Efficacy and Safety of the Melphalan/Hepatic Delivery System in Patients with Unresectable Metastatic Uveal Melanoma: Results from an Open-Label, Single-Arm, Multicenter Phase 3 Study.

BACKGROUND: Uveal melanoma (UM) has a poor prognosis once liver metastases occur. The melphalan/Hepatic Delivery System (melphalan/HDS) is a drug/device combination used for liver-directed treatment of metastatic UM (mUM) patients. The purpose of the FOCUS study was to assess the efficacy and safety of melphalan/HDS in patients with unresectable mUM. METHODS: Eligible patients with mUM received treatment with melphalan (3.0 mg/kg ideal body weight) once every 6 to 8 weeks for a maximum of six cycles. The primary end point was the objective response rate (ORR). The secondary end points included duration of response (DOR), overall survival (OS), and progression-free survival (PFS). RESULTS: The study enrolled 102 patients with mUM. Treatment was attempted in 95 patients, and 91 patients received treatment. In the treated population (n = 91), the ORR was 36.3 % (95 % confidence interval [CI], 26.44-47.01), including 7.7 % of patients with a complete response. Thus, the study met its primary end point because the lower bound of the 95 % CI for ORR exceeded the upper bound (8.3 %) from the benchmark meta-analysis. The median DOR was 14 months, and the median OS was 20.5 months, with an OS of 80 % at 1 year. The median PFS was 9 months, with a PFS of 65 % at 6 months. The most common serious treatment-emergent adverse events were thrombocytopenia (15.8 %) and neutropenia (10.5 %), treated mostly on an outpatient basis with observation. No treatment-related deaths were observed. CONCLUSION: Treatment with melphalan/HDS provides a clinically meaningful response rate and demonstrates a favorable benefit-risk profile in patients with unresectable mUM (study funded by Delcath; ClinicalTrials.gov identifier: NCT02678572; EudraCT no. 2015-000417-44).

Temporary treatment cessation versus continuation of first-line tyrosine kinase inhibitor in patients with advanced clear cell renal cell carcinoma (STAR): an open-label, non-inferiority, randomised, controlled, phase 2/3 trial.

BACKGROUND: Temporary drug treatment cessation might alleviate toxicity without substantially compromising efficacy in patients with cancer. We aimed to determine if a tyrosine kinase inhibitor drug-free interval strategy was non-inferior to a conventional continuation strategy for first-line treatment of advanced clear cell renal cell carcinoma. METHODS: This open-label, non-inferiority, randomised, controlled, phase 2/3 trial was done at 60 hospital sites in the UK. Eligible patients (aged ≥18 years) had histologically confirmed clear cell renal cell carcinoma, inoperable loco-regional or metastatic disease, no previous systemic therapy for advanced disease, uni-dimensionally assessed Response Evaluation Criteria in Solid Tumours-defined measurable disease, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) at baseline to a conventional continuation strategy or drug-free interval strategy using a central computer-generated minimisation programme incorporating a random element. Stratification factors were Memorial Sloan Kettering Cancer Center prognostic group risk factor, sex, trial site, age, disease status, tyrosine kinase inhibitor, and previous nephrectomy. All patients received standard dosing schedules of oral sunitinib (50 mg per day) or oral pazopanib (800 mg per day) for 24 weeks before moving into their randomly allocated group. Patients allocated to the drug-free interval strategy group then had a treatment break until disease progression, when treatment was re-instated. Patients in the conventional continuation strategy group continued treatment. Patients, treating clinicians, and the study team were aware of treatment allocation. The co-primary endpoints were overall survival and quality-adjusted life-years (QALYs); non-inferiority was shown if the lower limit of the two-sided 95% CI for the overall survival hazard ratio (HR) was 0·812 or higher and if the lower limit of the two-sided 95% CI of the marginal difference in mean QALYs was -0·156 or higher. The co-primary endpoints were assessed in the intention-to-treat (ITT) population, which included all randomly assigned patients, and the per-protocol population, which excluded patients in the ITT population with major protocol violations and who did not begin their randomisation allocation as per the protocol. Non-inferiority was to be concluded if it was met for both endpoints in both analysis populations. Safety was assessed in all participants who received a tyrosine kinase inhibitor. The trial was registered with ISRCTN, 06473203, and EudraCT, 2011-001098-16. FINDINGS: Between Jan 13, 2012, and Sept 12, 2017, 2197 patients were screened for eligibility, of whom 920 were randomly assigned to the conventional continuation strategy (n=461) or the drug-free interval strategy (n=459; 668 [73%] male and 251 [27%] female; 885 [96%] White and 23 [3%] non-White). The median follow-up time was 58 months (IQR 46-73 months) in the ITT population and 58 months (46-72) in the per-protocol population. 488 patients continued on the trial after week 24. For overall survival, non-inferiority was demonstrated in the ITT population only (adjusted HR 0·97 [95% CI 0·83 to 1·12] in the ITT population; 0·94 [0·80 to 1·09] in the per-protocol population). Non-inferiority was demonstrated for QALYs in the ITT population (n=919) and per-protocol (n=871) population (marginal effect difference 0·06 [95% CI -0·11 to 0·23] for the ITT population; 0·04 [-0·14 to 0·21] for the per-protocol population). The most common grade 3 or worse adverse events were hypertension (124 [26%] of 485 patients in the conventional continuation strategy group vs 127 [29%] of 431 patients in the drug-free interval strategy group); hepatotoxicity (55 [11%] vs 48 [11%]); and fatigue (39 [8%] vs 63 [15%]). 192 (21%) of 920 participants had a serious adverse reaction. 12 treatment-related deaths were reported (three patients in the conventional continuation strategy group; nine patients in the drug-free interval strategy group) due to vascular (n=3), cardiac (n=3), hepatobiliary (n=3), gastrointestinal (n=1), or nervous system (n=1) disorders, and from infections and infestations (n=1). INTERPRETATION: Overall, non-inferiority between groups could not be concluded. However, there seemed to be no clinically meaningful reduction in life expectancy between the drug-free interval strategy and conventional continuation strategy groups and treatment breaks might be a feasible and cost-effective option with lifestyle benefits for patients during tyrosine kinase inhibitor therapy in patients with renal cell carcinoma. FUNDING: UK National Institute for Health and Care Research.

