J.B.A.G. Haanen

Choi response criteria for early prediction of clinical outcome in patients with metastatic renal cell cancer treated with sunitinib

Background:Because sunitinib can induce extensive necrosis in metastatic renal cell cancer (mRCC), we examined whether criteria defined by Choi might be valuable to predict early sunitinib efficacy.Methods:Computed tomography was used for measurement of tumour lesions in mm and lesion attenuation in Hounsfield units (HUs). According to Choi criteria partial response (PR) was defined as ⩾10% decrease in size or ⩾15% decrease in attenuation.Results:A total of 55 mRCC patients treated with sunitinib were included. At first evaluation, according to the Response Evaluation Criteria in Solid Tumours (RECIST) 7 patients had PR, 38 stable disease (SD), and 10 progressive disease (PD), whereas according to Choi criteria 36 patients had PR, 6 SD and 13 PD. Median tumour attenuation decreased from 66 to 47 HUs (P⩽0.001). In patients with PR, Choi criteria had a significantly better predictive value for progression-free survival and overall survival (both Ps<0.001) than RECIST (P=0.685 and 0.191 respectively). The predictive value for RECIST increased (P=0.001 and <0.001 respectively), when best response during treatment was taken into account.Conclusion:Choi criteria could be helpful to define early mRCC patients who benefit from sunitinib, but the use of these criteria will not change the management of these patients.

Predictive factors for severe toxicity of sunitinib in unselected patients with advanced renal cell cancer

Sunitinib has been registered for the treatment of advanced renal cell cancer (RCC). As patient inclusion was highly selective in previous studies, experience with sunitinib in general oncological practice remains to be reported. We determined the efficacy and safety of sunitinib in patients with advanced RCC included in an expanded access programme. ECOG performance status >1, histology other than clear cell and presence of brain metastases were no exclusion criteria. Eighty-two patients were treated: 23% reached a partial response, 50% had stable disease, 20% progressed and six patients were not evaluable. Median progression-free survival (PFS) was 9 months and median overall survival (OS) was 15 months. Importantly, 47 patients (57%) needed a dose reduction, 35 (43%) because of treatment-related adverse events, 10 (12%) because of continuous dosing, and two because of both. Stomatitis, fatigue, hand–foot syndrome and a combination of grade 1–2 adverse events were the most frequent reasons for dose reduction. In 40 patients (49%), there was severe toxicity, defined as dose reduction or permanent discontinuation, which was highly correlated with low body surface area, high age and female gender. On the basis of age and gender, a model was developed that could predict the probability of severe toxicity.

Sunitinib-induced hemoglobin changes are related to the dosing schedule.

REFERENCES 1. Goldstein LJ, Gray R, Badve S, et al: Prognostic utility of the 21-gene assay in hormone receptor-positive operable breast cancer compared with classical clinicopathologic features. J Clin Oncol 26:4063-4071, 2008 2. Goldstein LJ, O’Neill A, Sparano JA, et al: Concurrent doxorubicin plus docetaxel is not more effective than concurrent doxorubicin plus cyclophosphamide in operable breast cancer with 0 to 3 positive axillary nodes: North American Breast Cancer Intergroup Trial E 2197. J Clin Oncol 26:4092-4099, 2008 3. McShane LM, Altman DG, Sauerbrei W, et al: Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst 97:1180-1184, 2005 4. Albain K, Barlow W, Shak S, et al: Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal, node-positive, ER-positive breast cancer (S8814, INT0100). Breast Cancer Res Treat 106:1, 2007 (suppl; abstr 10) 5. Paik S, Tang G, Shak S, et al: Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor–positive breast cancer. J Clin Oncol 24:3726-3734, 2006 6. Dowsett M, Cuzick J, Wales C, et al on behalf of the ATAC Trialists: Risk of distant recurrence using oncotype DX in postmenopausal primary breast cancer patients treated with anastrozole or tamoxifen: A TransATAC study. Breast Cancer Res Treat 107:1, 2008 (suppl; abstr 53)

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

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

Short-term CTLA-4 blockade directly followed by PD-1 blockade in advanced melanoma patients: a single-center experience

Background Combination of T cell checkpoint blockade by CTLA-4- and PD-1-blockade is one of the most promising therapies in patients with advanced melanoma. It induces superior response rates when compared with single-agent therapy, but at the cost of a high percentage of grade 3 and 4 adverse events (AEs). This combination therapy was until July 2016 not available in the Netherlands, which prompted several physicians to treat patients with less than standard numbers of courses of ipilimumab followed directly by nivolumab or pembrolizumab. Patients and methods In this retrospective analysis, patients were included who were treated with two courses (day 0 and 21) anti-CTLA-4 (ipilimumab 3 mg/kg q3wk), directly followed by anti-PD-1 (starting at day 22 with nivolumab 3mg/kg q2wk or pembrolizumab 2 mg/kg q3wk). Data on treatment-related AEs were collected from electronic patient records and scored according to CTCAE 4.03 criteria. Overall response was evaluated using RECIST 1.1 for CT-scans and EORTC criteria for PET-scans. Results Forty advanced melanoma patients could be included (29/40 pembrolizumab, 11/40 nivolumab). Median follow-up (FU) was 51 weeks (range: 4–63 weeks) with a minimum FU of 26 weeks. Treatment-related AEs of grade 3 and 4 occurred in 38% of the patients. The best overall response rate (BORR) was 55% (95% CI 39–70) and disease control rate was 75% (95% CI 59–87). Ongoing responses were observed in 82% of responding patients. Conclusion Treatment with short-term CTLA-4 blockade directly followed by PD-1 blockade may have similar efficacy but potentially lower toxicity when compared with concurrent therapy with anti-CTLA-4 and anti-PD-1. These results warrant further investigation in a prospective randomized controlled clinical trial.

