Early Access Program Research Articles

911P - Patients (pts) with metastatic non-clear cell renal cell carcinoma (mnccRCC) treated with Nivolumab (Nivo) based immunotherapy as advanced treatment (ATL) line: analysis of a national early access program (EAP)

911P - Patients (pts) with metastatic non-clear cell renal cell carcinoma (mnccRCC) treated with Nivolumab (Nivo) based immunotherapy as advanced treatment (ATL) line: analysis of a national early access program (EAP)

One-year effectiveness and safety of vedolizumab therapy for inflammatory bowel disease: a prospective multicentre cohort study.

We recently showed that vedolizumab is effective in patients with Crohn's disease (CD) and ulcerative colitis (UC) with prior anti-TNF failure in a multicentre compassionate early-access programme before marketing authorisation was granted to vedolizumab. To assess effectiveness and safety of vedolizumab at week 54 in patients UC and CD. Between June and December 2014, 173 patients with Crohn's disease (CD) and 121 with ulcerative colitis (UC) were treated with vedolizumab induction therapy. Among those 294 patients, 272 completed the induction period and were evaluated at the week 14 visit (161 patients with CD and 111 with UC). Disease activity was assessed using the Harvey-Bradshaw Index for CD and the partial Mayo Clinic score for UC. The primary outcome was steroid-free clinical remission at week 54. At week 54, steroid-free clinical remission rates at week 54 were 27.2% and 40.5% in patients with CD and UC respectively. In addition, the sustained steroid-free clinical remission (from week 14 to week 54) rates were 8.1% and 19.0% respectively. No deaths were observed. Severe adverse events occurred in 17 (7.2%) patients, including six (2.5%) leading to vedolizumab discontinuation. Vedolizumab is able to maintain steroid-free clinical remission in up to one-third of patients with UC and CD at week 54 with a reasonable safety profile. A significant number of patients experienced loss of response during the first year of treatment, particularly in patients with CD.

Cabazitaxel in patients with metastatic castration-resistant prostate cancer: safety and quality of life data from the Australian early access program.

Cabazitaxel is a next generation taxane that has been shown to improve overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC) whose disease progressed during or after docetaxel-based therapy. A worldwide early access program (EAP) study was established to provide access to cabazitaxel ahead of commercial availability and to evaluate its safety and tolerability. The Australian EAP included patient-reported outcomes to evaluate the impact of cabazitaxel on quality of life (QoL). The final safety and QoL results from the Australian EAP for cabazitaxel are reported. Australian patients with mCRPC previously treated with a docetaxel-containing regimen received cabazitaxel (25 mg/m2 ) every 3 weeks plus prednisone/prednisolone (10 mg daily) until disease progression, death, unacceptable toxicity, physician's decision or patient's refusal of further treatment. QoL data was collected using the AQoL-8D questionnaire. 104 patients from 18 Australian sites (median age at baseline, 70) enrolled in the EAP and completed at least one AQoL-8D questionnaire. Patients received a median of 6 cycles of cabazitaxel. 67 patients (64.4%) experienced grade ≥3 treatment-emergent adverse events (TEAEs); the most frequent TEAEs were neutropenia, febrile neutropenia, diarrhoea, and vomiting. QoL scores remained stable with increasing treatment cycles. The results suggest that the safety profile cabazitaxel is manageable in the Australian clinical practice setting and that QoL is maintained with little or no detrimental effect of cabazitaxel in patients continuing on treatment without disease progression.

Daclatasvir plus sofosbuvir, with or without ribavirin, for hepatitis C virus genotype 3 in a French early access programme.