Percutaneous hepatic perfusion with melphalan in uveal melanoma: A safe and effective treatment modality in an orphan disease.

BACKGROUND: Metastatic uveal melanoma (UM) carries a poor prognosis; liver is the most frequent and often solitary site of recurrence. Available systemic treatments have not improved outcomes. Melphalan percutaneous hepatic perfusion (M-PHP) allows selective intrahepatic delivery of high dose cytotoxic chemotherapy. METHODS: Retrospective analysis of outcomes data of UM patients receiving M-PHP at two institutions was performed. Tumor response and toxicity were evaluated using RECIST 1.1 and Common Terminology Criteria for Adverse Events (CTCAE) v4.03, respectively. RESULTS: A total of 51 patients received 134 M-PHP procedures (median of 2 M-PHPs). 25 (49%) achieved a partial (N = 22, 43.1%) or complete hepatic response (N = 3, 5.9%). In 17 (33.3%) additional patients, the disease stabilized for at least 3 months, for a hepatic disease control rate of 82.4%. After median follow-up of 367 days, median overall progression free (PFS) and hepatic progression free survival (hPFS) was 8.1 and 9.1 months, respectively and median overall survival was 15.3 months. There were no treatment related fatalities. Non-hematologic grade 3-4 events were seen in 19 (37.5%) patients and were mainly coagulopathic (N = 8) and cardiovascular (N = 9). CONCLUSIONS: M-PHP results in durable intrahepatic disease control and can form the basis for an integrated multimodality treatment approach in appropriately selected UM patients.

Quality of life after melphalan percutaneous hepatic perfusion for patients with metastatic uveal melanoma.

BACKGROUND: Recent studies indicate that melphalan percutaneous hepatic perfusion (M-PHP) for liver metastases from ocular melanoma (mUM) improves survival. Importantly, this benefit must be carefully balanced with changes in a patient's quality of life (QoL). This study examines the QoL changes post-M-PHP. METHODS: Retrospective analysis of the change in QoL using the Functional Assessment of Cancer Therapy-General (FACT-G) with mUM patients receiving M-PHP ( n  = 20). The FACT-G scores, which comprise physical (PWB), social (SWB), emotional (EWB) and functional (FWB) wellbeing were measured pre-procedure and at day 1, day of discharge (mean = 2.4 days), 7, 14 and 28 days after M-PHP therapy. Wilcoxon signed-rank test gauged QoL domain changes. RESULTS: Baseline FACT-G median (IQR) scores were 101.8 (21.8). QoL scoring significantly decreased immediately after the procedure [day 1; 85 (27.5); P  = 0.002] and gradually improved over time. By day 28, QoL almost returned to pre-procedure levels [100.3 (13.8); P  = 0.31]. Subscore analysis revealed that the initial drop in QoL at day 1 post-procedure was attributable to the PWB (28 vs. 24; P  = 0.001) and FWB domains (26 vs. 18.5; P  < 0.001). By day 28 there was a statistically significant improvement in EWB ( P  = 0.01). CONCLUSION: QoL following M-PHP decreases immediately after therapy and is not significantly different from baseline by the day of discharge. By day 28 there is improved emotional well-being. This study could help to optimize the time between treatment cycles when combined with toxicity data and blood count recovery.

