters with talc pleurodesis (NVALT-14)

BACKGROUND Symptomatic malignant pleural effusion (MPE) occurs frequently in patients with metastatic cancer. The associated prognosis is poor and the success rate of talc pleurodesis (TP) is low. Indwelling pleural catheters (IPCs) are commonly inserted when TP has been unsuccessful. METHODS We compared talc pleurodesis with the use of an indwelling pleural catheter in patients with recurrent MPE in a multicenter randomized controlled trial (superiority design). The primary endpoint was improvement from baseline in Modified Borg Score (MBS) 6weeks after randomized treatment. Secondary endpoints were hospitalization days, re-interventions, and adverse events. RESULTS Dyspnea improved significantly (p<0.01) after either treatment, but the magnitude of this improvement did not differ significantly between arms (median 3 and 1 for TP:IPC respectively in rest, p=0.16, (TP 13:IPC 16) and 3 and 1 during exercise, p=0.72 (TP 13:IPC 17)). There was no difference in dyspnea during exercise between TP and IPC at week 6 following treatment, while at rest TP patients (n=13) reported less dyspnea than IPC patients (n=18) (median 0 vs 1, p=0.002). Compared to TP, patients with an IPC had significantly less hospital days during randomized treatment (median: 0 vs 5, p<0.0001), and total hospitalizations for all causes (median: 1.6 vs 1.0, p=0.0035). Fewer IPC patients underwent more than one re-intervention (7/45 vs 15/43, p=0.09). The mean number of re-interventions was lower following IPC (0.21 vs 0.53, p=0.05). Equal number of adverse events occurred. CONCLUSIONS IPC was not superior in the primary endpoint, improvement of the modified Borg scale (MBS). However, IPC patients had lower hospital stay, fewer admissions and fewer re-interventions. The IPC is an effective treatment modality in patients with symptomatic malignant pleural effusion.

Scenario drafting for early technology assessment of next generation sequencing in clinical oncology

BackgroundNext Generation Sequencing (NGS) is expected to lift molecular diagnostics in clinical oncology to the next level. It enables simultaneous identification of mutations in a patient tumor, after which targeted therapy may be assigned. This approach could improve patient survival and/or assist in controlling healthcare costs by offering expensive treatment to only those likely to benefit. However, NGS has yet to make its way into the clinic. Health Technology Assessment can support the adoption and implementation of a novel technology, but at this early stage many of the required variables are still unknown.MethodsScenario drafting and expert elicitation via a questionnaire were used to identify factors that may act as a barrier or facilitate adoption of NGS-based molecular diagnostics. Attention was paid to predominantly elicit quantitative answers, allowing their use in future modelling of cost-effectiveness.ResultsAdequately informing patients and physicians, the latters’ opinion on clinical utility and underlying evidence as well as presenting sequencing results within a relevant timeframe may act as pivotal facilitators. Reimbursement for NGS-based testing and accompanying therapies (both general and in case of off-label prescription) was found to be a potential barrier. Competition on the market and demonstrating clinical utility may also be challenging. Importantly, numerous quantitative values for variables related to each of these potential barriers/facilitators, such as such as desired panel characteristics, willingness to pay or the expected number of targets identified per person, were also elicited.ConclusionsWe have identified several factors that may either pose a barrier or facilitate the adoption of NGS in the clinic. We believe acting upon these findings, for instance by organizing educational events, advocating new ways of evidence generation and steering towards the most cost-effective solution, will accelerate the route from bench-to-bedside. Moreover, due to the methodology of expert elicitation, this study provides parameters that can be incorporated in future cost-effectiveness modeling to steer the development of NGS gene panels towards the most optimal direction.

