Background: KRAS is mutated in similar to 90% of pancreatic ductal adenocarcinomas, similar to 35% of colorectal cancers and w20% of non-small-cell lung cancers. There has been recent progress in targeting G12CKRAS specifically, but therapeutic options for other mutant forms of KRAS are limited, largely because the complexity of downstream signaling and feedback mechanisms mean that targeting individual pathway components is ineffective. Design: The protein kinases RAF and SRC are validated therapeutic targets in KRAS-mutant pancreatic ductal adenocarcinomas, colorectal cancers and non-small-cell lung cancers and we show that both must be inhibited to block growth of these cancers. We describe CCT3833, a new drug that inhibits both RAF and SRC, which may be effective in KRAS-mutant cancers. Results: We show that CCT3833 inhibits RAF and SRC in KRAS-mutant tumors in vitro and in vivo, and that it inhibits tumor growth at well-tolerated doses in mice. CCT3833 has been evaluated in a phase I clinical trial (NCT02437227) and we report here that it significantly prolongs progression-free survival of a patient with a G12VKRAS spindle cell sarcoma who did not respond to a multikinase inhibitor and therefore had limited treatment options. Conclusions: New drug CCT3833 elicits significant preclinical therapeutic efficacy in KRAS-mutant colorectal, lung and pancreatic tumor xenografts, demonstrating a treatment option for several areas of unmet clinical need. Based on these preclinical data and the phase I clinical unconfirmed response in a patient with KRAS-mutant spindle cell sarcoma, CCT3833 requires further evaluation in patients with other KRAS-mutant cancers.

Introduction/Background Treatment for ovarian cancer (OC) usually involves systemic therapy (ST) and surgery. Radiotherapy (RT) is used for palliation, however for limited relapse may provide improved local control (LC) and defer the need for ST. We investigated the benefit of higher doses of RT in localised relapse of OC. Methodology We performed a retrospective institutional review of patients with OC who received RT from 07/1998–12/2015. Radical prescription doses ≥30 Gy were included, palliative treatments <30 Gy and brain metastases were excluded. Data was collected to determine LC, progression free survival (PFS) and time to next ST (TNT) and correlated with lines of previous treatment, location of disease, histology, RT dose/fractionation, and platinum sensitivity. Results 534 courses of RT for OC were identified. Of these, 65 courses in 59 patients (range 33–84 years)were eligible for inclusion. Histological subtypes were: serous (67.7%), endometrioid (12.3%), clear cell (6.1%), mucinous (6.1%), granulosa cell (3.07%), carcinosarcoma (3.07%) and borderline (1.5%). Table 1 shows the number of lines of previous ST. Table 2 show sites and modality of RT delivered. The median dose was 45Gy in 25# (range 33–64.8 Gy) for stereotactic treatments 30 Gy/3# (range 27–36 gy). Table 2 show sites and modality of RT delivered. The median dose was 45Gy in 25# (range 33–64.8 Gy) for stereotactic treatments 30 Gy/3# (range 27–36 gy). Conclusion RT is underutilised and should be considered as an alternative to ST in limited relapse OC. Higher doses of RT can provide high rates of LC, improve PFS and delay time to ST in different histological subtypes and in heavily pre-treated patients. Disclosure Nothing to disclose.

Background ADATPeR is the first prospective study evaluating the role of anti-PD1 agents in the neoadjuvant setting prior to cytoreductive nephrectomy in treatment-naive patients with metastatic clear cell renal cell carcinoma (mccRCC). We performed multi-omic analyses to resolve spatial heterogeneity and temporal dynamics in putative biomarkers of response to anti-PD1 blockade. Methods In a single center study, patients received nivolumab (3mg/kg every 2 weeks) pre- and post-operatively until progressive disease (PD). Primary endpoint was safety, secondary endpoints were response evaluation and exploratory biomarker analysis. Multiregion tumour biopsies were obtained at baseline, on-treatment (week 9) and at PD. Whole-exome sequencing was performed to infer somatic mutations and predict candidate neoantigens (NAs). Tumour immune microenvironment was evaluated using a RNA-seq-derived immune signature and by stromal and intraepithelial tumour infiltrating lymphocytes (TILs) assessments. Results 15 patients were treated. At median follow-up of 12.5 months(m), nivolumab had an acceptable side-effect profile. Overall response rate was 37%. Preliminary transcriptome analyses of pre-treatment biopsies (33 samples from 14 patients; up to 4 regions per case) revealed enrichment for primary-resistance (defined as PD within 2m; n = 4) with immune ‘cold’ tumours, distinct from ’hot’ tumours. Histologic TILs scoring showed concordant immune phenotypic clusters. Primary-resistant cases demonstrated 0% on-treatment stromal- and IE-TILs (2 evaluable patients). In contrast, we observed heavy on-treatment stromal TILs (70-90%) and intraepithelial TILs (30-90%) across 7 regions at nephrectomy in an exceptional responder receiving ongoing treatment (>24 cycles). Conclusions ADATPeR is the first neoadjuvant immune checkpoint inhibitor study pre-cytoreductive nephrectomy, and incorporated multi-omic analyses of putative biomarkers. Baseline immune gene expression signature is distinct in responders compared with non-responders. On-treatment intraepithelial TILs were prominent in those deriving durable clinical benefit. Integrative analyses are ongoing. Clinical trial identification NCT02446860. Legal entity responsible for the study The authors. Funding Bristol-Myers Squibb; The National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research; Cancer Research UK (CRUK). Disclosure All authors have declared no conflicts of interest.

