Background: Small cell lung cancer (SCLC) is an unmet medical need, representing ∼15% of lung cancer diagnosed/year. Two-thirds of patients (pts) are diagnosed with extensive stage (ES) SCLC with a 2-year survival rate of 5%. Delta-like protein 3 (DLL3), an atypical Notch receptor family ligand, is highly expressed in SCLC and other neuroendocrine tumors with little to no expression in normal tissue. Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate composed of a humanized DLL3-specific IgG1 monoclonal antibody tethered to a toxic DNA cross-linking agent. A Phase 1 study of Rova-T in SCLC pts showed encouraging progression-free and overall survival and a manageable safety profile1. Studies show that nivolumab (nivo, anti-PD-1 antibody) +/- ipilimumab (ipi, anti-CTLA-4 antibody) has antitumor activity and is well-tolerated in 2nd line SCLC. Given the complementary mechanisms of action and non-overlapping toxicities, futher study is warranted to evaluate if a combination of Rova-T and nivo, or all 3 agents leads to more pts with long-term responses and prolonged survival. Trial design: This Phase 1/2 study (NCT03026166) will enroll ∼90 pts in 3 cohorts. Each cohort will receive Rova-T 0.3 mg/kg IV on Day 1 of the 1st and 3rd 3-week cycle in combination with: nivo 360 mg/kg IV q3wk x 2 cycles (cohort 1) or nivo 1 mg/kg q3wk + ipi 1 mg/kg (cohort 2) or 3mg/kg (cohort 3) IV q3wk x 4 cycles. Maintenance nivo will be administered in all cohorts at 480 mg IV q4wk. The dose limiting toxicity (DLT) evaluation period is 12 weeks. Pt eligibility: ≥ 18 years; histologically or cytologically confirmed 2nd line or later ES SCLC; confirmed DLL3-positive status based on immunohistochemistry of baseline tumor tissue (for DLT evaluable pts); ECOG 0-1; no autoimmune disease; no prior exposure to immuno-oncology or pyrrolobenzodiazepine-based drugs. Primary and secondary objectives: assess safety and efficacy of Rova-T in combination with nivo or nivo + ipi. Exploratory objectives: assess expression of DLL3 and PD-L1 and their relationship to clinical outcome, pharmacokinetics, incidence of neutralizing antibodies, and effects on pharmacodynamic biomarkers. 1. Rudin et al., Lancet Oncol, 2016. Clinical trial identification: NCT03026166 Legal entity responsible for the study: AbbVie Stemcentrx Funding: AbbVie Stemcentrx Disclosure: C. Scripture, I. Lakatos, K. Boynton, S. Lally, T.H. Han, S.L. Peng, S.J. Dylla: Employee of AbbVie Stemcentrx and may own stock. G. Selvaggi: Employee of Bristol-Myers Squibb. Keywords: small cell lung cancer, immunotherapy, Rovalpituzumab tesirine, DLL3

Summary Background Acknowledging that eosinophilic esophagitis (EoE) is a disease with variable involvement throughout the oesophagus, studies have suggested a minimum of five biopsies to diagnose EoE. Although it is accepted that furrows and exudates appear to represent areas of inflammation, no research to date has looked specifically at EoE endoscopic findings to see if eosinophilic infiltrate correlates with specific endoscopic findings. Aim To evaluate the distribution of eosinophils in EoE and determine whether endoscopic appearances predict the degree of eosinophilia at various locations of the oesophagus. Methods We performed a prospective cross sectional study of EoE (treated and untreated) patients to study the distribution of eosinophils according to endoscopic findings. The oesophagus of 10 EoE patients were biopsied up to 32 times in a circumferential manner. The mucosal changes were documented at the site of each biopsy. Histological determination of eosinophil counts and related histopathology of the oesophagus were then correlated with endoscopic findings. Similar biopsy assessments were made in treated (resolved) EoE patients ( n = 6) to determine the permanence of specific endoscopic appearances. Results A total of 16 patients were biopsied (10 EoE, 6 treated EoE). A total of 432 biopsies were obtained in all with 294 biopsies from 10 EoE subjects. Eosinophil density was increased distally in the majority of EoE patients. Biopsies performed in areas of exudates and furrows demonstrated higher eosinophil counts. Lines and normal‐appearing oesophagi in EoE subjects were not commonly associated with elevated eosinophil counts (>15 eos/HPF). Rings alone without associated furrows or plaques did not demonstrate elevated eosinophil counts and were seen in resolved EoE (Rx‐EoE) as well as in active EoE patients. Conclusions Eosinophilic esophagitis remains a variable disease with some patients manifesting extensive disease throughout the oesophagus. Characteristics of furrows and exudates found during endoscopy are associated with higher peak eosinophil counts, requiring fewer biopsies to make a diagnosis. Lines and otherwise normal appearances of the oesophagus suggest a milder mucosal eosinophilia, requiring substantial biopsies to adequately identify fields with diagnostic eosinophil counts.