Background & AimsOptimally effective treatment for hepatitis C virus genotype 3 (GT3) is urgently needed, particularly in advanced liver disease. Daclatasvir plus sofosbuvir was efficacious in phase 3 studies. Real‐world data for daclatasvir+sofosbuvir in advanced GT3 infection are presented from the French Temporary Authorisation for Use programme, which allowed patients in need without other treatment options access to daclatasvir ahead of its market authorization.MethodsPatients with F3/F4 fibrosis and/or extrahepatic hepatitis C virus manifestations, post‐liver transplant hepatitis C virus recurrence and/or indication for liver/kidney transplant, were treated with daclatasvir+sofosbuvir (60+400 mg daily) for a recommended duration of 24 weeks. Addition of ribavirin and/or shorter treatment was at physician's discretion. The primary efficacy analysis was sustained virological response at post‐treatment week 12 (SVR12; modified intention‐to‐treat). Safety was assessed by spontaneous adverse event reporting.ResultsThe efficacy population comprised 333 patients, mostly cirrhotic (77%, of whom 18% were decompensated) and treatment experienced (72%). After 24 weeks of daclatasvir+sofosbuvir, SVR12 was 89% (174/196) overall (95% CI 83.6‐92.5%), 98% (43/44) without cirrhosis (95% CI 88.2‐99.6%) and 86% (129/150) with any degree of cirrhosis (95% CI 79.5‐90.7%), without SVR12 increase in those who received additional ribavirin for 24 weeks (SVR12 82% [50/61; 95% CI 70.5‐89.6%]). Among 516 GT3‐infected patients with safety data, 5 discontinued for adverse events and 11 died.ConclusionsDaclatasvir+sofosbuvir achieved high SVR12 rates and was well tolerated in this large real‐world cohort of GT3‐infected patients with advanced liver disease, without benefit of ribavirin in those treated 24 weeks.

A Global Perspective on Compassionate Use and Expanded Access.

Whilst the complex ethical and benefit/risk questions that need to be considered when determining whether an investigational treatment should be given to a patient remain constant throughout the world, the practical and logistical realities of running an Early Access Program (EAP) differ widely globally presenting a whole range of challenges if the objective is to find solutions that are in the patients best interest and are as fair and equitable as possible. Some of the complexities can create extreme challenges for Pharma Companies looking to set up global programs, but with the right planning and strategy it is possible to overcome hurdles allowing patients to access critical treatments they desperately need. The exact design and scope of any global EAP will depend on country scope, expected demand, regulatory feasibility, the license status of the product, necessary drug pricing structure, as well as company strategy, costs, and product supply. Having worked in this space for many years, I am constantly reminded of the dramatic positive impact early access to critical treatments can have on the lives of patients and their families. I am also well aware of the potential risks that need to be well thought through and managed in order to provide access in a timely and compliant manner to the right patients and to compliment and support, rather than disrupt, traditional development pathways.

57 - Radium-223 (Ra-223) in sequence or in concurrent use with abiraterone acetate (AA) or enzalutamide (E) in metastatic castration resistant prostate cancer (mCRPC) patients treated in an international early access program (iEAP)

57 - Radium-223 (Ra-223) in sequence or in concurrent use with abiraterone acetate (AA) or enzalutamide (E) in metastatic castration resistant prostate cancer (mCRPC) patients treated in an international early access program (iEAP)

Effectiveness of interferon-free therapy for the treatment of HCV-patients with compensated cirrhosis treated through the Irish early access program

ABSTRACTBackground: We investigated the real-world effectiveness of interferon-free regimens for the treatment of patients with compensated cirrhosis infected with hepatitis C virus (HCV).Method: Using the Irish national HCV treatment registry, the effectiveness and safety of interferon-free regimens for HCV-infected patients treated between April 2015 and August 2016, was determined.Results: A SVR12 was achieved in 86% of subjects treated with sofosbuvir/ledipasvir ± ribavirin (SOF/LDV±RBV), 93% treated with paritaprevir, ombitasvir and ritonavir combined with dasabuvir ± ribavirin (3D±RBV) and 89% treated with sofosbuvir/daclatasvir ± ribavirin (SOF/DCV±RBV). The discontinuation rate was 5% and the on-treatment mortality rate was 1%.Conclusion: The availability of interferon-free regimens represents a significant breakthrough for the treatment of HCV infection. Treatments options, with high SVR12 rates, are now available for patients with compensated cirrhosis who were unsuitable for treatment with interferon-based regimens. Data obtained from studies conducted in real world practice provide robust information fundamental for input into future economic evaluations for agents used for the treatment of HCV infection.

Radium-223 (Ra-223) in asymptomatic metastatic castration-resistant prostate cancer (mCRPC) patients treated in an international early access program (iEAP).