Background: Anti-CTLA-4 antibodies (mAbs) display impressive activity in mouse models relative to human subjects, yet this is rarely acknowledged. Translational efforts to date have focused principally on identifying mechanisms of response and resistance in humans, with little reference to pre-clinical models. Through parallel analysis of mouse and human tumours, we sought to characterise respective in vivo determinants of response to anti-CTLA-4 mAbs. Methods: Through multi-parametric flow-based profiling of blood, lymph node and tumour in mouse models and human cancers, we identified lymphocyte and innate effector cell subsets and compared expression of immune checkpoints and activatory/inhibitory Fc gamma receptors (FcγRs) required for ADCC. Thereafter, with use of a transgenic mouse model in which human FcγR expression is effectively recapitulated, we characterised in vivo mechanisms underlying the activity of anti-CTLA-4 mAbs. The translational relevance of such findings was confirmed through analysis of tumour exomes in patients with advanced melanoma treated with ipilimumab. Results: Antibodies of isotype equivalent to ipilimumab and tremelimumab exert their activity principally through depletion of intra-tumoural regulatory T cells (Treg) in vivo, increasing the CD8+ to Treg ratio and promoting tumour rejection. However, this activity only appears relevant in the context of inflamed tumour models. In this setting, engineered antibodies with improved FcγR binding profiles drive superior anti-tumour responses and survival in mouse models. In keeping with these observations, in patients with advanced melanoma, the presence of the germline CD16-V158F polymorphism, which confers a higher binding affinity to FcγRs, is associated with response to anti-CTLA-4 therapy, but only in tumours with high mutational or neoantigen burden. Conclusions: Treg depletion contributes to the activity of human anti-CTLA-4 mAbs but only in the context of inflamed tumours, explaining the modest response rates observed in the clinical setting relative to mouse models. The activity of anti-CTLA-4 mAbs in inflamed tumours may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumours will likely require combination approaches. Legal entity responsible for the study: The Royal Marsden NHS Foundation Trust, University College London Cancer Institute and The Francis Crick Institute. Funding: UCL/UCL Hospitals Biomedical Research Centre, the CRUK-UCL Centre (C416/A18088), CRUK's Lung Cancer Centre of Excellence (C5759/A20465), the Comprehensive Cancer Imaging Centre (CCIC), the Cancer Immunotherapy Accelerator Award (CITA-CRUK) (C33499/A20265), CRUK's TRACERx (led by C.S.) (C11496/A17786), the Sam Keen Foundation/UCL NIHR Biomedical Research Centre (A.J.S.F.), the UK MRC Skills Development Fellowship Award (K.L.), Bloodwise (formerly Leukaemia and Lymphoma Research) (08022/P4664), the Department of Health, and CRUK funding schemes for NIHR BRC and Experimental Cancer Medicine Centres. Disclosure: J. Larkin: Institutional research support: BMS, MSD, Novartis, Pfizer Consultancy: Eisai, BMS, MSD, GSK, Kymab, Pfizer, Novartis, Roche/Genentech, Secarna, Pierre Fabre, EUSA Pharma Support from NIHR RM/ICR Biomedical Research Centre for Cancer. C. Swanton: Grants: Pfizer, AstraZeneca Honoraria or consultant fees: Roche Ventana, Celgene, Pfizer, Novartis, Genentech, BMS Stock shareholder: GRAIL, Epic Biosciences, Apogen Biotech. Co-founder of Achilles Therapeutics. All other authors have declared no conflicts of interest.

We identified a patient with metastatic bladder cancer who presented with shoulder pain. His initial magnetic resonance imaging (MRI) scan of the spine did not identify a metastasis in the first cervical (C1) vertebra. Subsequently he developed severe neck pain and was found to have a fracture of the C1 vertebra. This case prompted an audit investigating symptoms and imaging modalities used to detect cervical spine bone metastases and fractures. There are no set standards for investigating cervical spine metastases except the use of MRI for suspected spinal cord compression [ [1] National Institute for Health and Care Excellence Metastatic spinal cord compression in adults: risk assessment, diagnosis and management. 2008https://www.nice.org.uk/guidance/cg75/chapter/Key-priorities-for-implementation Google Scholar ].