Lack of anti-tumour reactivity despite enhanced numbers of circulating natural killer T cells in two patients with metastatic renal cell carcinoma

Natural killer T (NK T) cells play a central role as intermediates between innate and adaptive immune responses important to induce anti‐tumour reactivity in cancer patients. In two of 14 renal cell carcinoma (RCC) patients, treated with interferon (IFN)‐α, we detected significantly enhanced numbers of circulating NK T cells which were typed phenotypically and analysed for anti‐tumour reactivity. These NK T cells were T cell receptor (TCR) Vα24/Vβ11+, 6B11+ and bound CD1d tetramers. No correlation was observed between NK T frequencies and regulatory T cells (Tregs), which were also enhanced. NK T cells expressed CD56, CD161, CD45RO and CD69 and were predominantly CD8+, in contrast to the circulating T cell pool that contained both CD4+ and CD8+ T cells, as is found in healthy individuals. It is unlikely that IFN‐α triggered the high NK T frequency, as all other patients expressed low to normal NK T numbers. A parallel was observed in IFN‐α‐related increase in activation of NK T cells with that in conventional T and non‐T cells. Normal interleukin (IL)‐7, IL‐12 and IL‐15 plasma levels were found. In one of the patients sporadic NK T cells were detected at the tumour site. α‐Galactosylceramide (αGalCer) stimulation of peripheral blood mononuclear cells or isolated NK T cell lines from both patients induced IFN‐γ, but no IL‐4 and no response towards autologous tumour cells or lysates. The clinical course of disease in both patients was not exceptional with regard to histological subtype and extent of metastatic disease. Therefore, despite a constitutive high peripheral frequency and in vitroαGalCer responsiveness, the NK T cells in the two RCC patients did not show anti‐tumour responsiveness.

Starting the Fight in the Tumor: Expert Recommendations for the Development of Human Intratumoral Immunotherapy (HIT-IT)

Abstract A European Society for Medical Oncology (ESMO)-sponsored expert meeting was held in Paris on 8 March 2018 which comprised 11 experts from academia, 11 experts from the pharmaceutical industry and 2 clinicians who were representatives of ESMO. The focus of the meeting was exclusively on the intratumoral injection/delivery of immunostimulatory agents with the aim of harmonizing the standard terms and methodologies used in the reporting of human intratumoral immunotherapy (HIT-IT) clinical trials to ensure quality assurance and avoid a blurring of the data reported from different studies. The goal was to provide a reference document, endorsed by the panel members that could provide guidance to clinical investigators, pharmaceutical companies, ethics committees, independent review boards, patient advocates and the regulatory authorities and promote an increase in the number and quality of HIT-IT clinical trials in the future. Particular emphasis was placed not only on the development of precise definitions to facilitate a better understanding between investigators but also on the importance of systematic serial biopsies as a driver for translational research and the need for the recording and reporting of data, to facilitate a better understanding of the key processes involved.

Adoptive Engineered T-Cell Trials to Achieve Cancer Killing (ATTACK)

Executive Summary: The ATTACK project involves two multi-centre clinical trials to treat cancer using a form of cell therapy called Adoptive T-Cell Therapy. Adoptive T-Cell therapy is a promising advance in cancer treatment and involves using a patient’s own immune cells. Trial I: A Phase II Trial to Assess the Activity of NY-ESO-1 Targeted T-Cells in Advanced Oesophagogastric Cancer’. The aim was to determine whether results seen in other trials of this type of cell therapy could be translated into other solid tumour types. The NY-ESO therapy was manufactured by CTL at GMP facilities in Manchester. The rst site and sponsor for the clinical trial was the Christie NHS Foundation Trust. The trial opened to recruitment in 2014. To date, two patients have been treated in the trial, one of whom passed away 46 days after initial treatment. The underlying cause of death was investigated by the ATTACK consortium and during the period of investigation, the Christie NHS Foundation Trust suspended enrolment in the trial. The conclusions of the investigation were that the NY-ESO therapy was unlikely to have directly caused the bone marrow failure seen in the applicable patient through on-target toxicity or mispairing. In February 2016, following review of the results, an independent data monitoring committee (IDMC) recommended that recruitment could resume once agreed changes to the protocol were in place. An amendment to the protocol is currently being considered prior to restarting any enrolment in the trial. Alongside the trial, another work package focused on assay standardization and the e cient monitoring of the trial patients with the aim of determining key markers of therapeutic bene t and potential predictive markers of response. We have established and validated screening assays to assess positivity of expression of NY-ESO-1/LAGE-1 in order to identify patients suitable for the trial. Further assays have also been developed and validated ( ow cytometry (FCM) NY-ESO-1 tetramer staining assays and gene-modi ed T-cell speci c real-time PCR assays) to assess the nal product and blood post treatment for each patient. The detailed protocols have been made available for participating clinical sites. Screening assays were applied on 39 patients, of which 4 were suitable for treatment. Presence of NY-ESO-1 TCR T cells in patient blood was assessed in two treated patients using both FCM and qPCR methods. Furthermore we have standardised the FCM research assays for quantitation and assessment of differentiation and activation status of NY-ESO-1 TCR T cells prior to infusion and in patient blood, including markers for T cell differentiation, T cell function, and exhaustion. An archive for storage of patient material for future research has been established at EMC. Due to early termination of the Grant agreement ID: 305863 Status Grant agreement terminated ATTACK