158 Background: Ra-223, a targeted alpha therapy, is currently used to treat mCRPC patients (pts). To investigate Ra-223 when used early in the disease course, we analyzed safety and efficacy in mCRPC pts with no symptoms at baseline treated in an iEAP. Methods: This was a prospective, single-arm phase 3b study of mCRPC pts (malignant lymphadenopathy not exceeding 6 cm was allowed, visceral disease was excluded). Pts received Ra-223, 55 kBq/kg IV, every 4 weeks for up to 6 cycles. Co-primary endpoints were safety and overall survival (OS). Post hoc analyses were performed according to asymptomatic or symptomatic disease status at baseline. Asymptomatic was defined as no pain and no opioid use at baseline. Results: 708 pts received ≥1 Ra-223 injection: 548 (77%) were defined as symptomatic and 135 (19%) were defined as asymptomatic. Asymptomatic pts had more favorable baseline characteristics than symptomatic pts (table). Fewer asymptomatic pts had received prior abiraterone (34 pts, 25% vs 190, 35%), enzalutamide (5 pts, 4% vs 43, 8%) and prior docetaxel (70 pts, 52% vs 339, 62%). More asymptomatic pts received 6 cycles of Ra-223 (96, 71% vs 300, 55%). Adverse events (AEs) were reported for fewer pts with asymptomatic vs symptomatic disease: any grade, 61% vs 79%; grade 3/4, 29% vs 40% and serious AEs, 22% vs 38%. OS was longer in asymptomatic pts and ALP normalization was more common (table). Conclusions: Asymptomatic pts were more likely to have a better prognosis and to complete all 6 cycles of Ra-223. Ongoing first-line combination studies (ERA-223: NCT02043678 and PEACE-3: NCT02194842) may show whether Ra-223 administered early in the disease course will lead to better outcomes. Clinical trial information: NCT01618370. [Table: see text]

Daclatasvir Plus Asunaprevir Dual Therapy for Chronic HCV Genotype 1b Infection: Results of Turkish Early Access Program

BackgroundDaclatasvir and asunaprevir dual therapy is approved for the treatment of HCV genotype 1b infection in several countries. AimTo evaluate the efficacy and safety of daclatasvir and asunaprevir dual therapy in Turkish patients. Material and MethodsSixty-one patients with HCV genotype 1b were enrolled in the Turkish early access program. Most of the patients were in difficult-to-treat category. Patients were visited at each 4 week throughout the follow-up period. Laboratory findings and adverse events were recorded at each visit. ResultsFifty-seven of 61 enrolled patients completed 24 weeks of treatment. Two patients died as a result of underlying diseases at 12-14th weeks of treatment. Two patients stopped the treatment early as a consequence of virological breakthrough, and 2 patients had viral relapse at the post-treatment follow-up. Overall SVR12 rates were 90% (55/61) and 93.2% (55/59) according to intention-to-treat (ITT) and per protocol (PP) analysis respectively. In ITT analysis, SVR12 was achieved by 93% (13/14) in relapsers, 80% (12/15) in interferon-ineligible patients and 91% (20/22) in previous nonresponder patients. SVR12 rates were 86.5% and 91.4% in patients with cirrhosis according to ITT and PP analysis respectively. SVR12 was 95.8% in non-cirrhosis group in both analysis. Patients with previous protease inhibitor experience had an SVR12 of 87.5%. Common adverse events developed in 28.8% of patients. There were no treatment related severe adverse event or grade-4 laboratory abnormality. ConclusionsDaclatasvir and asunaprevir dual therapy is found to be effective and safe in difficult-to-treat Turkish patients with HCV genotype 1b infection.

P3.02c-089 ImmunoCHIC: A Prospective Nivolumab Monotherapy Cohort in Advanced Non-Small Cell Lung Cancer Patients in Routine Clinical Practice: Topic: IT Biomarkers

In France, in May 2015, Nivolumab early access program was established for patients with advanced NSCLC progressing during or after platinum-based chemotherapy. There is little evidence of Nivolumab use out of clinical trials. We report here one year of Nivolumab use in a French University hospital. Observational prospective review of patients with advanced NSCLC treated with Nivolumab monotherapy (3 mg/kg/2weeks) in our center, in routine clinical practice. Patients in clinical trial were excluded. Analyze was done on clinico-pathological features, tolerance and outcomes. 63 patients were included (men: 76.1%, age: 65 (range: 40–78), squamous: 33.3%; smoker: 93.7%%, EGFR/ALK negatives: 98.4%, unknown PDL1: 70%; at least one significant comorbidity: 54%; performans status 0/1/2: 34%/49%/17%; cerebral metastasis: 38%; nivolumab as second, third and more than third lines: 38%/38%/24%. Median number of nivolumab cycles: 6 (1-24), more than 12 cycles: 20.6% Disease control rate : 59% (3 complete responses) ; Clinically significant adverse event: 13 (20%) patients (asthenia: 4 patients, grade 2 to 4 colitis: 3 patients, pneumoniae: 3 patients, nephritis: 1 patient). After Nivolumab, 50% of the patients received an another systemic therapy. Two patients were able to go back to work. In real life setting, nivolumab had the efficacy level reported by pivotal clinical trial but with a higher rate of clinically significant adverse events, particularly colitis.