Background: PARP inhibitors (PARPi) have transformed the management of platinum sensitive ovarian cancer, Olaparib maintenance has been shown to improve PFS in patients who responded to platinum based chemotherapy regardless of BRCA status. Real world experience is needed to better understand the toxicity profile and standard care management in a non-trial setting. Methods: A Single cancer centre (UK) analysis evaluating the toxicity profile, rate of dose modifications and survival was performed. 16 BRCA mutation carrier patients commenced maintenance olaparib (capsules) between April 2015 to June 2018 in standard practice (non-trial). Median follow up time was 28.7 months. Clinico-pathological characteristics, adverse events and survival data were recorded, Kaplan-Meier and log-rank test were used to assess survival. Results: Median number of lines prior to PARPi was 3 (2-4). Median age was 58 (35-70), 25% of patients were of asian background. Median treatment duration was 16.6 months (9.6 – 23.7). 12.5% of patients experienced grade 3 AEs (fatigue and thrombocytopenia). 44% (7pts) required a dose modification due to toxicity (3 gastrointestinal, 2 haematological, 2 fatigue). Median time to 1st dose modification was 56 days (11.6 – 100). 2 patients discontinued olaparib due to toxicity. Median number of lines after PARPi was 2 (1-3). 8/9 patients with progressive disease started a subsequent line (56% platinum sensitive), median time to next treatment was 8.4 months (2.5 – 14.3). Median progression free survival was 15.6 months (4.87 – 26.4) and overall survival was 30.86 months (25.56 – 36.2). Conclusions: Olaparib maintenance therapy has an acceptable tolerability profile in real world practice. 44% required a dose modification within the first 3 months of treatment. However, discontinuation rate due to toxicity was low (12.5%). In this small series in clinical practice, the survival outcomes and toxicity profile are in keeping with clinical studies. Legal entity responsible for the study: Royal Marsden NHS Foundation Trust. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Background Immune checkpoint inhibitors (CPI) against lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) are a novel therapeutic breakthrough in an increasing number of malignancies. CPI induced acute liver injury (ALI) is the second most frequently encountered organ toxicity occurring in up to 30% patients. There are no reported data on ALI disease pathogenesis, clinical evolution and outcome of patients treated with CPI therapy. Our multicentre cohort study evaluated clinico-pathological aspects of CPI-induced ALI. Method A retrospective analysis was performed of patients with CPI induced ALI presenting to 6 UK oncology centres between 2013 and 2017. Indices of acute liver injury, treatment related complications and outcome were recorded. Severity scoring of liver injury was based on Common Terminology Criteria for Adverse Events (ALI grade 1–4). Results 65% (36/57) patients received ipilimumab +pembrolizumab or nivolumab (combo group) and 35% (21/57) pembrolizumab or nivolumab alone (mono group). Median treatment duration to development of ALI was 96 days in the mono and 22 days in the combo group. All patients presented with acute elevations in transaminases (ALT 325 [155–543], ALP 111 [72–250]). Immungolulins and autoantibodies were normal. One patient developed acute synthetic dysfunction with no encephalopathy (Bilirubin 64, INR 1.5). 79% received steriods (mean dose:1.3 mg/kg); 34% MMF. Steroid refractory ALI was treated with anti-thymocyte globulin (ATG) in 4 patients. Pathological findings (n=6 liver biopsies) revealed lobular hepatitis and myelo-lymphoid cell infiltrate/aggregates (CD3+,CD8+,CD68+). Patients with severe, refractory (grade 4) ALI had signifcant reductions in circulating lymphocytes/monocytes. 63% (n=35) had a temporal association between recent infection and ALI. 15% (n=8) had colitis prior to onset of ALI. Anti-TNF-a administration for colitis was not associated with more severe ALI. 21% (n=11) developed bacterial infections. Fungal sepsis (aspergillus) occurred in all ATG (n=4) treated patients. Overall 14 patients died with 93% (n=13) due to disease progression and 7% (n=1) due to immunotherapy related neuropathy. All deaths due to progressive disease were in patients with grade 3–4 ALI. Acturial median survival was significantly lower in grade 3–4 (14.5 months) vs grade 1–2 (25 months) liver injury. Conclusion Our data report on the largest cohort of CPI induced ALI identifying disease evolution, markers of disease severity and strong correlation with increased morbidity and mortality. Further research is required to delineate triggers and pathogenesis of CPI induced ALI in order to develop calibrated therapies to ameliorate liver injury.