Colorectal cancer accounts for more than 10% of all cancer deaths but is curable, if detected early. We reported previously on a stool-based screening test in which DNA from stool samples is subjected to genome analysis; sensitivity of the test has been limited in part by inefficiency of retrieving DNA from stool. Our aim was to test the impact of a new purification method that would increase the yield of human DNA from stool. DNA from 86 cancer and 100 non-cancer subjects (diagnosed by colonoscopy) were purified from stool with a new method for DNA recovery based on sequence-specific capture with acrylamide gel immobilized capture probes as well as with a previously developed magnetic bead-capture procedure. The new purification method gives an average 5.4-fold increase in the quantity of human DNA that can routinely be retrieved from fecal samples. The increased recovery of DNA corresponds with an increase in assay sensitivity from 53% (CI: 42 to 64%) to 70% (CI: 59 to 79%); P = 0.0005 (by McNemar's test), with no change in specificity. The newly developed sample preparation method mitigates a major problem in detecting rare cancer-associated genetic changes in heterogeneous clinical samples such as stool.

BACKGROUND:Noninvasive methods for detecting colorectal tumors have the potential to reduce morbidity and mortality from this disease. The mutations in the adenomatous polyposis coli (APC) gene that initiate colorectal tumors theoretically provide an optimal marker for detecting colorectal tumors. The purpose of our study was to determine the feasibility of detecting APC mutations in fecal DNA with the use of newly developed methods.METHODS:We purified DNA from routinely collected stool samples and screened for APC mutations with the use of a novel approach called digital protein truncation. Many different mutations could potentially be identified in a sensitive and specific manner with this technique.RESULTS:Stool samples from 28 patients with nonmetastatic colorectal cancers, 18 patients with adenomas that were at least 1 cm in diameter, and 28 control patients without neoplastic disease were studied. APC mutations were identified in 26 of the 46 patients with neoplasia (57 percent; 95 percent confidence interval, 41 to 71 percent) and in none of the 28 control patients (0 percent; 95 percent confidence interval, 0 to 12 percent; P<0.001). In the patients with positive tests, mutant APC genes made up 0.4 to 14.1 percent of all APC genes in the stool.CONCLUSIONS:APC mutations can be detected in fecal DNA from patients with relatively early colorectal tumors. This feasibility study suggests a new approach for the early detection of colorectal neoplasms.

Detection of mutations in faecal DNA represents a promising, non-invasive approach for detecting colorectal cancers in average-risk populations. One of the first practical applications of this technology involves the examination of microsatellite markers in sporadic cancers with mismatch-repair deficiencies. Since such cancers nearly always occur in the proximal colon, this test might be useful as an adjunct to sigmoidoscopy, which detects only distal colorectal lesions. We report here the first in-depth analysis of faecal DNA from patients with proximal cancers to determine the feasibility, sensitivity, and specificity of this approach. Using a sensitive method for microsatellite mutation detection, we found that 18 of 46 cancers had microsatellite alterations and that identical mutations could be identified in the faecal DNA of 17 of these 18 cases.

BACKGROUND Colorectal cancer cells are shed into the stool, providing a potential means for the early detection of the disease using noninvasive approaches. Our goal was to develop reliable, specific molecular genetic tests for the detection of colorectal cancer in stool samples. METHODS Stool DNA was isolated from paired stools and primary tumor samples from 51 colorectal cancer patients. Three genetic targets-TP53, BAT26, and K-RAS-were used to detect tumor-associated mutations in the stool prior to or without regard to the molecular analyses of the paired tumors. TP53 gene mutations were detected with a mismatch-ligation assay that detects nine common p53 gene mutations. Deletions within the BAT26 locus were detected by a modified solid-phase minisequencing method. Mutations in codons 12 and 13 of K-RAS were detected with a digital polymerase chain reaction-based method. RESULTS TP53 gene mutations were detected in the tumor DNA of 30 patients, all of whom had the identical TP53 mutation in their stools. Tumors from three patients contained a noninherited deletion at the BAT26 locus, and the same alterations were identified in these patients' stool specimens. Nineteen of 50 tumors tested had a K-RAS mutation; identical mutations were detected in the paired stool DNA samples from eight patients. In no case was a mutation found in stool that was not also present in the primary tumor. Thus, the three genetic markers together detected 36 (71%) of 51 patients (95% confidence interval [CI] = 56% to 83%) with colorectal cancer and 36 (92%) of 39 patients (95% CI = 79% to 98%) whose tumors had an alteration. CONCLUSION We were able to detect the majority of colorectal cancers by analyzing stool DNA for just three genetic markers. Additional work is needed to determine the specificity of these genetic tests for detecting colorectal neoplasia in asymptomatic patients and to more precisely estimate the prevalence of the mutations and sensitivity of the assay.