Liver resection for metastatic uveal melanoma: experience from a supra-regional centre and review of literature.

Management of liver metastases from uveal melanoma (LMUM) requires multimodal approach. This study describes evolution of liver resection for LMUM, reviewing current literature and institutional outcomes. Records of patients referred to the Melanoma Multi-Disciplinary Team between February 2005 and August 2018 were reviewed. All publications describing surgery for LMUM were identified from PubMed, Embase, and Google Scholar. Thirty-one of 147 patients with LMUM underwent laparoscopic liver biopsy, and 29 (14 females) had liver resections. Nineteen liver resections were performed locally [7 major (≥3 seg), 14 laparoscopic] without major complications or mortality. Overall survival positively correlated with the time from uveal melanoma to LMUM (Spearman's rho rs = 0.859, P < 0.0001). Overall and recurrence-free survivals were comparable following R1 or R0 resections (OS 25 vs. 28 months, P = 0.404; RFS 13 vs. 6 months, P = 0.596). R1 resection cohort had longer lead-time (median 100 vs. 24 months, P = 0.0408). Eleven publications describing liver resection for LMUM were identified and included in the narrative review. Surgery for LMUM is safe and complements multidisciplinary management. Despite heterogeneity in literature, time from diagnosis of uveal melanoma to LMUM remains a key factor affecting survival after liver resection.

Comparison of three-weekly and six-weekly pembrolizumab United Kingdom prescribing practice for advanced and resected melanoma.

BACKGROUND: Pembrolizumab is approved for the treatment of advanced and resected melanoma and was originally licensed as a three-weekly infusion (Q3W). In April 2019, a six-weekly infusion schedule (Q6W) was also approved. We retrospectively reviewed pembrolizumab prescribing for patients with melanoma across multiple United Kingdom (UK) centres to compare the safety and efficacy of Q6W with Q3W in real-world clinical practice. METHODS: Case notes for melanoma patients treated with pembrolizumab between April 2019 and August 2020 at eight UK centres were reviewed. Prespecified baseline characteristics of the Q3W and Q6W cohorts were compared, as well as toxicity and efficacy outcomes. Prescribers were surveyed about their prescribing practice. RESULTS: Two hundred seventy-seven patients were included: 116 commenced Q3W and 161 commenced Q6W pembrolizumab. The proportion of Q6W prescriptions varied by the centre (range 32-88%). Patient factors associated with an increased likelihood of receiving Q3W over Q6W were preexisting autoimmune comorbidity (odds ratio [OR] 0.33; 95% confidence interval [CI] 0.12-0.82) and treatment for advanced (versus resected) disease (OR 0.54; 95%CI 0.33-0.90). Toxicity outcomes were broadly similar for Q6W and Q3W: 14.9% versus 15.5% ≥ grade 3 Common Terminology Criteria for Adverse Events. Estimated 12-month recurrence-free survival for adjuvantly treated patients was 78.9% for Q6W and 74.2% for Q3W (hazard ratio [HR] 0.93; 95%CI 0.50-1.73). Estimated 12-month progression-free survival for advanced patients was 41.8% for Q6W and 55.9% for Q3W (HR 1.21, 95%CI 0.67-2.18). CONCLUSIONS: Q6W is an appropriate option for administering pembrolizumab, given the opportunity to reduce the health service resource burden.

Chemosaturation with percutaneous hepatic perfusion of melphalan for metastatic uveal melanoma.