Monoclonal antibodies targeting the immune checkpoints programmed death-1 (PD-1) and programmed death-ligand-1 (PD-L1) have shown activity leading to approval globally in multiple tumour types. However, even in the context of a relatively sensitive tumour type, melanoma, responses to monotherapy with agents such as nivolumab and pembrolizumab do not exceed 40% [1.Robert C. Schachter J. Long G.V. et al.Pembrolizumab versus ipilimumab in advanced melanoma.N Engl J Med. 2015; 372: 2521-2532Crossref PubMed Scopus (4051) Google Scholar, 2.Weber J.S. D'Angelo S.P. Minor D. et al.Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial.Lancet Oncol. 2015; 16: 375-384Abstract Full Text Full Text PDF PubMed Scopus (2014) Google Scholar] and as such there is a need to develop approaches with greater efficacy. An obvious strategy is to enrich for responders through the use of biomarkers that can predict therapeutic efficacy (and toxicity). While PD-L1 expression is approved to guide patient selection in some tumour types, it does not have enough specificity to guide therapy in melanoma patients at present [3.Daud A.I. Wolchok J.D. Robert C. et al.Programmed death-ligand 1 expression and response to the anti-programmed death 1 antibody pembrolizumab in melanoma.J Clin Oncol. 2016; 34: 4102-4109Crossref PubMed Scopus (417) Google Scholar]. Mutational and neoantigen burden [4.Hugo W. Zaretsky J.M. Sun L. et al.Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma.Cell. 2017; 168: 542.Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, 5.Turajlic S. Litchfield K. Xu H. et al.Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis.Lancet Oncol. 2017; 18: 1009-1021Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar] have demonstrated potential in retrospective analyses but will need prospective evaluation. An alternative or complementary strategy to improving therapeutic efficacy is combining checkpoint inhibitors with other agents and a number of such approaches are under investigation in clinical trials. Ipilimumab, a monoclonal antibody targeting CTLA-4, was approved for the treatment of advanced melanoma in 2011. When given as a single-agent at 3 mg/kg in four infusions over 12 weeks, ipilimumab is associated with durable disease control in around 20% of patients [6.Hodi F.S. O'Day S.J. McDermott D.F. et al.Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med. 2010; 363: 711-723Crossref PubMed Scopus (11191) Google Scholar]. A strong rationale for combining ipilimumab with nivolumab was provided by preclinical evidence [7.Curran M.A. Montalvo W. Yagita H. Allison J.P. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors.Proc Natl Acad Sci USA. 2010; 107: 4275-4280Crossref PubMed Scopus (1330) Google Scholar], and early clinical data demonstrated high response rates [8.Postow M.A. Chesney J. Pavlick A.C. et al.Nivolumab and ipilimumab versus ipilimumab in untreated melanoma.N Engl J Med. 2015; 372: 2006-2017Crossref PubMed Scopus (2099) Google Scholar]. The phase III Checkmate 067 study enrolled 945 patients into three arms: single-agent ipilimumab, single-agent nivolumab and the combination of these two agents. The trial was designed and powered to compare single-agent nivolumab and the combination regimen against single-agent ipilimumab, the standard of care at the time the trial was enrolling. Importantly, Checkmate 067 was not designed or powered to compare the two experimental arms with each other. In 2015, it was reported that both experimental arms demonstrated improvements in progression-free survival and response rate in comparison to ipilimumab monotherapy; in an exploratory analysis, the hazard ratio for progression-free survival for a comparison of the combination treatment to nivolumab was 0.74 [9]. The first report on the overall survival for this study was recently published [10.Wolchok J.D. Chiarion-Sileni V. Gonzalez R. et al.Overall survival with combined nivolumab and ipilimumab in advanced melanoma.N Engl J Med. 2017; 377: 1345-1356Crossref PubMed Scopus (2214) Google Scholar]. Response rates, progression-free survival and toxicity were similar to the initial report. The overall survival data demonstrated that both experimental arms were associated with significant improvements in overall survival compared with ipilimumab monotherapy. The hazard ratio for an exploratory comparison between nivolumab monotherapy and the combination treatment was 0.85 (3-year landmark: 52% for nivolumab and 58% for the combination of ipilimumab and nivolumab) and not statistically significant. How should we interpret these overall survival data, what are their broader implications and do they have any immediate implications for our clinical practice? Caution is required when interpreting the overall survival results for the following reasons: (i) the analysis was conducted at a pre-specified, albeit protocol-defined, time point and was not event driven; as such the number of deaths at the time of the analysis was considerably lower than predicted (approximately 25% less) and (ii) the trial was not powered for the comparison between nivolumab and the combination of ipilimumab and nivolumab. The combination of anti-CTLA4 therapy with anti-PD-1/anti-PD-L1 therapy is currently under investigation across a number of solid tumour types in phase III studies. Combination strategies, particularly as approved for the treatment of advanced melanoma (ipilimumab 3 mg/kg plus nivolumab 1 mg/kg 12-week 'induction' followed by single-agent nivolumab 3 mg/kg 'maintenance') can lead to significant toxicity, mainly in the induction phase, in around half of patients [9.Larkin J. Hodi F.S. Wolchok J.D. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.N Engl J Med. 2015; 373: 1270-1271Crossref PubMed Scopus (557) Google Scholar]. Such regimens must have clear overall survival benefit compared with single-agent sequential approaches because the latter tend to be associated with significantly reduced toxicity. However, registration studies are rarely designed to test sequential versus combination therapy. In our view, there is still a place for the combination of ipilimumab and nivolumab as delivered in Checkmate 067 in patients with advanced melanoma because of its numerically higher and durable response rate and the relative immaturity of the overall survival data. Moreover, patients with melanoma seen in real-world clinical practice such as those with brain metastases and high lactate dehydrogenase are underrepresented in clinical trials, and in both groups, there is evidence to suggest that combination therapy may be preferred upfront over single agent anti-PD-1 therapy [11.Larkin J. Ferrucci F.P. Gonzalez R. et al.Efficacy of nivolumab plus ipilimumab combination in patients with advanced melanoma and elevated serum lactate dehydrogenase a pooled analysis Society for Melanoma Research Boston. 2016; Google Scholar]. However, a very full discussion with patients is required and there are patient groups where combination therapy may be inadvisable such as those with a limited performance status, the frail elderly and those with significant comorbidities. It is also important that only centres with experience of managing immune-related side-effects deliver combination regimens. Predictive factors are currently being elucidated and they are likely to be a helpful guide as to who might derive benefit from combination therapy. These factors include clinical parameters, molecular markers such as tumour expression of PD-L1 and serum lactate dehydrogenase levels. All this will become clearer when more mature survival data from the Checkmate 067 study becomes available. None declared.