Effectiveness and safety of ombitasvir, paritaprevir, ritonavir ± dasabuvir ± ribavirin: An early access programme for Spanish patients with genotype 1/4 chronic hepatitis C virus infection.

Over the last 5 years, therapies for hepatitis C virus (HCV) infection have improved significantly, achieving sustained virologic response (SVR) rates of up to 100% in clinical trials in patients with HCV genotype 1. We investigated the effectiveness and safety of ombitasvir/paritaprevir/ritonavir±dasabuvir in an early access programme. This was a retrospective, multicentre, national study that included 291 treatment-naïve and treatment-experienced patients with genotype 1 or 4 HCV infection. Most patients (65.3%) were male, and the mean age was 57.5years. The mean baseline viral load was 6.1 log, 69.8% had HCV 1b genotype, 72.9% had cirrhosis and 34.7% were treatment-naïve. SVR at 12 weeks posttreatment was 96.2%. Four patients had virological failure (1.4%), one leading to discontinuation. There were no statistical differences in virological response according to genotype or liver fibrosis. Thirty patients experienced serious adverse events (SAEs) (10.3%), leading to discontinuation in six cases. Hepatic decompensation was observed in five patients. Four patients died during treatment or follow-up, three of them directly related to liver failure. Multivariate analyses showed a decreased probability of achieving SVR associated with baseline albumin, bilirubin and Child-Pugh score B, and a greater probability of developing SAEs related to age and albumin. This combined therapy was highly effective in clinical practice with an acceptable safety profile and low rates of treatment discontinuation.

Cabazitaxel for Hormone-Relapsed Metastatic Prostate Cancer Previously Treated With a Docetaxel-Containing Regimen: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the company that manufactures cabazitaxel (Jevtana®, Sanofi, UK) to submit evidence for the clinical and cost effectiveness of cabazitaxel for treatment of patients with metastatic hormone-relapsed prostate cancer (mHRPC) previously treated with a docetaxel-containing regimen. The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology based upon the company's submission to NICE. Clinical evidence for cabazitaxel was derived from a multinational randomised open-label phase III trial (TROPIC) of cabazitaxel plus prednisone or prednisolone compared with mitoxantrone plus prednisone or prednisolone, which was assumed to represent best supportive care. The NICE final scope identified a further three comparators: abiraterone in combination with prednisone or prednisolone; enzalutamide; and radium-223 dichloride for the subgroup of people with bone metastasis only (no visceral metastasis). The company did not consider radium-223 dichloride to be a relevant comparator. Neither abiraterone nor enzalutamide has been directly compared in a trial with cabazitaxel. Instead, clinical evidence was synthesised within a network meta-analysis (NMA). Results from TROPIC showed that cabazitaxel was associated with a statistically significant improvement in both overall survival and progression-free survival compared with mitoxantrone. Results from a random-effects NMA, as conducted by the company and updated by the ERG, indicated that there was no statistically significant difference between the three active treatments for both overall survival and progression-free survival. Utility data were not collected as part of the TROPIC trial, and were instead taken from the company's UK early access programme. Evidence on resource use came from the TROPIC trial, supplemented by both expert clinical opinion and a UK clinical audit. List prices were used for mitoxantrone, abiraterone and enzalutamide as directed by NICE, although commercial in-confidence patient-access schemes (PASs) are in place for abiraterone and enzalutamide. The confidential PAS was used for cabazitaxel. Sequential use of the advanced hormonal therapies (abiraterone and enzalutamide) does not usually occur in clinical practice in the UK. Hence, cabazitaxel could be used within two pathways of care: either when an advanced hormonal therapy was used pre-docetaxel, or when one was used post-docetaxel. The company believed that the former pathway was more likely to represent standard National Health Service (NHS) practice, and so their main comparison was between cabazitaxel and mitoxantrone, with effectiveness data from the TROPIC trial. Results of the company's updated cost-effectiveness analysis estimated a probabilistic incremental cost-effectiveness ratio (ICER) of £45,982 per quality-adjusted life-year (QALY) gained, which the committee considered to be the most plausible value for this comparison. Cabazitaxel was estimated to be both cheaper and more effective than abiraterone. Cabazitaxel was estimated to be cheaper but less effective than enzalutamide, resulting in an ICER of £212,038 per QALY gained for enzalutamide compared with cabazitaxel. The ERG noted that radium-223 is a valid comparator (for the indicated sub-group), and that it may be used in either of the two care pathways. Hence, its exclusion leads to uncertainty in the cost-effectiveness results. In addition, the company assumed that there would be no drug wastage when cabazitaxel was used, with cost-effectiveness results being sensitive to this assumption: modelling drug wastage increased the ICER comparing cabazitaxel with mitoxantrone to over £55,000 per QALY gained. The ERG updated the company's NMA and used a random effects model to perform a fully incremental analysis between cabazitaxel, abiraterone, enzalutamide and best supportive care using PASs for abiraterone and enzalutamide. Results showed that both cabazitaxel and abiraterone were extendedly dominated by the combination of best supportive care and enzalutamide. Preliminary guidance from the committee, which included wastage of cabazitaxel, did not recommend its use. In response, the company provided both a further discount to the confidential PAS for cabazitaxel and confirmation from NHS England that it is appropriate to supply and purchase cabazitaxel in pre-prepared intravenous-infusion bags, which would remove the cost of drug wastage. As a result, the committee recommended use of cabazitaxel as a treatment option in people with an Eastern Cooperative Oncology Group performance status of 0 or 1 whose disease had progressed during or after treatment with at least 225mg/m2 of docetaxel, as long as it was provided at the discount agreed in the PAS and purchased in either pre-prepared intravenous-infusion bags or in vials at a reduced price to reflect the average per-patient drug wastage.

