A randomised phase 2 study of intermittent versus continuous dosing of dabrafenib plus trametinib in patients with BRAFV600 mutant advanced melanoma (INTERIM).

BACKGROUND: BRAF+MEK inhibitors extend life expectancy of patients with BRAFV600 mutant advanced melanoma. Acquired resistance limits duration of benefit, but preclinical and case studies suggest intermittent dosing could overcome this limitation. INTERIM was a phase 2 trial evaluating an intermittent dosing regimen. METHODS: Patients with BRAFV600 mutant advanced melanoma due to start dabrafenib+trametinib were randomised to receive either continuous (CONT), or intermittent (INT; dabrafenib d1-21, trametinib d1-14 every 28 days) dosing. A composite primary endpoint included progression-free survival (PFS) and quality of life (QoL). Secondary endpoints included response rate (ORR), overall survival (OS) and adverse events (AEs). Mutant BRAFV600E ctDNA was measured by droplet digital PCR (ddPCR), using mutant allele frequency of > 1 % as the detection threshold. RESULTS: 79 patients (39 INT, 40 CONT) were recruited; median age 67 years, 65 % AJCC (7th ed) stage IV M1c, 29 % had brain metastases. With 19 months median follow-up, INT was inferior in all efficacy measures: median PFS 8.5 vs 10.7mo (HR 1.39, 95 %CI 0.79-2.45, p = 0.255); median OS 18.1mo vs not reached (HR 1.69, 95 %CI 0.87-3.28, p = 0.121), ORR 57 % vs 77 %. INT patients experienced fewer treatment-related AEs (76 % vs 88 %), but more grade > 3 AEs (53 % vs 42 %). QoL favoured CONT. Detection of BRAFV600E ctDNA prior to treatment correlated with worse OS (HR 2.55, 95 %CI 1.25-5.21, p = 0.01) in both arms. A change to undetected during treatment did not significantly predict better OS. CONCLUSION: INTERIM findings are consistent with other recent clinical trials reporting that intermittent dosing does not improve efficacy of BRAF+MEK inhibitors.

Standard Versus Modified Ipilimumab, in Combination With Nivolumab, in Advanced Renal Cell Carcinoma: A Randomized Phase II Trial (PRISM).

PURPOSE: Ipilimumab (IPI), in combination with nivolumab (NIVO), is an approved frontline treatment option for patients with intermediate- or poor-risk advanced renal cell carcinoma (aRCC). We conducted a randomized phase II trial to evaluate whether administering IPI once every 12 weeks (modified), instead of once every 3 weeks (standard), in combination with NIVO, is associated with a favorable toxicity profile. METHODS: Treatment-naïve patients with clear-cell aRCC were randomly assigned 2:1 to receive four doses of modified or standard IPI, 1 mg/kg, in combination with NIVO (3 mg/kg). The primary end point was the proportion of patients with a grade 3-5 treatment-related adverse event (trAE) among those who received at least one dose of therapy. The key secondary end point was 12-month progression-free survival (PFS) in the modified arm compared with historical sunitinib control. The study was not designed to formally compare arms for efficacy. RESULTS: Between March 2018 and January 2020, 192 patients (69.8% intermediate/poor-risk) were randomly assigned and received at least one dose of study drug. The incidence of grade 3-5 trAEs was significantly lower among participants receiving modified versus standard IPI (32.8% v 53.1%; odds ratio, 0.43 [90% CI, 0.25 to 0.72]; P = .0075). The 12-month PFS (90% CI) using modified IPI was 46.1% (38.6 to 53.2). At a median follow-up of 21 months, the overall response rate was 45.3% versus 35.9% and the median PFS was 10.8 months versus 9.8 months in the modified and standard IPI groups, respectively. CONCLUSION: Rates of grade 3-5 trAEs were significantly lower in patients receiving modified versus standard IPI. Although 12-month PFS did not meet the prespecified efficacy threshold compared with historical control, informal comparison of treatment groups did not suggest any reduction in efficacy with the modified schedule.

Efficacy and safety of immune checkpoint inhibitors in young adults with metastatic melanoma.