157P: Serum tumor markers and the response to immunotherapy in advanced non-small cell lung carcinoma.

correlation of its baseline values to the efficacy of pemetrexed and performed a dynamic monitoring study in NSCLC patients who underwent first-line platinum-based chemotherapy. Methods: This study enrolled 70 NSCLC patients who received first-line platinum-based chemotherapy. The CTCs were quantified by negative enrichment using immunomagnetic beads in combination with folate receptor-directed PCR that allows secondary amplification of tiny amounts of CTCs in peripheral blood. In this study, the CTC levels were examined by collecting 3mL of anti-EDTA whole blood samples before the treatment and after every chemotherapy, and followed up until progressive disease (PD) or completion of first-line chemotherapy. Results: Of twenty-two patients who received pemetrexed disodium/platinum combined therapy (AP/AC), the patients harboring high levels of folate receptor showed greater efficacy than those with low expression levels (8.7 < CTC level < 16, n = 7; PFS: 448 vs.94 days, P = 0.0199; ORR: 75% vs.11%). In the dynamic monitoring study, the CTC level (AUC=0.8026, P = 0.0033), the CTC ratio (AUC=0.8422, P = 0.0003), the rate of CTC changes (OR=102.005, P = 0.0012) after the second chemotherapy and the CTC level (AUC=0.9487, P < 0.0001), the CTC ratio (AUC=0.8889, P < 0.0001), the changing rate of CTCs (OR=51.662, P = 0.0031) after the fourth chemotherapy positively correlated to the disease progression. Conclusions: The patients with high expression of folate receptor-positive CTCs appear to have superior response to pemetrexed than those with low expression. Additionally, the changes of CTC count can be used as a dynamic monitoring indicator in the treatment process to evaluate tumor burden and therapeutic outcomes. Legal entity responsible for the study: Shanghai Pulmonary Hospital, Tongji University of Medicine Funding: Genosaber Biotech Co.Ltd Disclosure: All authors have declared no conflicts of interest.

Association of molecular status and metastatic organs at diagnosis in patients with stage IV non-squamous non-small cell lung cancer

OBJECTIVES Biological predisposition for specific metastatic organs might differ between molecular subgroups of lung cancer. We aimed to assess the association between molecular status and metastatic organs at diagnosis in a nationwide stage IV non-squamous non-small cell lung cancer ((ns)-NSCLC) cohort. METHODS All ns-NSCLC from 2013 that were stage IV at diagnosis were identified from the Netherlands Cancer Registry, which records information on metastatic organs at diagnosis. Tumors were matched to the Dutch Pathology Registry (PALGA) from which data on molecular status established in routine practice was extracted. Four molecular subgroups (EGFR+, KRAS+, ALK+, triple-negative) were identified. For each metastatic organ, proportions of tumors metastasized to this organ were, per molecular subgroup, compared to triple-negative tumors by multivariable logistic regression analyses (adjusted odds ratios (OR) with 95% confidence intervals (CI)), taking clinicopathological variables into account. RESULTS 160 EGFR+ (exon 19 del, exon 21 L858R), 784 KRAS+, 42 ALK+, and 1008 triple-negative tumors were identified. Most frequent metastatic organs were the bone (34%), pleura (24%), lung (23%), and brain (22%). Compared to triple-negatives, EGFR+ tumors had more often metastases to the bone (31.5 vs 53.8%; OR 2.55 (95% CI 1.80-3.62)) and pleura (24.1 vs 37.5%; OR 2.06 (1.42-2.98)), and less often to the brain (22.0 vs 12.5%; OR 0.53 (0.32-0.88)) and adrenal glands (19.1 vs 7.5%; OR 0.46 (0.28-0.75)). Compared to triple-negatives, KRAS+ and ALK+ tumors had at diagnosis metastasized more often to the lung (20.3 vs 26.7%; OR 1.40 (1.12-1.76)) and the liver (13.1 vs 23.8%; OR 2.07 (1.00-4.32)), respectively. CONCLUSION NSCLC molecular status was associated with metastatic pattern at diagnosis. 54% of stage IV EGFR+ ns-NSCLC patients had bone metastases at diagnosis. These observational results are hypothesis generating, and call for a prospective study where EGFR+ patients are screened for bone metastases, and treated to prevent skeletal related events.