Uveal melanoma, the most common primary ocular malignancy in adults, carries a poor prognosis: 50% of patients develop the metastatic disease with a 10-25% 1-year survival and no established standard of care treatment. Prior studies of melphalan percutaneous hepatic perfusion (M-PHP) have shown promise in metastatic uveal melanoma (mUM) patients with liver predominant disease but are limited by small sample sizes. We contribute our findings on the safety and efficacy of the procedure in the largest sample population to date. A retrospective analysis of outcome and safety data for all mUM patients receiving M-PHP was performed. Tumour response and treatment toxicity were evaluated using RECIST 1.1 and Common Terminology Criteria for Adverse Events v5.03, respectively. 250 M-PHP procedures were performed in 81 patients (median of three per patient). The analysis demonstrated a hepatic disease control rate of 88.9% (72/81), a hepatic response rate of 66.7% (54/81), and an overall response rate of 60.5% (49/81). After a median follow-up of 12.9 months, median overall progression-free (PFS) and median overall survival (OS) were 8.4 and 14.9 months, respectively. There were no fatal treatment-related adverse events (TRAE). Forty-three grade 3 (29) or 4 (14) TRAE occurred in 23 (27.7%) patients with a significant reduction in such events between procedures performed in 2016-2020 vs. 2012-2016 (0.17 vs. 0.90 per patient, P < 0.001). M-PHP provides excellent response rates and PFS compared with other available treatments, with decreasing side effect profile with experience. Combination therapy with systemic agents may be viable to further advance OS.

The clinical features and management of testicular germ cell tumours in patients aged 60 years and older.

UNLABELLED: What's known on the subject ? and What does the study add? The treatment of younger men with testicular germ cell cancers is well documented with established intensive chemotherapy regimens for those with advanced disease. Although the majority of patients present in the third or fourth decade, men also present in later life. These patients are typically excluded from clinical trials and there are no contemporary published series describing their management. This series describes the management of older patients with testicular germ cell tumours at both early and advanced stages of disease. Patients with stage I seminoma can be safely managed with all recognised treatment strategies and state I non-seminomas were managed with surveillance. Cure can still be achieved in older patients with advance germ cell tumours however chemotherapy regimens developed in younger patients must be tailored to the presence of co-morbidity. OBJECTIVES: • To review the practice of a large referral centre for the management of older patients with testicular germ cell cancer (GCC). • There are few published data available on the management of testicular GCC in elderly patients, who often have medical comorbidities and have been excluded from clinical trials. PATIENTS AND METHODS: • We reviewed our prospectively collected database for patients presenting with GCC who were aged ≥60 years. • Details of presentation, management and outcome were recorded. RESULTS: • In total, 60 patients aged ≥60 years were identified from 1461 patients treated with GCC from 1979-2005, representing 4% of the total population. • Median age was 67 years, 44 had seminoma (73%) and 16 had non-seminoma histology (27%). • Stage I seminoma patients were managed with surveillance, adjuvant radiotherapy and adjuvant carboplatin. All stage I non-seminomas underwent surveillance. • In total, 15 patients received systemic chemotherapy for metastatic disease with modified bleomycin, etoposide and cisplatin; etoposide and cisplatin; carboplatin-based regimens; or other combinations. Toxicity was manageable, with no toxic deaths. • In total, four patients (6.7%) died of GCC. CONCLUSIONS: • In elderly patients, GCC should be managed with curative intent. • Conventional therapies are tolerable for most men with stage I seminoma. In metastatic disease, comorbidity may necessitate treatment modifications. • Most patients are cured with manageable toxicity.

Late relapse (>2 years) on surveillance in stage I non-seminomatous germ cell tumours; predominant seminoma only histology.

OBJECTIVES: Surveillance is a standard management approach following orchidectomy for stage I non-seminomatous and mixed germ cell tumours. Patients who relapse following this approach are treated with cisplatin-based chemotherapy, with retroperitoneal lymph node dissection considered for patients with post-chemotherapy residual masses. PATIENTS AND METHODS: We reviewed the clinicopathological data for all patients who relapse greater than 24 months after commencing our surveillance programme. RESULTS: Between 1989 and 2008, 453 patients with a median age of 30 years were entered into our surveillance program for stage I non-seminomatous germ cell tumours (NSGCTs) after orchidectomy alone. All primary tumour specimens contained NSGCT, with seminomatous elements identified in 168 cases (37%). One-hundred patients (22%) relapsed and the majority of relapses occurred within the first 2 years (76 ≤ 12 months, 15 ≥ 12 months ≤ 2 years). Nine patients relapsed after more than 2 years of surveillance. We found a high incidence of pure seminoma (56%) at sites of metastatic disease in this group. All late-relapsing patients were alive and disease free at a median follow up of 45 months from relapse. CONCLUSIONS: We recommend that late-relapsing patients with normal serum alpha fetoprotein levels undergo biopsy to define histologically the nature of recurrent disease. In those with pure seminoma retroperitoneal lymph node dissection for post chemotherapy residual masses can be avoided.