BACKGROUND: The integration of immune checkpoint inhibitors (ICI) for the treatment of melanoma has resulted in remarkable and durable responses. Given the potential role of immunosenescence, age may contribute to differential ICI efficacy and toxicity. While older patients have been studied in detail, outcomes from ICI in young patients (≤40 years) are not well characterised. METHODS: We performed a multi-institutional, retrospective study of patients with advanced melanoma treated with anti-PD-1 monotherapy or ICI combination (ipilimumab and anti-PD-1). Response rates, survival, and toxicities were examined based on age comparing those under 40 years of age with older patients (age 41-70 and ≥ 71 years). RESULTS: A total of 676 patients were included: 190 patients (28%) aged ≤40 years, 313 (46%) between ages 41-70, and 173 patients (26%) aged ≥71. Patients ≤40 years had higher response rates (53% vs 38%, p = 0.035) and improved progression-free survival (median 13.7 vs 4.0 months, p = 0.032) with combination ICI compared to monotherapy. Progression-free survival was similar among groups while overall survival was inferior in patients >70 years, who had low response rates to combination therapy (28%). ICIs had a similar incidence of severe toxicities, though hepatotoxicity was particularly common in younger patients vs. patients >40 with monotherapy (9% vs. 2%, p = 0.007) or combination ICI (37% vs. 10%, p < 0.001). CONCLUSIONS: ICIs had comparable efficacy between younger and older patients, although outcomes were superior with combination ICI compared to monotherapy in patients aged ≤40 years. Toxicity incidence was similar across age groups, though organs affected were substantially different.

REFINE (REduced Frequency ImmuNE checkpoint inhibition in cancers): A multi-arm phase II basket trial testing reduced intensity immunotherapy across different cancers.

BACKGROUND: Immune checkpoint inhibitors (ICI) have revolutionised treating advanced cancers. ICI are administered intravenously every 2-6 weeks for up to 2 years, until cancer progression/unacceptable toxicity. Physiological efficacy is observed at lower doses than those used as standard of care (SOC). Pharmacodynamic studies indicate sustained target occupancy, despite a pharmacological half-life of 2-3 weeks. Reducing frequency of administration may be possible without compromising outcomes. The REFINE trial aims to limit individual patient exposure to ICI whilst maintaining efficacy, with potential benefits in quality of life and reduced drug treatment/attendance costs. METHODS/DESIGN: REFINE is a randomised phase II, multi-arm, multi-stage (MAMS) adaptive basket trial investigating extended interval administration of ICIs. Eligible patients are those responding to conventionally dosed ICI at 12 weeks. In stage I, patients (n = 160 per tumour-specific cohort) will be randomly allocated (1:1) to receive maintenance ICI at SOC vs extended dose interval. REFINE is currently recruiting UK patients with locally advanced or metastatic renal cell carcinoma (RCC) who have tolerated and responded to initial nivolumab/ipilimumab, randomised to receive maintenance nivolumab SOC (480 mg 4 weekly) vs extended interval (480 mg 8 weekly). Additional tumour cohorts are planned. Subject to satisfactory outcomes (progression-free survival) stage II will investigate up to 5 different treatment intervals. Secondary outcome measures include overall survival, quality-of-life, treatment-related toxicity, mean incremental pathway costs and quality-adjusted life-years per patient. REFINE is funded by the Jon Moulton Charity Trust and Medical Research Council, sponsored by University College London (UCL), and coordinated by the MRC CTU at UCL. Trial Registration ISRCTN79455488. NCT04913025 EUDRACT #: 2021-002060-47. CTA 31330/0008/001-0001; MREC approval: 21/LO/0593. REFINE Protocol version 4.0.

The spectrum of cardiovascular complications related to immune-checkpoint inhibitor treatment : Including myocarditis and the new entity of non inflammatory left ventricular dysfunction.