Background: MAPK pathway mutations leading to signaling hyperactivation are common in many ST; as RAF kinases play a key role in MAPK signaling, they represent a valid target for therapy. As a pan-RAF inhibitor, TAK-580 is differentiated from approved BRAF-specific RAF inhibitors. Here we report the expanded cohort data from a single-agent, first-in-human study of TAK-580 (NCT01425008). Methods: Patients with advanced ST or inoperable stage III/IV MEL received TAK-580 Q2D or QW in 28-d cycles. Primary objectives were safety and maximum tolerated doses [MTD] of TAK-580; secondary objectives included preliminary antitumor activity, PK and PD effects. Safety and PK were compared between 2 MTD regimens (200 mg Q2D vs 600 mg QW). Preliminary antitumor activity of TAK-580 Q2D vs QW was evaluated in NRAS-mutation positive (mut) MEL. Activity and efficacy (PFS) were assessed in BRAF-mut MEL. Plasma PK were assessed pre- and post-dose between d1 and d28 of cycle 1 (C1). Tumor biopsies were taken at screening and post-dose on d21 or 22 of C1. Disease assessments were performed at baseline and every 2 cycles thereafter. Results: 80 patients received TAK-580 200 mg Q2D (60 MEL + 20 PK-evaluable ST) and 19 MEL patients received 600 mg QW. DLTs observed were: periorbital edema and maculopapular rash (280 mg Q2D); rash and hyperbilirubinemia (800 mg QW). For Q2D and QW, 41% and 32% of patients, respectively, had Gr ≥ 3 drug-related adverse events (AE); 19% and 11% discontinued due to AEs. Total weekly exposure (AUC168h) after TAK-580 600 mg QW was comparable to 3-fold AUC48h after 200 mg Q2D. Of 14 NRAS-mut MEL Q2D patients, 1 achieved PR (1.5 mos). In comparison, none of 17 NRAS-mut MEL QW patients had an objective response. 50% of the 16 BRAF-mut MEL Q2D patients achieved a PR with a median PFS of 4.6 mos (range 1.0–40.8). Conclusions: The safety and PK profiles of TAK-580 Q2D and QW at MTD were acceptable. QW dosing improved safety but not efficacy over Q2D dosing. PD results were consistent with the proposed mechanism of action of TAK-580 with observed RAF pathway inhibition. These data support the use of QW dosing in the assessment TAK-580 given in combination. Clinical trial identification: NCT01425008 Legal entity responsible for the study: Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited Funding: Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited Disclosure: A.J. Olszanski: Consulting or advisory role: Merck, Takeda, BMS, Kyowa Hakko Kirin, G1 Therapuetics; Research funding: Takeda, Immunocore, EMD Serono, Amgen, Incyte, Kyowa Hakko Kirin, Lilly, Advaxis, Mirati Therapuetics, Ignyta, Novartis, Pfizer, BMS, Kura; Travel/accommodation/expenses: Takeda, Churchill Pharmaceuticals, Kyowa Hakko Kirin, G1 Therapuetics. R. Gonzalez: Consultant: Bristol-Myers Squibb, Novartis, Genentech. Research support: Merck, Novartis, Genentech, Bristol-Myers Squibb, Incyte, Syndax, Takeda. P. Corrie: Advisory boards; Novartis, Pierre Fabre, Bristol-Myers Squibb, MSD, Celgene. Research funding: Celgene. Speaker honoraria: MSD, Novartis. M. Middleton: Consulting or advisory role: GSK, BMS, Amgen, Merck, Roche (all compensated); Clovis, Immunocore (both uncompensated); Travel/accommodation/expenses: Roche, Merck; Corporate-sponsored research: GSK, AZ, Eisai, Clovis, BMS, Amgen, Roche, Merck, Vertex, Immunocore, Pfizer, Medimmune. P. Lorigan: Advisory board: GSK, Novartis, Roche, Bristol-Myers Squibb, Merck, Amgen. Travel/accommodation/expenses: Bristol-Myers Squibb, MSD. A. Daud: Stock ownership: OncoSec, Inc.; Advisory board or board of directors: Novartis, Merck, Pfizer, Genentech; Corporate-sponsored research: Merck, Pfizer, Genentech, BMS. S. Zhang, E. Hoberman: Employment: Millennium Pharmaceuticals. Inc. B. Bahamon, L. Rangachari, M. Kneissl: Employment: Millennium Pharmaceuticals, Inc. D. Rasco: Corporate-sponsored research: Takeda Oncology. All other authors have declared no conflicts of interest.