Radium-223 with concomitant bone-targeting agents in metastatic castration-resistant prostate cancer (CRPC) patients treated in an international early access program (EAP)

Background: The bone-targeting agents (BTAs) denosumab and bisphosphonates (BPs) are widely used in the supportive care of patients (pts) with CRPC and bone metastases. We present data on pts treated with radium-223 dichloride (Ra-223) with or without a concomitant BTA in an international EAP.Methods: This was a prospective single-arm phase IIIb study of CRPC pts with symptomatic or asymptomatic bone metastases (no visceral disease) recruited from 14 countries. Pts received Ra-223 55 kBq/kg (iv injection) every 4 weeks for 6 cycles. Co-primary endpoints were safety and overall survival (OS). Exploratory analyses investigated the effects of concomitant denosumab (no BPs) or BPs (no denosumab) on OS and symptomatic skeletal events (SSE). Results: 696 pts received at least one Ra-223 cycle. Of those, 127 (18%) pts were treated with concomitant denosumab (no BPs) and 435 (63%) without any concomitant BTAs. Key baseline characteristics are reported in pts treated with Ra-223 with or without a concomitant BTA (Table). Median OS (mOS) and median time to first SSE (mSSE) were longer in pts treated with Ra-223 and denosumab versus pts without a concomitant BTA (Table). While key baseline characteristics in pts treated with Ra-223 and denosumab were similar to pts treated with Ra-223 and BPs, adding BPs to Ra-223 did not appear to improve mOS. However, mSSE was prolonged in pts receiving Ra-223 and BPs versus pts who received Ra-223 without a concomitant BTA (Table). Conclusions: In this EAP, pts treated with Ra-223 and a concomitant BTA appeared to have longer time to first SSE than those treated without a concomitant BTA. However, improvement in OS was observed with denosumab but not with BPs. Prospective randomized controlled studies are required to confirm the benefit of this specific treatment combination in metastatic CRPC.Table: B7DenosumabBPsNo denosumab/ no BPsN = 127N = 125N = 435Baseline characteristicsECOG PS, n (%)058 (46%)55 (44%)144 (33%)155 (43%)54 (43%)234 (54%)≥214 (11%)16 (13%)57 (13%)Pain, n (%)123122413Mild75 (61%)72 (59%)218 (53%)Moderate-severe19 (15%)24 (20%)113 (27%)None29 (24%)26 (21%)82 (20%)ALP (U/L), n127125433Median121.0137.0168.0PSA (µg/L), n127124433Median91.2118.5174.6Efficacy outcomeOverall survivalMedian, monthsNR12.713.495% CINA10.9–NA11.7–NAHazard ratio (95% CI)0.630 (0.431– 0.922)0.846 (0.584– 1.226)-Time to first SSEMedian, months17.0NR15.895% CI17.0–17.5NA10.9–19.1Hazard ratio (95% CI)0.761 (0.493– 1.173)0.498 (0.294– 0.845)-NR/A = not reached/available. Open table in a new tab NR/A = not reached/available.