BACKGROUND: The full range of cardiovascular complications related to the use of Immune checkpoint inhibitors (ICI) is not fully understood. We aim to describe the spectrum of cardiovascular adverse events (cvAEs) by presenting our real-world experience of the diagnosis and management of these complications. METHODS: Two thousand six hundred and forty-seven (2647) patients were started on ICI treatment between 2014 and 2020. Data from 110 patients referred to the cardio-oncology service with a suspected cvAE was collected prospectively and analysed. RESULTS: Eighty-nine patients (3.4%) were confirmed to have cvAEs while on ICI therapy. Myocarditis was the most frequent event (33/89), followed by tachyarrhythmia (27/89), non-inflammatory left ventricular dysfunction (NILVD) (15/89) and pericarditis (7/89). Results from myocarditis and non-inflammatory left ventricular dysfunction cohorts were compared. Myocarditis and NILVD showed significant differences in respect toof troponin elevation, cardiac magnetic resonance abnormalities and ventricular function. Dual ICI therapy and other immune related adverse events were more frequently associated with myocarditis than NILVD. There was a significant difference in the median time from starting ICI treatment to presentation with myocarditis versus NILVD (12 vs 26 weeks p = 0.049). Through early recognition of myocarditis, prompt treatment with steroids and interruption of ICI, there were no cardiovascular in-hospital deaths. NILVD did not require steroid treatment and ICI could be restarted safely. CONCLUSIONS: The full spectrum of cardiovascular complications in patients with immune checkpoint inhibitors is much broader than initially described. Myocarditis remains the most frequent cvAE related to ICI treatment. A novel type of myocardial injury was observed and defined as Atrial tachyarrhythmias and NILVD were also frequent in this cohort. NILVD has a This differs fromdifferent presentation from ICI-related myocarditis, mainly usually presenting afterby the lack of inflammatory features on CMR and biomarkers and a later presentation in time.

Real-world outcomes with ipilimumab and nivolumab in advanced melanoma: a multicentre retrospective study.

PURPOSE: To assess efficacy and toxicity of combination immunotherapy with ipilimumab plus nivolumab in routine practice in a retrospective multicentre cohort of patients with advanced melanoma. PATIENTS AND METHODS: This retrospective analysis included patients with advanced melanoma treated with ipilimumab and nivolumab between October 2015 and January 2020 at six centres in Australia, Europe and the United States of America. We describe efficacy outcomes (overall survival [OS], progression-free survival [PFS] and objective response rate [ORR]) in treatment-naïve and pre-treated patients, with and without brain metastases, plus treatment-related adverse events (trAEs) in all patients treated. RESULTS: A total of 697 patients were identified; 472 were treatment-naïve of which 138 (29.2%) had brain metastases, and 225 were previously treated of which 102 (45.3%) had brain metastases. At baseline, 32.3% had stage M1c and 34.4% stage M1d disease. Lactate dehydrogenase was high in 280 patients (40.2%). With a median follow-up of 25.9 months, median OS in the 334 treatment-naïve patients without brain metastases was 53.7 months (95% confidence interval [CI] 40.8-NR) and 38.7 months (95% CI 18.6-NR) for the 138 treatment-naïve patients with brain metastases. For the entire cohort the ORR was 48%, for treatment-naïve patients without brain metastases ORR was 56.6% with a median PFS of was 13.7 months (95% CI 9.6-26.5). Median PFS was 7.9 months (95% CI 5.8-10.4) and OS 38 months (95% CI 31-NR) for the entire cohort. Grade 3-4 trAE were reported in 44% of patients, and 4 (0.7%) treatment-related deaths (1 pneumonitis, 2 myocarditis and 1 colitis) were recorded. CONCLUSION: The outcome and toxicity of combination immunotherapy with ipilimumab and nivolumab in a real-world patient population are similar to those reported in pivotal trials.

Oral beclomethasone dipropionate is an effective treatment for immune checkpoint inhibitor induced colitis.