The 111 Study: A Single-arm, Phase 3 Trial Evaluating One Cycle of Bleomycin, Etoposide, and Cisplatin as Adjuvant Chemotherapy in High-risk, Stage 1 Nonseminomatous or Combined Germ Cell Tumours of the Testis.

BACKGROUND: Standard management in the UK for high-risk stage 1 nonseminoma germ cell tumours of the testis (NSGCTT) is two cycles of adjuvant bleomycin, etoposide (360 mg/m2), and cisplatin (BE360P) chemotherapy, or surveillance. OBJECTIVE: To test whether one cycle of BE500P achieves similar recurrence rates to two cycles of BE360P. DESIGN, SETTING, AND PARTICIPANTS: A total of 246 patients with vascular invasion-positive stage 1 NSGCTT or combined seminoma + NSGCTT were centrally registered in a single-arm prospective study. INTERVENTION: One cycle comprising bleomycin 30000 IU on days 1, 8, and 15, etoposide 165 mg/m2 on days 1-3, and cisplatin 50 mg/m2 on days 1-2, plus antibacterial and granulocyte colony stimulating factor prophylaxis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was 2-yr malignant recurrence (MR); the aim was to exclude a rate of ≥5%. Participants had regular imaging and tumour marker (TM) assessment for 5 yr. RESULTS AND LIMITATIONS: The median follow-up was 49 mo (interquartile range 37-60). Ten patients with rising TMs at baseline were excluded. Four patients had MR at 6, 7, 13, and 27 mo; all received second-line chemotherapy and surgery and three remained recurrence-free at 5 yr. The 2-yr MR rate was 1.3% (95% confidence interval 0.3-3.7%). Three patients developed nonmalignant recurrences with localised teratoma differentiated, rendered disease-free after surgery. Grade 3-4 febrile neutropenia occurred in 6.8% of participants. CONCLUSIONS: BE500P is safe and the 2-yr MR rate is consistent with that seen following two BE360P cycles. The 111 study is the largest prospective trial investigating one cycle of adjuvant BE500P in high-risk stage 1 NSGCTT. Adoption of one cycle of BE500P as standard would reduce overall exposure to chemotherapy in this young population. PATIENT SUMMARY: Removing the testicle fails to cure many patients with high-risk primary testicular cancer since undetectable cancers are often present elsewhere. A standard additional treatment in Europe is two cycles of chemotherapy to eradicate these. This trial shows one cycle has few adverse effects and comparable outcomes to those seen with two cycles.

Outcome of Men With Relapses After Adjuvant Bleomycin, Etoposide, and Cisplatin for Clinical Stage I Nonseminoma.

PURPOSE: Clinical stage I (CSI) nonseminoma (NS) is a disease limited to the testis without metastases. One treatment strategy after orchiectomy is adjuvant chemotherapy. Little is known about the outcome of patients who experience relapse after such treatment. PATIENTS AND METHODS: Data from 51 patients with CSI NS who experienced a relapse after adjuvant bleomycin, etoposide, and cisplatin (BEP) from 18 centers/11 countries were collected and retrospectively analyzed. Primary outcomes were overall and progression-free survivals calculated from day 1 of treatment at first relapse. Secondary outcomes were time to, stage at, and treatment of relapse and rate of subsequent relapses. RESULTS: Median time to relapse was 13 months, with the earliest relapse 2 months after start of adjuvant treatment and the latest after 25 years. With a median follow-up of 96 months, the 5-year PFS was 67% (95% CI, 54% to 82%) and the 5-year OS was 81% (95% CI, 70% to 94%). Overall, 19 (37%) of 51 relapses occurred later than 2 years. Late relapses were associated with a significantly higher risk of death from NS (hazard ratio, 1.10 per year; P = .01). Treatment upon relapse was diverse: the majority of patients received a combination of chemotherapy and surgery. Twenty-nine percent of patients experienced a subsequent relapse. At last follow-up, 41 patients (80%) were alive and disease-free, eight (16%) had died of progressive disease, and one patient (2%) each had died from therapy-related or other causes. CONCLUSION: Outcomes of patients with relapse after adjuvant BEP seem better compared with patients who experience relapse after treatment of metastatic disease but worse compared with those who have de-novo metastatic disease. We found a substantial rate of late and subsequent relapses. There seem to be three patterns of relapse with different outcomes: pure teratoma, early viable NS relapse (< 2 years), and late viable NS relapse (> 2 years).