1105PVEMURAFENIB FOR BRAF V600 MUTATED ADVANCED MELANOMA: RESULTS OF TREATMENT BEYOND PROGRESSION

ABSTRACT Aim: Background Selective BRAF inhibition (BRAFi) by vemurafenib or dabrafenib has become approved standard treatment in BRAFV600 mutated advanced stage melanoma. While the response rate is high, the response duration is limited with a progression-free survival (PFS) of 5-6 months months. Our observation of accelerated disease progression within some patients after stopping vemurafenib treatment has fostered the idea of treatment beyond progression (TBP). Methods: In this retrospective study, we analyzed 70 metastatic melanoma patients, treated at our institute, who experienced progression after prior objective response upon treatment with vemurafenib. Thirtyfive patients that continued treatment beyond progression are compared with 35 patients who stopped BRAFi treatment at disease progression. Results: Median overall survival beyond documented progression was found to be 5.2 months versus 1.4 months (95% CI: 3.8-7.4 vs. 0.6-3.4; Log-Rank p = 0.0001) in favour of TBP. In the multivariate survival analysis, stopping treatment at disease progression was independently and significantly associated with shorter survival (Hazard Ratio: 1.92; 95% CI: 1.04-3.55; p = 0.04). Conclusions: Our results clearly suggest that continuing vemurafenib treatment beyond progression may be beneficial in advanced melanoma patients. Prospective confirmation, however, is warranted before implementation into daily practice. Disclosure: J.B.A.G. Haanen: Advisory role and research grant form GSK. All other authors have declared no conflicts of interest.

Single-nucleotide polymorphisms (SNPs) in the endothelial nitric oxide synthase (NOS3) and vascular endothelial growth factor (VEGF) and its relationship to sunitinib-induced hypertension

4611 Background: Hypertension is a common side-effect in patients treated with sunitinib and is likely associated with inhibition of the VEGF/VEGF receptor(R)-2 pathway. SNPs in VEGF-A, VEGFR-2, but also in NOS3and endothelin-1 (EDN1) have been mentioned as possible candidates associated with a higher risk on development of hypertension. METHODS A retrospective multicenter study was performed in 255 patients with advanced renal cell cancer and gastrointestinal stromal tumor treated with sunitinib 50 mg/day in a 4 weeks on 2 weeks off or 37.5 mg/day continuous schedule. Office systolic (SBP) and diastolic blood pressure (DBP) were measured at baseline and on days 14 and 28 of the first treatment cycle. Hypertension was graded according to the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE). Seven SNPs in genes encoding for VEGF-A (rs2010963, rs833061, rs3025039, rs699947), VEGFR-2 (rs1870377), EDN1 (rs5370) and NOS3 (rs2070744) were selected. SNPs were univariately tested against hypertension grades according to CTCAE. RESULTS During the first treatment cycle, sunitinib induced a mean increase of 13 ± 23 mmHg and 10 ± 12 mmHg in SBP and DBP (t-test, P < 0.001), respectively. According to CTCAE, 36.5 % of patients developed hypertension. Among these patients, 10.6%, 12.9% and 12.9% had hypertension grade 1, 2, and 3, respectively. Development of grade 3 hypertension was associated with two copies of the C-allele in VEGF-A (rs833061; Chi-square, P = 0.048), two copies of the A-allele in VEGF-A(rs699947; P = 0.053) and a C-allele in NOS3 (rs2070744; P = 0.051). CONCLUSIONS SNPs in genes of NOS3 and VEGF-A are associated with the development of severe hypertension in patients treated with sunitinib. In particular, the association between the NOS3 pathway and hypertension induced by an inhibitor of the VEGF/VEGFR-2 pathway is a new finding. Hence, SNPs in VEGF-A and NOS3 genes may identify patients predisposed to develop hypertension on sunitinib treatment.