INTRODUCTION: Systemic corticosteroids are the mainstay of treatment for immune checkpoint inhibitor induced (CPI) colitis but are associated with complications including life-threatening infection. The topically acting oral corticosteroid beclomethasone dipropionate (BD) is an effective treatment for mild to moderate flares of ulcerative colitis, and has fewer side effects than systemic corticosteroids. We hypothesized that BD would be an effective treatment for CPI-induced colitis. METHODS: We performed a retrospective analysis of all patients who started BD for CPI-induced colitis at three UK cancer centers between November 2017 and October 2020. All patients underwent endoscopic assessment and biopsy. The initial regimen of BD was 5 mg once daily for 28 days. Data were collected from electronic patient records. Clinical outcomes were assessed at 28 days after initiation of treatment. RESULTS: Twenty-two patients (14 male) with a median age of 64 (range 45-84) with CPI-induced colitis were treated with BD. At baseline, the median number of loose stools in a 24-hour period was six (common terminology criteria for adverse events, CTCAE grade diarrhea=2). Thirteen patients (59%) were dependent on systemic corticosteroids prior to starting BD. Baseline sigmoidoscopy showed moderate inflammation (Mayo Endoscopic Score (MES) = 2) in two patients (9%), mild inflammation (MES=1) in nine patients (41%) and normal findings (MES=0) in eleven patients (50%). Twenty patients (91%) had histopathological features of inflammation. All 22 patients (100%) had a clinical response to BD and 21 (95%) achieved clinical remission with a return to baseline stool frequency (CTCAE diarrhea=0). Ten patients (45%) had symptomatic relapse on cessation of BD, half within 7 days of stopping. All patients recaptured response on restarting BD. No adverse events were reported in patients treated with BD. CONCLUSIONS: Topical BD represents an appealing alternative option to systemic immunosuppressive treatments to treat colonic inflammation. In this study, BD was effective and safe at inducing remission in CPI-induced colitis, which was refractory to systemic corticosteroids. Further randomized studies are needed to confirm these findings and determine the optimum dosing regimen.

Clinical Models to Define Response and Survival With Anti-PD-1 Antibodies Alone or Combined With Ipilimumab in Metastatic Melanoma.

PURPOSE: Currently, there are no robust biomarkers that predict immunotherapy outcomes in metastatic melanoma. We sought to build multivariable predictive models for response and survival to anti-programmed cell death protein 1 (anti-PD-1) monotherapy or in combination with anticytotoxic T-cell lymphocyte-4 (ipilimumab [IPI]; anti-PD-1 ± IPI) by including routine clinical data available at the point of treatment initiation. METHODS: One thousand six hundred forty-four patients with metastatic melanoma treated with anti-PD-1 ± IPI at 16 centers from Australia, the United States, and Europe were included. Demographics, disease characteristics, and baseline blood parameters were analyzed. The end points of this study were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The final predictive models for ORR, PFS, and OS were determined through penalized regression methodology (least absolute shrinkage and selection operator method) to select the most significant predictors for all three outcomes (discovery cohort, N = 633). Each model was validated internally and externally in two independent cohorts (validation-1 [N = 419] and validation-2 [N = 592]) and nomograms were created. RESULTS: The final model for predicting ORR (area under the curve [AUC] = 0.71) in immunotherapy-treated patients included the following clinical parameters: Eastern Cooperative Oncology Group Performance Status, presence/absence of liver and lung metastases, serum lactate dehydrogenase, blood neutrophil-lymphocyte ratio, therapy (monotherapy/combination), and line of treatment. The final predictive models for PFS (AUC = 0.68) and OS (AUC = 0.77) included the same variables as those in the ORR model (except for presence/absence of lung metastases), and included presence/absence of brain metastases and blood hemoglobin. Nomogram calculators were developed from the clinical models to predict outcomes for patients with metastatic melanoma treated with anti-PD-1 ± IPI. CONCLUSION: Newly developed combinations of routinely collected baseline clinical factors predict the response and survival outcomes of patients with metastatic melanoma treated with immunotherapy and may serve as valuable tools for clinical decision making.

VinCaP: a phase II trial of vinflunine in locally advanced and metastatic squamous carcinoma of the penis.