Salvage Chemotherapy With Gemcitabine, Paclitaxel, Ifosfamide, and Cisplatin for Relapsed Germ Cell Cancer.

BACKGROUND: Metastatic germ cell tumors remain potentially curable when treated with salvage chemotherapy at first relapse. In the present phase I/II study, we sought to improve on the response rate and duration of the TIP (paclitaxel, ifosfamide, cisplatin) regimen by adding gemcitabine (Gem-TIP). MATERIALS AND METHODS: Twenty patients were recruited after failure of first-line cisplatin-containing chemotherapy. The primary objectives were to determine the maximum tolerated dose of gemcitabine when combined with TIP and to establish the dose intensity of the TIP drugs in this combination. The secondary objectives were the response rates, failure-free survival, and overall survival. RESULTS: The maximum tolerated dose of gemcitabine was 1200 mg/m2. The mean relative dose intensity was 95% (95% confidence interval [CI], 90.2%-99.2%) for gemcitabine, 96% (95% CI, 92.9%-98.7%) for paclitaxel, 92% (95% CI, 84.5%-98.8%) for ifosfamide, and 94% (95% CI, 89.3%-99.0%) for cisplatin. The overall complete response rate was 50%; another 30% of the patients achieved a partial response. The 1-year failure-free survival and overall survival rates were 68% (95% CI, 43%-84%) and 89.5% (95% CI, 64%-97%), respectively. CONCLUSION: Gemcitabine can be added to TIP chemotherapy at the full dose, with manageable toxicity and no detrimental effect on the dose intensity of the TIP drugs. The response rate and duration were improved compared with those reported from the Medical Research Council TIP trial; further evaluation is warranted.

Outcome of Men With Relapse After Adjuvant Carboplatin for Clinical Stage I Seminoma.

Purpose Adjuvant carboplatin is one of three management strategies that may follow inguinal orchiectomy in clinical stage I seminoma. However, little is known about the outcome of patients who experience a relapse after such treatment. Patients and Methods Data from 185 patients who relapsed after adjuvant carboplatin between January 1987 and August 2013 at 31 centers/groups from 20 countries were collected and retrospectively analyzed. Primary outcomes were disease-free survival and overall survival. Secondary outcomes were time to, stage at, and treatment of relapse as well as rate of subsequent relapses. Results With a median follow-up of 53 months (95% CI, 48 to 60 months) the 5-year disease-free survival was 82% (95% CI, 77% to 89%), and the 5-year overall survival was 98% (95% CI, 95% to 100%). The median time from orchiectomy to relapse was 19 months (95% CI, 17 to 23 months); 15% (95% CI, 10% to 21%) of relapses occurred > 3 years after treatment. The majority of relapses were detected by computed tomography scan during routine follow-up, 98% in the International Germ Cell Cancer Collaborative Group good prognosis group. Chemotherapy was administered to 92% of patients, mostly as standard first-line treatment corresponding to stage; 8% of patients had additional local treatments. Only 28 patients experienced a second relapse. At last follow-up, 174 (94%) of 185 patients were alive without disease, and four patients with disease. Seven patients died, three of whom due to progressive disease. Conclusion Within the limitations of a retrospective analysis, the results suggest that the majority of patients who experience a relapse after adjuvant carboplatin for clinical stage I seminoma can be successfully treated with a cisplatin-based chemotherapy regimen adequate for stage. Because 15% of the relapses occurred > 3 years after adjuvant treatment, a minimum of 5 years follow-up is recommended.

Evaluation of immune infiltration in the colonic mucosa of patients with ipilimumab-related colitis.

Approximately 30% of patients treated with ipilimumab will develop gastrointestinal toxicity. The immunological drivers that underpin the clinical observations in human tissues are poorly understood. We report here on the immune consequences of ipilimumab treatment in the colorectal mucosa of patients with treatment-related colitis. Using immunohistochemistry, we evaluated the immune infiltrate by CD8+, FoxP3, and granzyme B (GzmB) in colonic biopsies from 20 patients with ipilimumab-related colitis. We assessed 10 cases with normal colon biopsies for comparison. In eight cases (four on steroids only, four on steroids and infliximab), we evaluated two sequential biopsies. We observed that CD8+, FoxP3+, and GzmB T cell counts were significantly higher in patients with ipilimumab-related colitis compared to normal colon (p < 0.0001). Patients who required infliximab for the resolution of their colitis had a significantly higher CD8+/FoxP3 ratio than those treated only with steroids and this correlated with clinical severity. The analysis of repeat samples revealed that resolution of the colitis was associated with a decrease in CD8+ and FoxP3+ cells both in patients treated with steroids and infliximab. Our data suggest that counts of cytotoxic T cells and Tregs in the colonic mucosa from patients with ipilimumab-related colitis correlate with clinical findings and may predict severity and guide management.