Diagnostic validation and interpretation of longitudinal circulating biomarkers using a biomarker response characteristic plot

BACKGROUND Serum-based tumor biomarkers are used to monitor cancer treatment, while clear guidance on the clinical usage is often lacking. We describe a graphical presentation to support diagnostic accuracy studies and clinical interpretation of longitudinal biomarker data. METHODS A biomarker response characteristic (BReC) plot was designed. To allow demonstration of the BReC plot application, software was developed that supported 1) dynamic generation of BReC plots, and 2) diagnostic accuracy studies of biomarker response-based medical tests. The BReC plot application was demonstrated using serial carcinoembryonic antigen (CEA) and Cyfra 21.1 results from 216 patients with metastasized non-small cell lung cancer, treated with Nivolumab in routine clinical practice. RESULTS The developed software supported the generation of BReC plots and diagnostic validation of biomarker response-based medical tests by generating the sensitivity, specificity and predictive values. Obtained BReC plots showed a clear relationship between clinical outcome and CEA and Cyfra 21.1 responses. Furthermore, using BReC plots, CEA and Cyfra 21.1 based medical tests were designed with a sensitivity for detection of treatment failure of 0.34 and 0.35 and a specificity of 0.96. CONCLUSIONS The BReC plot appears to support diagnostic validation studies and the interpretation of longitudinal biomarkers though further validation is warranted.

160 Identification of fusion genes through kinome-centered RNA sequencing in different types of solid tumors

after anthracycline-based chemotherapy. AC induces lower levels of plasma miR-34a and doesn’t modify miR-122. The tumorectomy alone doesn’t deregulate miR-34a and miR-122. Circulating miR-34a and miR-122 are downregulated in NAC treated breast cancer patients compare to controls and normalized after treatments. Conclusion: This study demonstrates for the first time that NAC specifically induces expression of tumor suppressor miRNAs in plasma and tumor tissue that might be involved in the anti-tumor effect of the chemotherapy.

155 Sorafenib Synergizes with the Antidiabetic Drug Metformin in Non-Small Cell Lung Cancer (NSCLC)

Background: Sorafenib (Nexavar) is a small molecule multitargeted kinase inhibitor targeting several tyrosine protein kinases (e.g. VEGFR, PDGFR) and Raf kinases. The drug is FDA-approved for the treatment of advanced hepatocellular carcinoma and advanced clear cell renal cell carcinoma. Sorafenib is currently tested in multiple phase I-III studies for a broad range of solid tumors, including Non-Small Cell Lung Cancer (NSCLC). In a phase II clinical trial in KRASmt advanced NSCLC with single agent sorafenib overall survival was different in 5/57 patients using the oral antidiabetic drug metformin (medians 9.0 vs 4.8 months, p = 0.13). Furthermore, it was observed that the two patients with the longest progression free survival were patients using metformin. Metformin has been described as 5′ AMP-activated protein kinase (AMPK)-activator. Results: In NSCLC cell lines, sorafenib in combination with metformin was found to act synergistically in inhibiting cellular proliferation. The synergistic effect closely paralleled AMPKalpha phosphorylation on the activation site threonine-172, that can be performed by the tumor suppressor LKB1 and the Ca-activated protein kinase CaMKKII. Consistent with our findings, the drug combination of sorafenib with the synthetic allosteric AMPK activator A-769662 led to an identical synergistic growth inhibition of NSCLC cells. AMPK acts as a cellular energy sensor regulating several intracellular metabolic systems and activation leads to suppression of mTOR signalling. The combination treatment showed a synergistic effect on inhibiting the phosphorylation of the downstream mTOR targets 4E-BP1 and the ribosomal protein S6. Conclusion: Our results suggest that the combination of sorafenib with metformin could have beneficial effects on tumor regression by synergistically activating AMPK. We are currently testing this concept in a NSCLC-xenograft study of sorafenib in combination with metformin.