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ObjectivesTo describe the clinical activity of metronomic cyclophosphamide in a population of patients with recurrent ovarian cancer, and to identify predictors of clinical response.MethodsWe retrospectively reviewed all patients treated at our institution with oral metronomic cyclophosphamide for relapsed ovarian cancer between January 2012 and December 2016. These were identified from electronic chemotherapy prescription records. The primary endpoint was response rate by combined Gynecologic Cancer InterGroup (GCIG) criteria. Data on patient demographics, previous therapies, platinum resistance, germline BRCA1/2 (gBRCA1/2) status, disease response by radiological or cancer antigen 125 (CA125) criteria alone, adverse events secondary to metronomic cyclophosphamide treatment, progression-free survival, and overall survival were also evaluated.Results50 out of 68 patients treated with oral metronomic cyclophosphamide were evaluable for disease response. By combination criteria (radiological plus CA125), complete response was 0%, partial response 32%, stable disease 16%, and progressive disease 52%. In the intention-to-treat population (n=68), progression-free survival and overall survival were 2.6 months and 6 months, respectively. Having a gBRCA1/2 mutation reduced the risk of disease progression by radiological criteria (OR 0.07, 95% CI 0.008 to 0.67, p=0.02), and patients with gBRCA1/2 mutations had improved progression-free survival (7.9 vs 2.5 months, HR 0.4, 95% CI 0.23 to 0.74, p=0.003) and overall survival (15.5 vs 6 months, HR 0.49, 95% CI 0.28 to 0.85, p=0.02) with metronomic cyclophosphamide when compared with patients without gBRCA1/2 mutations (or unknown gBRCA1/2 status).ConclusionOral metronomic cyclophosphamide showed a clinical benefit in 48% of patients with recurrent ovarian cancer. gBRCA1/2 status can be an independent predictor of response.

Oncolytic viruses (OVs) can trigger profound innate and adaptive immune responses, which have the potential both to potentiate and reduce the activity of OVs. Natural killer (NK) cells can mediate potent anti-viral and anti-tumoral responses, but there are no data on the role of NK cells in oncolytic adenovirus activity. Here, we have used two different oncolytic adenoviruses—the Ad5 E1A CR2-deletion mutant dl922-947 (group C) and the chimeric Ad3/Ad11p mutant enadenotucirev (group B)—to investigate the effect of NK cells on overall anti-cancer efficacy in ovarian cancer. Because human adenoviruses do not replicate in murine cells, we utilized primary human NK cells from peripheral blood and ovarian cancer ascites. Our results show that dl922-947 and enadenotucirev do not infect NK cells, but induce contact-dependent activation and anti-cancer cytotoxicity against adenovirus-infected ovarian cancer cells. Moreover, manipulation of NK receptors DNAM-1 (DNAX accessory molecule-1) and TIGIT (T cell immunoreceptor with Ig and ITIM domains) significantly influences NK cytotoxicity against adenovirus-infected cells. Together, these results indicate that NK cells act to increase the activity of oncolytic adenovirus in ovarian cancer and suggest that strategies to augment NK activity further via the blockade of inhibitory NK receptor TIGIT could enhance therapeutic potential of OVs. Keywords: Ovarian cancer, Oncolytic virus, Adenovirus, NK cell, DNAM-1, TIGIT

Background Epertinib (S-222611) is a potent reversible inhibitor of HER2, EGFR and HER4. This trial evaluated the safety, tolerability, pharmacokinetics and antitumour activity of daily oral epertinib combined with trastuzumab (arm A), with trastuzumab plus vinorelbine (arm B) or with trastuzumab plus capecitabine (arm C), in patients with HER2-positive metastatic breast cancer (MBC). Methods Eligible patients, with or without brain metastases, had received prior HER2-directed therapy. A dose-escalation phase determined the tolerability of each combination and established a dose for further study. Further, patients were recruited to expansion cohorts in each of the 3 arms to further explore efficacy and safety. Results The recommended doses of epertinib were 600 mg, 200 mg and 400 mg in arms A, B and C, respectively. The most frequent grade 3/4 adverse event (AE) was diarrhoea in all arms, which was manageable with medical intervention and dose modification. The objective response rate (complete response [CR] plus partial response [PR]) in heavily pre-treated HER2-positive MBC patients at the recommended doses of epertinib combined with trastuzumab was 67% (N = 9), with trastuzumab plus vinorelbine was 0% (N = 5) and with trastuzumab plus capecitabine was 56% (N = 9). Notably, 4 of 6 patients previously treated with T-DM1 responded in the arm A expansion cohort (epertinib plus trastuzumab). In the arm C expansion cohort (epertinib plus trastuzumab plus capecitabine), 4 of 7 patients responded despite previous exposure to capecitabine. Measurable regression of brain metastases was observed in patients with CNS target lesions treated in both arms A and C. Conclusion We observed safety, tolerability and encouraging antitumour activity of epertinib combined with trastuzumab, or with trastuzumab plus capecitabine. This supports further evaluation of these combinations in patients with pre-treated HER2-positive MBC, with or without brain metastases. Trial registration EudraCT Number: 2013-003894-87; registered 09-September-2013.