BACKGROUND: We investigated the first-line activity of vinflunine in patients with penis cancer. Cisplatin-based combinations are commonly used, but survival is not prolonged; many patients are unfit for such treatment or experience toxicity that outweighs clinical benefit. METHODS: Twenty-five patients with inoperable squamous carcinoma of the penis were recruited to a single-arm, Fleming-A'Hern exact phase II trial. Treatment comprised 4 cycles of vinflunine 320 mg/m2, given every 21 days. Primary endpoint was clinical benefit rate (CBR: objective responses plus stable disease) assessed after 4 cycles. Seven or more objective responses or disease stabilisations observed in 22 evaluable participants would exclude a CBR of <15%, with a true CBR of >40% being probable. RESULTS: Twenty-two participants were evaluable. Ten objective responses or disease stabilisations were confirmed. CBR was 45.5%, meeting the primary endpoint; partial response rate was 27.3%. Seven patients received >4 cycles of vinflunine. Dose reduction or treatment delay was required for 20% of cycles. In all, 68% of patients experienced at least one grade 3 adverse event. Two deaths on treatment were not caused by disease progression. CONCLUSIONS: Pre-specified clinical activity threshold was exceeded. Toxicity was in keeping with experience in other tumours. Vinflunine merits further study in this disease. TRIAL REGISTRATION: NCT02057913.

Spatial patterns of tumour growth impact clonal diversification in a computational model and the TRACERx Renal study.

Genetic intra-tumour heterogeneity fuels clonal evolution, but our understanding of clinically relevant clonal dynamics remain limited. We investigated spatial and temporal features of clonal diversification in clear cell renal cell carcinoma through a combination of modelling and real tumour analysis. We observe that the mode of tumour growth, surface or volume, impacts the extent of subclonal diversification, enabling interpretation of clonal diversity in patient tumours. Specific patterns of proliferation and necrosis explain clonal expansion and emergence of parallel evolution and microdiversity in tumours. In silico time-course studies reveal the appearance of budding structures before detectable subclonal diversification. Intriguingly, we observe radiological evidence of budding structures in early-stage clear cell renal cell carcinoma, indicating that future clonal evolution may be predictable from imaging. Our findings offer a window into the temporal and spatial features of clinically relevant clonal evolution.

Tissue based biomarkers in non-clear cell RCC: Correlative analysis from the ASPEN clinical trial.

Biomarkers are needed in patients with non-clear cell renal cell carcinomas (NC-RCC), particularly papillary renal cell carcinoma, in order to inform on initial treatment selection and identify potentially novel targets for therapy. We enrolled 108 patients in ASPEN, an international randomized open-label phase 2 trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC treated with the mTOR inhibitor everolimus (n=57) or the vascular endothelial growth factor (VEGF) receptor inhibitor sunitinib (n=51), stratified by MSKCC risk and histology. The primary endpoint was overall survival (OS) and secondary efficacy endpoints for this exploratory biomarker analysis were radiographic progression-free survival (rPFS) defined by intention-to-treat using the RECIST 1.1 criteria and radiographic response rates. Tissue biomarkers (n=78) of mTOR pathway activation (phospho-S6 and -Akt, c-kit) and VEGF pathway activation (HIF-1α, c-MET) were prospectively explored in tumor tissue by immunohistochemistry prior to treatment and associated with clinical outcomes. We found that S6 activation was more common in poor risk NC-RCC tumors and S6/Akt activation was associated with worse PFS and OS outcomes with both everolimus and sunitinib, while c-kit was commonly expressed in chromophobe tumors and associated with improved outcomes with both agents. C-MET was commonly expressed in papillary tumors and was associated with lower rates of radiographic response but did not predict PFS for either agent. In multivariable analysis, both pAkt and c-kit were statistically significant prognostic biomarkers of OS. No predictive biomarkers of treatment response were identified for clinical outcomes. Most biomarker subgroups had improved outcomes with sunitinib as compared to everolimus.

Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma.

ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action.

Clinical outcomes of patients with corticosteroid refractory immune checkpoint inhibitor-induced enterocolitis treated with infliximab.