Clinical activity and safety of Pembrolizumab in Ipilimumab pre-treated patients with uveal melanoma.

BACKGROUND: Untreated metastatic uveal melanoma (UM) carries a grave prognosis. Unlike cutaneous melanoma (CM), there are no established treatments known to significantly improve outcomes for a meaningful proportion of patients. Inhibition of the PD1-PDL1 axis has shown promise in the management of CM and we here report a two center experience of UM patients receiving pembrolizumab. METHODS: To assess the efficacy and safety of pembrolizumab, we retrospectively analyzed outcome data of 25 consecutive UM patients participating in the MK3475 expanded access program (EAP) who received pembrolizumab at 2 mg/kg 3 weekly. Tumor assessment was evaluated using RECIST 1.1 and immune-related Response Criteria (irRC) by CT scanning. Toxicity was recorded utilizing Common Terminology Criteria for Adverse Events ("CTCAE") v4.03. RESULTS: Twenty-five patients were identified receiving a median of six cycles of treatment. Two patients achieved a partial response and six patients stable disease. After a median follow-up of 225 d median progression free survival (PFS) was 91 d and overall survival (OS) was not reached. There was a significant trend for improved outcomes in patients with extrahepatic disease progression as opposed to liver only progression at the outset. Five patients experienced grade 3 or 4 adverse events (AEs); there were no treatment related deaths. CONCLUSIONS: Pembrolizumab 2mg/kg q3w is a safe option in UM patients. Disease control rates, particularly in the subgroup of patients without progressive liver disease at the outset are promising; these results merit further investigation in clinical trials possibly incorporating liver targeted treatment modalities.

A Randomised Phase 2 Study of AZD2014 Versus Everolimus in Patients with VEGF-Refractory Metastatic Clear Cell Renal Cancer.

BACKGROUND: Everolimus is a mammalian target of rapamycin (mTOR) inhibitor used in vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma (mRCC). It acts on only part of the mTOR complex (TORC1 alone). In vitro data support the use of mTOR inhibitors with broader activity (TORC1 and TORC2). OBJECTIVE: The purpose of this study was to determine whether combined TORC1 and TORC2 inhibition with AZD2014 has superior activity to everolimus in VEGF-refractory clear cell mRCC. DESIGN, SETTING, AND PARTICIPANTS: Patients with measurable mRCC and VEGF-refractory disease were eligible for this trial. INTERVENTION: Starting in February 2013, patients were randomised (1:1) to AZD2014 (50 mg twice daily) or everolimus (10 mg once daily) until progression of disease at 10 centres across the United Kingdom. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Progression-free survival (PFS) was the primary end point and was compared using the stratified log-rank test. Secondary end points included tolerability, response rates, overall survival (OS), and pharmacokinetics (PK) analysis. The study was planned to recruit 120 patients. RESULTS AND LIMITATIONS: Recruitment into the trial was stopped early (June 2014) due to lack of efficacy of AZD2014. At that point, 49 patients were randomised (26 to AZD2014 and 23 to everolimus). The PFS for AZD2014 and everolimus was 1.8 and 4.6 mo, respectively (hazard ratio: 2.8 [95% confidence interval (CI), 1.2-6.5]; p=0.01). Progression of disease as the best response to therapy was 69% for AZD2014 and 13% for everolimus (p<0.001). Grade 3-4 adverse events (AEs) occurred in 35% of AZD2014 and 48% of everolimus patients (p=0.3). Only 4% of patients stopped AZD2014 due to AEs. PK analysis suggested concentrations of AZD2014 were compatible with the therapeutic range. Final stratified OS hazard ratio at the time of trial closure (January 2015) was 3.1 (95% CI, 1.1-8.4; p<0.02). CONCLUSIONS: The PFS and OS of AZD2014 were inferior to everolimus in this setting despite acceptable AE and PK profiles. PATIENT SUMMARY: There is a strong rationale for testing mTOR inhibitors with a broader spectrum of activity than everolimus in metastatic clear cell renal cell carcinoma. AZD2014 is such an agent, but in this study, it was inferior to everolimus despite its attractive toxicity profile.