Changes in alkaline phosphatase (ALP) dynamics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients treated with radium-223 in an international early access program (EAP)

Changes in alkaline phosphatase (ALP) dynamics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients treated with radium-223 in an international early access program (EAP)

Effectiveness and safety of aflibercept for metastatic colorectal cancer: retrospective review within an early access program in Spain.

In the VELOUR study, aflibercept+FOLFIRI regimen resulted in improved survival in metastatic colorectal cancer (mCRC) patients who progressed after oxaliplatin. The use of aflibercept outside the clinical trial framework needs to be further assessed in terms of effectiveness and tolerability. Early access to aflibercept through a named patient programme (NPP) was provided to mCRC patients receiving FOLFIRI as second-line treatment in Spain. The effectiveness of aflibercept was assessed as progression-free survival (PFS) achieved within the NPP population. Post hoc analyses on PFS were done according to certain baseline characteristics (K-RAS mutation, prior targeted therapy) or prognostic factors. Registries from 71 mCRC patients included in the NPP were reviewed retrospectively. The median age for the NPP population was 64years (19.7% aged≥70years) and 63.4% patients had ≥2 metastases. A median PFS of 5.3months (95% CI, 3.6-8.5months) was achieved, which did not depend on K-RAS mutation status or prior targeted therapy received. The risk of progression or death increased in patients with a poor prognosis as per the GERCOR score (performance status [PS] 1-2 and increased baseline lactate dehydrogenase [LDH] level) compared with patients with a good prognosis (PS 0 and normal LDH level) (median PFS: 2.6 vs. 8.3months, respectively; p=0.0124). Aflibercept was well tolerated, with a manageable toxicity profile. Bearing in mind the differences in sample size, the PFS achieved with the aflibercept+FOLFIRI regimen in the real-life practice setting is comparable to that observed in the clinical trial setting.

750P - Radium-223 with concomitant bone-targeting agents in metastatic castration-resistant prostate cancer (CRPC) patients treated in an international early access program (EAP)

750P - Radium-223 with concomitant bone-targeting agents in metastatic castration-resistant prostate cancer (CRPC) patients treated in an international early access program (EAP)

751P - Changes in alkaline phosphatase (ALP) dynamics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients treated with radium-223 in an international early access program (EAP)

751P - Changes in alkaline phosphatase (ALP) dynamics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients treated with radium-223 in an international early access program (EAP)

OR38 Whole gene HLA class I genotyping with the minion nanopore sequencer

In 2014 Oxford Nanopores Technologies released the MinION, a portable miniaturized sequencer delivering multi-kb DNA reads based on nanopore sensing technology. Sequencing accuracy is improved by consecutive sequencing both strands of the DNA (2D reads). Being part of the MinION early access program we evaluated this new technology for whole gene HLA sequencing. As the sequencing yield exceeds the requirements for a targeted approach we developed a strategy for barcoding and demultiplexing of samples. Barcoded amplicons were generated by two subsequent long range PCRs covering the complete genes of HLA-A, -B and -C. Amplicons were pooled and library preparation was performed according to the Oxford Nanopore protocol (SQK-MAP006). Sequencing was performed on a MinION MKI with R7.3 flow cells. NGSengine from GenDX was used for sequence analysis and HLA genotyping. 96 randomly picked class I samples were pooled and sequenced. Over 170,000 reads were generated, approximately 65% of them as 2D reads. Two thirds of the 2D reads could be assigned to a unique barcode sequence. The HLA genotyping results were compared to allelic resolution genotypes obtained by full length sequencing the samples on both Illumina and PacBio instruments. The ONT typing results had a 95% concordance rate when considering 1st to 3rd field. Even when taking the fourth field in account concordance rate was above 90%. Given that the nanopore technology is rapidly evolving and the genotyping software has not yet been optimized for nanopore data, this study clearly underlines the great potential of the MinION for high resolution HLA genotyping.