Background: Treatment with immune checkpoint inhibitors (ICPi) has greatly improved survival for patients with advanced melanoma in recent years. Anti-CTLA-4 and anti-PD1 antibodies have been approved following large Phase III trials. Immunerelated neurological toxicity of varying severity has been reported in the literature. The cumulative incidence of neurotoxicity among ipilimumab, nivolumab and pembrolizumab is reported as< 1% in published clinical trials. We aimed to identify the incidence of neurotoxicity in our institution across anti-CTLA4 and anti-PD-1 antibodies, including the combination of ipilimumab with nivolumab. We also review the existing literature and propose an investigation and management algorithm.Methods: All patients with advanced melanoma treated with ipilimumab, nivolumab, pembrolizumab or the combination of ipilimumab and nivolumab (ipi_nivo), managed at the Royal Marsden Hospital between September 2010 and December 2015, including patients on (published) clinical trials were included. Medical records for each patient were reviewed and information on neurotoxicity recorded. A systematic search strategy was performed to collate existing reports of neurological toxicity.Results: In total, 413 immunotherapy treatment episodes in 352 patients were included, with median follow-up of 26.7 months. Ten cases of neurotoxicity were recorded, affecting 2.8% of patients overall, ranging from grade 1 to 4, affecting both central and peripheral nervous systems. A rate of 14% was noted with ipi_nivo. Three of five patients commenced on corticosteroids responded to these. Six patients had made a full recovery at the time of reporting. A favorable radiological response was found in 7 of the 10 cases. Unusual presentations are described in detail.Conclusions: Neurological toxicity is not uncommon, and may be more frequent in patients treated with combination ipinivo. Patterns of presentation and response to treatment are varied. A prompt and considered approach is required to optimize outcomes in this group of patients.

Checkpoint inhibitors are emerging as important cancer therapies but are associated with a high rate of immune side effects, including endocrinopathy.To determine the burden of thyroid dysfunction in patients with melanoma treated with immune checkpoint inhibitors and describe the clinical course.Consecutive patients with melanoma treated with either ipilimumab, nivolumab, pembrolizumab or the combination of ipilimumab and nivolumab were identified. Baseline thyroid function tests were used to exclude those with pre-existing thyroid abnormalities, and thyroid function tests during treatment used to identify those with thyroid dysfunction.Rates of overt thyroid dysfunction were in keeping with the published phase 3 trials. Hypothyroidism occurred in 13·0% treated with a programmed death receptor-1 (PD-1) inhibitor and 22·2% with a combination of PD-1 inhibitor and ipilimumab. Transient subclinical hyperthyroidism was observed in 13·0% treated with a PD-1 inhibitor, 15·9% following a PD-1 inhibitor, and 22·2% following combination treatment with investigations suggesting a thyroiditic mechanism rather than Graves' disease, and a high frequency of subsequent hypothyroidism. Any thyroid abnormality occurred in 23·0% following ipilimumab, 39·1% following a PD-1 inhibitor and 50% following combination treatment. Abnormal thyroid function was more common in female patients.Thyroid dysfunction occurs commonly in patients with melanoma treated with immune checkpoint inhibitors, with rates, including subclinical dysfunction, occurring in up to 50%.