INTRODUCTION: Immune checkpoint inhibitors (CPIs) have changed the treatment landscape for many cancers, but also cause severe inflammatory side effects including enterocolitis. CPI-induced enterocolitis is treated empirically with corticosteroids, and infliximab (IFX) is used in corticosteroid-refractory cases. However, robust outcome data for these patients are scarce. METHODS: We conducted a multicenter (six cancer centers), cohort study of outcomes in patients treated with IFX for corticosteroid-refractory CPI-induced enterocolitis between 2007 and 2020. The primary outcome was corticosteroid-free clinical remission (CFCR) with Common Terminology Criteria for Adverse Events (CTCAE) grade 0 for diarrhea at 12 weeks after IFX initiation. We also assessed cancer outcomes at 1 year using RECIST V1.1 criteria. RESULTS: 127 patients (73 male; median age 59 years) were treated with IFX for corticosteroid-refractory CPI-induced enterocolitis. Ninety-six (75.6%) patients had diarrhea CTCAE grade >2 and 115 (90.6%) required hospitalization for colitis. CFCR was 41.2% at 12 weeks and 50.9% at 26 weeks. In multivariable logistic regression, IFX-resistant enterocolitis was associated with rectal bleeding (OR 0.19; 95% CI 0.04 to 0.80; p=0.03) and absence of colonic crypt abscesses (OR 2.16; 95% CI 1.13 to 8.05; p=0.03). Cancer non-progression was significantly more common in patients with IFX-resistant enterocolitis (64.4%) as compared with patients with IFX-responsive enterocolitis (37.5%; p=0.013). CONCLUSION: This is the largest study to date reporting outcomes of IFX therapy in patients with corticosteroid-refractory CPI-induced enterocolitis. Using predefined robust endpoints, we have demonstrated that fewer than half of patients achieved CFCR. Our data also indicate that cancer outcomes may be better in patients developing prolonged and severe inflammatory side effects of CPI therapy.

Cytokine release syndrome in a patient with colorectal cancer after vaccination with BNT162b2.

Patients with cancer are currently prioritized in coronavirus disease 2019 (COVID-19) vaccination programs globally, which includes administration of mRNA vaccines. Cytokine release syndrome (CRS) has not been reported with mRNA vaccines and is an extremely rare immune-related adverse event of immune checkpoint inhibitors. We present a case of CRS that occurred 5 d after vaccination with BTN162b2 (tozinameran)-the Pfizer-BioNTech mRNA COVID-19 vaccine-in a patient with colorectal cancer on long-standing anti-PD-1 monotherapy. The CRS was evidenced by raised inflammatory markers, thrombocytopenia, elevated cytokine levels (IFN-γ/IL-2R/IL-18/IL-16/IL-10) and steroid responsiveness. The close temporal association of vaccination and diagnosis of CRS in this case suggests that CRS was a vaccine-related adverse event; with anti-PD1 blockade as a potential contributor. Overall, further prospective pharmacovigillence data are needed in patients with cancer, but the benefit-risk profile remains strongly in favor of COVID-19 vaccination in this population.

Selection of metastasis competent subclones in the tumour interior.

The genetic evolutionary features of solid tumour growth are becoming increasingly well described, but the spatial and physical nature of subclonal growth remains unclear. Here, we utilize 102 macroscopic whole-tumour images from clear cell renal cell carcinoma patients, with matched genetic and phenotypic data from 756 biopsies. Utilizing a digital image processing pipeline, a renal pathologist marked the boundaries between tumour and normal tissue and extracted positions of boundary line and biopsy regions to X and Y coordinates. We then integrated coordinates with genomic data to map exact spatial subclone locations, revealing how genetically distinct subclones grow and evolve spatially. We observed a phenotype of advanced and more aggressive subclonal growth in the tumour centre, characterized by an elevated burden of somatic copy number alterations and higher necrosis, proliferation rate and Fuhrman grade. Moreover, we found that metastasizing subclones preferentially originate from the tumour centre. Collectively, these observations suggest a model of accelerated evolution in the tumour interior, with harsh hypoxic environmental conditions leading to a greater opportunity for driver somatic copy number alterations to arise and expand due to selective advantage. Tumour subclone growth is predominantly spatially contiguous in nature. We found only two cases of subclone dispersal, one of which was associated with metastasis. The largest subclones spatially were dominated by driver somatic copy number alterations, suggesting that a large selective advantage can be conferred to subclones upon acquisition of these alterations. In conclusion, spatial dynamics is strongly associated with genomic alterations and plays an important role in tumour evolution.