Cytotoxic Cutaneous Adverse Drug Reactions during Anti-PD-1 Therapy.

Immunotherapy has experienced impressive progress in cancer treatment. Antibodies against PD-1 improved survival in different types of cancer including melanoma. They are generally well tolerated. However, skin toxicities including pruritus, rashes, and vitiligo are reported. Although frequent, they have not been characterized further yet. In this analysis, we aimed to systematically assess and characterize the adverse cutaneous reactions observed in patients with melanoma treated with anti-PD-1 antibodies. Patients with melanoma were treated with anti-PD-1 antibodies within clinical trials and an early-access program. Adverse cutaneous eruptions that emerged in our melanoma patient cohort were systematically investigated and classified using histology and gene expression profiling in comparison with maculopapular drug rash, cutaneous GVHD, and the severe drug eruption toxic epidermal necrolysis (TEN). Between February 2013 and September 2015, 68 patients with stage IV melanoma were treated at the University Hospital Zurich (Zurich, Switzerland); 15 patients (22%) developed cutaneous reactions and 10 (15%) vitiligo. The cutaneous reactions ranged from small erythematous papules with mild pruritus to disseminated erythematous maculopapular rashes (MPR) without signs of epidermal involvement to severe MPRs, including epidermal detachment and mucosal involvement. Although skin involvement varied from mild rash to bullous drug eruptions, gene expression profiling pathogenically classified all investigated cases as TEN-like reactions. As predicted by the PD-1 knockout mouse, anti-PD-1 antibodies frequently cause adverse cutaneous reactions. Gene expression profiling reminds in all cases of a TEN-like pattern, suggesting that PD-1/PD-L1 interaction is required to preserve epidermal integrity during inflammatory skin reactions. Clin Cancer Res; 22(16); 4023-9. ©2016 AACR.

Efficacy and safety of boceprevir based triple therapy in Hungarian patients with hepatitis C genotype 1 infection, advanced stage fibrosis and prior treatment failure

During 2011 and 2013, 155 Hungarian hepatitis C genotype 1 infected patients, mostly with advanced liver fibrosis, who did not respond to prior peginterferon + ribavirin dual therapy, started boceprevir based triple therapy in an early access program. Efficacy and safety of the therapy was retrospectively assessed based on sustained virologic responses, as well as on frequency and type of serious adverse events and of those leading to therapy discontinuation. In an intent-to-treat analysis 39.4% patients (61/155) reached sustained virologic response. Amongst pervious relapsers, partial responders and null-responders 59.5%, 41.4 % and 22.9% (p<0.05 compared to the other two categories) reached sustained virologic response, respectively, while amongst non-cirrhotics and cirrhotics 52.5% and 31.3% (p<0.05 compared to the non-cirrhotics) achieved sutained virologic response, respectively. Six out of the 33 most difficult to cure patients (previous null responder and cirrhotic) have reached sustained virologic response (18.2%). Frequency of early discontinuations due to insufficient virologic response was 31.1%, while due to adverse event 10.3%. Reported frequency of serious adverse event was 9.8%. These events represented anemia, diarrhoea, depression, agranulocytosis, elevated aminotransferases, generalized dermatitis and severe gingivitis with loss of teeth, prolonged QT interval on ECG, generalized oedema and severe dyspnoea, uroinfection, exacerbation of Crohn's disease, Campylobacter pylori infection and unacceptable weakness and fatigue. Eight patients received transfusion, 4 patients erythropoietin and 1 granulocyte colony stimulating factor during therapy. No death has been reported. With boceprevir based triple therapy, one of the bests available in 2011-2013 in Hungary, a relevant proportion of hepatitis C infected patients with advanced liver fibrosis achieved sustained viral response. In this cohort, side-effects resembled those reported in registration studies, and resulted in therapy discontinuation with consequent treatment failure in a relevant number of patients. Efficacy and tolerability of boceprevir-based triple therapy are suboptimal, particularly in the most difficult to cure patient population. Orv. Hetil., 2016, 157(34), 1366-1374.