Background: Immunotherapy and VEGF-targeting therapies improve mRCC outcomes; however, immune escape and/or resistance often develops so new agents and combinations are needed. Here, we prospectively explore novel efficacy endpoints and report updated data from IMmotion150 (NCT01984242), a Ph II trial of atezo (anti–PD-L1) with or without bev (anti-VEGF) vs sun (TKI) in 1L mRCC.

AIMS:Despite recent advances in the primary and secondary prevention of cervical cancer, a significant number of women present with or develop metastatic disease. There is currently no consensus on the standard of care for second-line systemic treatment of recurrent/metastatic cervical cancer. The purpose of this study was to evaluate the second-line systemic therapy used and the associated outcomes in a single cancer centre. MATERIALS AND METHODS:A retrospective review of patients with cervical cancer who received one or more lines of treatment for recurrent or metastatic cervical cancer at the Royal Marsden Hospital between 2004 and 2014 was carried out. The primary objective was to establish the types of second-line systemic treatment used. Secondary end points included objective response rate, progression-free survival and overall survival after second-line therapy. RESULTS:In total, 75 patients were included in the study; 53 patients (70.7%) received second-line therapy for recurrent/metastatic disease. The most common second-line therapy was weekly paclitaxel (28.3%). Carboplatin-based chemotherapy (24.5%), targeted agent monotherapy within clinical trials (22.6%), docetaxel-based chemotherapy (13.2%), topotecan (9.4%) and gemcitabine (1.9%) were also used. The objective response rate to second-line therapy was 13.2%, which included three partial responses to carboplatin and paclitaxel, two partial responses to docetaxel-based chemotherapy, one partial response to weekly paclitaxel and one partial response to cediranib. Twenty-two patients (41.5%) achieved stable disease at 4 months. The median progression-free survival for women treated with second-line therapy was 3.2 months (95% confidence interval 2.1-4.3) and median overall survival was 9.3 months (95% confidence interval 6.4-12.5). Thirty-nine per cent of patients received third-line therapy. CONCLUSION:Seventy per cent of patients treated with first-line systemic therapy for recurrent/metastatic cervical cancer subsequently received second-line treatment but response rates were poor. There remains no standard of care for second-line systemic therapy for advanced cervical cancer. Patients should be considered for clinical trials whenever feasible, including novel targeted agents and immunotherapy.

Background: Treatment with programmed death receptor-1 (PD-1) antibodies is associated with high response rates in patients with advanced melanoma. Reliable markers for early response and outcome are still sparse. Methods: We evaluated 66 consecutive patients with advanced/metastatic melanoma treated with nivolumab or pembrolizumab between 2013 and 2014. The main objectives of this study were to investigate whether, first, serum lactate dehydrogenase (LDH) at baseline (normal vs above the upper limit of normal) correlates with overall survival (OS), and, second, whether the change of LDH during treatment predicts response before the first scan and OS in patients with an elevated baseline LDH. Results: After a median follow-up of 9 months, patients with an elevated baseline LDH ( N =34) had a significantly shorter OS compared with patients with normal LDH ( N =32; 6-month OS: 60.8% vs 81.6% and 12-month OS: 44.2% vs 71.5% (log-rank P =0.0292). In those 34 patients with elevated baseline LDH, the relative change during treatment was significantly associated with an objective response on the first scan: the 11 (32%) patients with partial remission had a mean reduction of −27.3% from elevated baseline LDH. In contrast, patients with progressive disease ( N =15) had a mean increase of +39%. Patients with a relative increase over 10% from elevated baseline LDH had a significantly shorter OS compared with patients with ⩽10% change (4.3 vs 15.7 months, log-rank P <0.00623). Conclusions: LDH could be a useful marker at baseline and during treatment to predict early response or progression in patients with advanced melanoma who receive anti-PD-1 therapy.