To determine the rates of germline BRCA1 and BRCA2 mutations in Scottish patients with ovarian cancer, before and after a change in testing policy.Retrospective cohort study.Four cancer/genetics centres in Scotland.Patients with ovarian cancer undergoing germline BRCA1 and BRCA2 (gBRCA1/2) sequencing before 2013 (under the 'old criteria', with selection based solely on family history), after 2013 (under the 'new criteria', with sequencing offered to newly presenting patients with non-mucinous ovarian cancer), and in the 'prevalent population' (who presented before 2013, but were not eligible for sequencing under the old criteria but were sequenced under the new criteria).Clinicopathological and sequence data were collected before and for 18 months after this change in selection criteria.Frequency of germline BRCA1, BRCA2, RAD51C, and RAD51D mutations.Of 599 patients sequenced, 205, 236, and 158 were in the 'old criteria', 'new criteria', and 'prevalent' populations, respectively. The frequency of gBRCA1/2 mutations was 30.7, 13.1, and 12.7%, respectively. The annual rate of gBRCA1/2 mutation detection was 4.2 before and 20.7 after the policy change. A total of 48% (15/31) 'new criteria' patients with gBRCA1/2 mutations had a Manchester score of15 and would not have been offered sequencing based on family history criteria. In addition, 20 patients with gBRCA1/2 were identified in the prevalent population. The prevalence of gBRCA1/2 mutations in patients aged70 years was 8.2%.Sequencing all patients with non-mucinous ovarian cancer gives a much higher annual gBRCA1/2 mutation detection rate, with the frequency of positive tests still exceeding the 10% threshold upon which many family history-based models operate.BRCA sequencing all non-mucinous cancer patients increases mutation detection five fold.

Janet Graham,1 Pavlina Spiliopoulou,1 Rob Arbuckle,2 Julie Ann Bridge,3 James Cassidy1 1Department of Medical Oncology, Beatson, West of Scotland Cancer Center, Glasgow, UK, 2Adelphi Values, Adelphi Mill Macclesfield, Cheshire, UK; 3Eli Lilly Pty Ltd., West Ryde, NSW, Australia Background: Traditional endpoints in oncology are based on measuring the tumor size and combining this with a time factor. Current studies with immunotherapy show that even when median survival is unaltered, a significant proportion of patients can achieve prolonged survival. Objective tumor response does not always mean “overall” improvement, especially if toxicity is harsh. Novel agents are significantly expensive, and it is therefore crucial to measure the impact on “quality” of life, in addition to “quantity”.Materials and methods: We studied the preferences and experiences of cancer patients and their caregivers, measuring subjective well-being (SWB) ratings, EQ5D descriptions and time trade-off preferences.Results: We studied 99 patients and 88 caregivers. Life satisfaction ratings were similar between the two groups, but daily mood was significantly lower in caregivers (P

For decades, effective cancer gene therapy has been a tantalising prospect; for a therapeutic modality potentially able to elicit highly effective and selective responses, definitive efficacy outcomes have often seemed out of reach. However, steady progress in vector development and accumulated experience from previous clinical studies has finally led the field to its first licensed therapy. Following a pivotal phase III trial, Imlygic (talimogene laherparepvec/T-Vec) received US approval as a treatment for cutaneous and subcutaneous melanoma in October 2015, followed several weeks later by its European authorisation. These represent the first approvals for an oncolytic virotherapy. Imlygic is an advanced-generation herpesvirus-based vector optimised for oncolytic and immunomodulatory activities. Many other oncolytic agents currently remain in development, providing hope that current success will be followed by other diverse vectors that may ultimately come to constitute a new class of clinical anti-cancer agents. In this review, we discuss some of the key oncolytic viral agents developed in the adenovirus and herpesvirus classes, and the prospects for further enhancing their efficacy by combining them with novel immunotherapeutic approaches.