Angiokines Associated with Targeted Therapy Outcomes in Patients with Non-Clear Cell Renal Cell Carcinoma.

PURPOSE: Biomarkers are needed in patients with non-clear cell renal cell carcinomas (NC-RCC) to inform treatment selection but also to identify novel therapeutic targets. We thus sought to profile circulating angiokines in the context of a randomized treatment trial of everolimus versus sunitinib. PATIENTS AND METHODS: ASPEN (NCT01108445) was an international, randomized, open-label phase II trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC with no prior systemic therapy. Patients were randomized to everolimus or sunitinib and treated until disease progression or unacceptable toxicity. The primary endpoint was radiographic progression-free survival (PFS) defined by RECIST 1.1. Plasma angiokines were collected at baseline, cycle 3, and progression and associated with PFS and overall survival (OS). RESULTS: We enrolled 108 patients, 51 received sunitinib and 57 everolimus; of these, 99 patients had evaluable plasma for 23 angiokines. At the final data cutoff, 94 PFS and 64 mortality events had occurred. Angiokines that were independently adversely prognostic for OS were osteopontin (OPN), TIMP-1, thrombospondin-2 (TSP-2), hepatocyte growth factor (HGF), and VCAM-1, and these were also associated with poor-risk disease. Stromal derived factor 1 (SDF-1) was associated with improved survival. OPN was also significantly associated with worse PFS. No statistically significant angiokine-treatment outcome interactions were observed for sunitinib or everolimus. Angiopoeitin-2 (Ang-2), CD-73, HER-3, HGF, IL6, OPN, PIGF, PDGF-AA, PDGF-BB, SDF-1, TGF-b1-b2, TGFb-R3, TIMP-1, TSP-2, VCAM-1, VEGF, and VEGF-R1 levels increased with progression on everolimus, while CD-73, ICAM-1, IL6, OPN, PlGF, SDF-1, TGF-b2, TGFb-R3, TIMP-1, TSP-2, VEGF, VEGF-D, and VCAM-1 increased with progression on sunitinib. CONCLUSIONS: In patients with metastatic NC-RCC, we identified several poor prognosis angiokines and immunomodulatory chemokines during treatment with sunitinib or everolimus, particularly OPN.

Long-term multicentre experience of adjuvant radiotherapy for pN3 squamous cell carcinoma of the penis.

OBJECTIVE: To present the long-term adjuvant radiotherapy outcomes of patients with pN3 squamous cell carcinoma of the penis (SCCp) treated at two UK centres. PATIENTS AND METHODS: We conducted a retrospective audit of all pN3 SCCp patients, deemed suitable for adjuvant therapy by a specialist multidisciplinary team at St George's and Leeds Hospitals, who received adjuvant radiotherapy. Primary outcomes were recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS). Secondary outcomes were time to adjuvant treatment, frequency of in-field recurrence, site and side of recurrence, and dose and schedule of radiotherapy. RESULTS: A total of 146 patients were included: 121 completed radiotherapy, 4 did not complete radiotherapy and 21 did not start it. The median (interquartile range [IQR]) age was 59 (54-70)years. The 5-year RFS was 51%, CSS was 51% and OS was 44%. Adjuvant radiotherapy was started at a median (IQR) of 75 (48-106) days. A dose of 45 Gy in 20 fractions was most commonly used. Of the 125 patients who started adjuvant treatment, 55 relapsed. Of these relapses, 30 occurred in an inguinal or pelvic nodal station and 26 of the 30 were in a radiation field. Relapses in 18 of the 55 cases were in visceral sites only and seven were in both nodal (non-irradiated sites) and visceral sites. Doses of <50 Gy were used more commonly before 2013 and higher doses (>50 Gy) were more commonly used after 2013. CONCLUSIONS: Application of a standard radiotherapy protocol within a centralized supra-network setting has achieved survival outcomes that would appear better than those previously documented for either radiotherapy or chemotherapy in a cohort with solely pN3 disease. The addition of adjuvant chemotherapy may improve these outcomes further. These data suggest that adjuvant radiotherapy has a role to play in the management of men with pN3 SCCp.