Outcome and Biomarker Analysis from a Multicenter Phase 2 Study of Ipilimumab in Combination with Carboplatin and Etoposide as First-Line Therapy for Extensive-Stage SCLC.

OBJECTIVES: Our aim was to evaluate the safety and efficacy of ipilimumab combined with standard first-line chemotherapy for patients with extensive-stage SCLC. METHODS: Patients with chemotherapy-naive extensive-stage SCLC were treated with carboplatin and etoposide for up to six cycles. Ipilimumab, 10 mg/kg, was given on day 1 of cycles 3 to 6 and every 12 weeks. Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0, and immune-related response criteria. The primary end point was 1-year progression-free survival (PFS) according to RECIST. Secondary end points included PFS according to immune-related PFS and overall survival. Autoantibody serum levels were evaluated and correlated with clinical outcomes. RESULTS: A total of 42 patients were enrolled between September 2011 and April 2014; 39 were evaluable for safety and 38 for efficacy. Six of 38 patients (15.8% [95% confidence interval (CI): 7.4-30.4]) were alive and progression-free at 1-year by RECIST. Median PFS was 6.9 months (95% CI: 5.5-7.9). Median immune-related PFS was 7.3 months (95% CI: 5.5-8.8). Median overall survival was 17.0 months (95% CI: 7.9-24.3). Of the patients evaluable for response, 21 of 29 (72.4%) achieved an objective response by RECIST and 28 of 33 (84.8%) achieved an objective response by the immune-related response criteria. All patients experienced at least one adverse event; at least one grade 3 or higher toxicity developed in 35 of 39 patients (89.7%); in 27 patients (69.2%) this was related to ipilimumab. Five deaths were reported to be related to ipilimumab. Positivity of an autoimmune profile at baseline was associated with improved outcomes and severe neurological toxicity. CONCLUSIONS: Ipilimumab in combination with carboplatin and etoposide might benefit a subgroup of patients with advanced SCLC. Autoantibody analysis correlates with treatment benefit and toxicity and warrants further investigation.

Systemic immune-inflammation index predicts the clinical outcome in patients with metastatic renal cell cancer treated with sunitinib.

BACKGROUND: In this retrospective analysis, we explored the prognostic and predictive value of the systemic immune-inflammation index (SII), based on lymphocyte, neutrophil, and platelet counts, at baseline and changes at week 6 during first-line sunitinib in patients with metastatic renal cell cancer (RCC). RESULTS: Patients were stratified into high SII (≥ 730) and low SII (< 730) groups. SII was associated with objective response, p < 0.0001. The median PFS was 6.3 months (95% CI 5.5-8.9) in patients with SII ≥ 730 and 18.7 months (95% CI 14.7-22.8) in those with SII < 730, p < 0.0001. The median OS was 43.6 months (95% CI 35.3-52.1) in patients with SII < 730, and 13.5 months (95% CI 9.8-18.5) in those with SII ≥ 730, p < 0.0001. In multivariate analysis, performance status, IMDC score and SII were able to predict OS (HR = 3.29, HR = 1.71 and HR = 1.79, respectively). MATERIALS AND METHODS: We included 335 consecutive RCC patients treated with first-line sunitinib. The X-tile 3.6.1 software (Yale University, New Haven, CT) was used for bioinformatic analysis of the data to determine the cutoff value of SII. Progression-free survival (PFS), overall survival (OS) and their 95% confidence interval (95% CI) were estimated by Kaplan-Meier method and compared with logrank test. The impact of SII conversion at week 6 of treatment on PFS and OS was evaluated by Cox regression analyses. CONCLUSIONS: The SII and its changes during treatment represent a powerful prognostic indicator of clinical outcome in patients with metastatic RCC.

Immunosuppression for ipilimumab-related toxicity can cause pneumocystis pneumonia but spare antitumor immune control.

Ipilimumab is a standard therapy for advanced melanoma. Severe immune related adverse events occur in up to 30% of patients and require treatment with immunosuppressants such as steroids or the anti-TNFα antibody, infliximab. We describe two patients with advanced melanoma treated with ipilimumab. Both suffered from severe immune related side effects and required prolonged immunosuppression with steroids and/or infliximab. Both patients recovered and in spite of the immune suppression, demonstrate clinical evidence of tumor control. This argues that distinct immunological effector functions control nosocomial infection and tumor, respectively. To our knowledge, these are also the first two case reports of pneumocystis pneumonia in this setting.