Summary Background Few effective treatments exist for patients with advanced urothelial carcinoma that has progressed after platinum-based chemotherapy. We assessed the activity and safety of nivolumab in patients with locally advanced or metastatic urothelial carcinoma whose disease progressed after previous platinum-based chemotherapy. Methods In this phase 1/2, multicentre, open-label study, we enrolled patients (age ≥18 years) with urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra at 16 sites in Finland, Germany, Spain, the UK, and the USA. Patients were not selected by PD-L1 expression, but tumour PD-L1 membrane expression was assessed retrospectively. Patients received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression or treatment discontinuation because of unacceptable toxicity or other protocol-defined reasons, whichever occurred later. The primary endpoint was objective response by investigator assessment. All patients who received at least one dose of the study drug were included in the analyses. We report an interim analysis of this ongoing trial. CheckMate 032 is registered with ClinicalTrials.gov, NCT01928394. Findings Between June 5, 2014, and April 24, 2015, 86 patients with metastatic urothelial carcinoma were enrolled in the nivolumab monotherapy group and 78 received at least one dose of treatment. At data cutoff (March 24, 2016), the minimum follow-up was 9 months (median 15·2 months, IQR 12·9–16·8). A confirmed investigator-assessed objective response was achieved in 19 (24·4%, 95% CI 15·3–35·4) of 78 patients. Grade 3–4 treatment-related adverse events occurred in 17 (22%) of 78 patients; the most common were elevated lipase (four [5%]), elevated amylase (three [4%]), and fatigue, maculopapular rash, dyspnoea, decreased lymphocyte count, and decreased neutrophil count (two [3%] each). Serious adverse events were reported in 36 (46%) of 78 patients and eight (10%) had a serious adverse event judged to be treatment related. Two (3%) of 78 patients discontinued because of treatment-related adverse events (grade 4 pneumonitis and grade 4 thrombocytopenia) and subsequently died. Interpretation Nivolumab monotherapy was associated with a substantial and durable clinical response and a manageable safety profile in previously treated patients with locally advanced or metastatic urothelial carcinoma. These data support further investigation of nivolumab monotherapy in advanced urothelial carcinoma. Funding Bristol-Myers Squibb.

Large-scale epidemiological studies have shown that the incidence of second primary thyroid cancer in subjects diagnosed and treated for testicular cancer is raised. This finding is strongly associated to treatment with radiotherapy and/or chemotherapy and it is explained by their mutagenic effect. On the other hand, inherited cancer susceptibility syndromes inducing both testicular and thyroid cancers denote that these tumours might share common genomic aberrations. We herein present our experience with three cases of metachronous development of thyroid cancer after diagnosis and treatment of testicular cancer in our tertiary cancer centre. Our case report contributes to the limited available literature on such findings and aims to raise awareness of the cancer physicians treating these particular tumour types.

414 Background: Nivolumab has shown efficacy and acceptable safety in 2 open-label, multicenter studies (CheckMate 032 and 275) and is approved for patients (pts) with metastatic urothelial carcinoma (mUC) after ≥1 platinum-based therapy. Here we report longer-term efficacy and safety results for pts with mUC in the phase 1/2 CheckMate 032 study who received nivolumab monotherapy based on > 2 years of follow-up. Methods: Pts with mUC, regardless of programmed death-1 ligand 1 (PD-L1) expression status, received nivolumab 3 mg/kg intravenously every 2 weeks until progression or discontinuation. Tumor PD-L1 membrane expression was assessed with Dako PD-L1 immunohistochemical staining. Primary endpoint: objective response rate (ORR; RECIST 1.1); other endpoints: safety, progression-free survival (PFS), overall survival (OS), and duration of response. Results: Of 78 treated pts (median age 65.5 years; range, 31-85), 52 (66.7%) had received ≥2 prior therapies. At a minimum follow-up of 24 months, 11 pts (14.1%) remain on treatment. Treatment discontinuation was mainly due to disease progression (52 pts [66.7%]). Tumor PD-L1 expression was evaluable in 68 pts (87.2%); 26 (38.2%) pts had ≥1% and 42 (61.8%) had < 1% expression. The table shows overall efficacy. Updated ORR was 25.6%, with 1 additional complete response (CR) achieved for a CR rate of 8%. Median duration of response was not reached. ORR, 1- and 2-year PFS and OS rates were similar between the PD-L1 < 1% and > 1% subsets. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 22 pts (28.2%); most frequent were ↑lipase (6.4%), ↑amylase (5.1%), and maculopapular rash (3.8%). One pt had a grade 5 TRAE (pneumonitis). Conclusions: Nivolumab showed clinically meaningful, durable efficacy with promising long-term survival regardless of PD-L1 expression, and no new toxicity signals with longer-term follow-up in previously treated pts with mUC. Clinical trial information: NCT01928394. [Table: see text]

4521Background: gemcitabine (G) plus cisplatin (C) is a standard-of-care, combination chemotherapy regimen for patients (pts) with bladder cancer (BC), in both neoadjuvant and palliative settings. ...

4501Background: Minimal antitumor activity of existing therapies and the observation of immune dysfunction in bladder cancer have prompted evaluation of immunotherapy in this malignancy. Nivolumab (fully human IgG4 programmed death-1 immune checkpoint inhibitor antibody) monotherapy has shown survival benefit in patients (pts) with melanoma, lung cancer, and renal cell carcinoma. Here, we report efficacy and safety of nivolumab monotherapy in pts with mUC after ≥1 prior line of platinum-based therapy in an open-label, multicenter phase I/II study (NCT01928394). Methods: Pts (unselected by PD-L1 expression status) with mUC received nivolumab 3 mg/kg intravenously every 2 weeks until progression or discontinuation. Primary endpoint was objective response rate (ORR; RECIST 1.1). Other endpoints included safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: Of 78 treated pts (median age 65.5 years; range, 31–85), 65.4% had received ≥2 prior therapies. At a me...