OBJECTIVES:To determine the impact on survival of symptomatic and asymptomatic venous thromboembolism (VTE) at time of diagnosis of primary ovarian malignancy.MATERIALS AND METHODS:The clinical records of 397 consecutive cases of primary ovarian malignancy were studied. Clinical, pathological and survival data were obtained.RESULTS AND CONCLUSIONS:Of 397 cases, 19 (4.8%) were found to have VTE at diagnosis, of which 63.2% (n=12) were asymptomatic. VTE was significantly associated with reduced overall median survival (28 vs. 45 months, p=0.004). Decreased survival was associated with symptomatic VTE compared to patients with asymptomatic VTE (21 vs. 36 months, p=0.02) whose survival was similar to that of patients without VTE. Decreased survival remained significant in symptomatic patients after controlling for stage of disease at diagnosis, cytoreductive status and adjuvant chemotherapy use. Overall these data suggest for the first time that symptomatic but not asymptomatic VTE prior to primary treatment of ovarian cancer is an independent adverse prognostic factor.

Low-grade serous carcinoma (LGSC) of the ovary/peritoneum is characterised by relative resistance to chemotherapy, however there are no reported prospective studies of chemotherapy specifically in this rare subtype. The purpose of this study was to evaluate the response to chemotherapy in patients with relapsed LGSC treated at a single cancer centre. A search of a database of patients with histologically confirmed LGSC treated at the Royal Marsden Hospital between 1990-2015 was performed. Patients treated with chemotherapy in the relapsed setting with radiologically evaluable disease were included in the study. Histological confirmation of LGSC was performed by a gynae-oncology pathologist. Response was determined by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 and confirmed by a radiologist. The primary endpoint was objective response rate (ORR). Secondary endpoints included overall survival (OS) and progression-free survival (PFS). Forty-six patients with relapsed LGSC with evaluable disease, treated with 77 separate chemotherapy regimens were included in the study. The median age at diagnosis was 49 years (range 22-80 years). There were 8 partial responses with an ORR of 10.4%. The median duration of response was 11.2 months. Stable disease was achieved in 58 of 77 (75.3%) treatment regimens. The stable disease rate at 6 months was 43%. The ORR for the platinum-sensitive cohort was 11.3% and 8.3% for the platinum-resistant cohort. The median OS was 62 months and median PFS was 8.2 months. Relapsed LGSC is relatively resistant to chemotherapy in comparison to the most common subtype, high-grade serous carcinoma. In our series, the response rate to chemotherapy (10.4%) for recurrent LGSC is higher than previously published retrospective series (3.7%). Chemotherapy should be considered an option for recurrent LGSC. There is an urgent need for better therapies and identification of LGSC patients who are more likely to respond to chemotherapy. Patients should be enrolled into clinical trials of novel targeted agents.

D/C is reported in up to 30% of patients treated with ICPI. Treatment algorithms advocate corticosteroids (CS) for moderate to severe symptoms. Patterns of endoscopic change and duration of CS are not described. Rates of CS toxicity in this group of patients are unclear. Medical records of melanoma patients treated with ICPI at the Royal Marsden Hospital from 2010-2015 were reviewed. The grade, duration of CS and infliximab (INF) use was recorded for each D/C episode. Patients who had flexible sigmoidoscopy (FS) were labeled as having macroscopic + /-microscopic (macro), microscopic (micro) changes alone or no changes (normal). CS toxicities were noted. 414 ICPI treatment episodes were undertaken in 353 patients. The rate of all-grade D/C was 23% (96/414): 27% (77/282) with ipilimumab, 8% (8/101) with anti-PD-1 agents and 38% (8/21) with combination ipilimumab + nivolumab. Median age 61 years, 54% were male.Tabled 1Steroid use by Flexible Sigmoidoscopy FindingsNReceived CS (%)No CSMedian CS duration days (range)UNK re CS durationOn CS at 3mths (%)UNK re CS at 3mths (%)INF (%)Median days CS to INF (range)Macro2724 (89)369 (5-278)410 (42)4 (15)8 (33)15 (6-60)Micro87 (88)151 (12-162)02 (29)00naNormal FS98 (89)140 (7-156)01 (13)02 (25)11 (2-20)Unknown65 (8)167 (36-91)11 (20)01 (20)9 Open table in a new tab 57% (55/96) required CS. 52% (50/96) underwent FS: 88% (44/50) received CS. Median duration of CS was higher in macro patients compared to a normal FS (69 vs 40 days; p = 0.07) and in micro patients compared to a normal FS (51 vs 40 days; p = 0.32; Table 1). 11% (11/96) of D/C was treated with INF and median CS duration in this population was 91 days, versus 52 days for those who received CS alone. Median time from first steroid to INF was 15 days (range 2-60). 25% (14/55) were on steroids at 3 months. At least 15% (8/55) developed new or worse diabetes, 13% (7/55) had mood change and 16% (9/55) developed an antibiotic-requiring infection. We describe different phenotypes of D/C associated with ICPI therapy. Appearances at FS may predict for duration of CS use. All patients should be monitored for stigmata of CS use and considered for PJP prophylaxis. CS sparing strategies should be prospectively evaluated.