Matthew Wheater

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.

Ipilimumab in the real world: the UK expanded access programme experience in previously treated advanced melanoma patients

Before licensing, ipilimumab was first made available to previously treated advanced melanoma patients through an expanded access programme (EAP) across Europe. We interrogated data from UK EAP patients to inform future clinical practice. Clinicians registered in the UK EAP provided anonymized patient data using a prespecified variable fields datasheet. Data collected were baseline patient characteristics, treatment delivered, toxicity, response, progression-free survival and overall survival (OS). Data were received for 193 previously treated metastatic melanoma patients, whose primary sites were cutaneous (82%), uveal (8%), mucosal (2%), acral (3%) or unknown (5%). At baseline, 88% of patients had a performance status (PS) of 0–1 and 20% had brain metastases. Of the patients, 53% received all four planned cycles of ipilimumab; the most common reason for stopping early was disease progression, including death from melanoma. Toxicity was recorded for 171 patients, 30% of whom experienced an adverse event of grade 3 or higher, the most common being diarrhoea (13%) and fatigue (9%). At a median follow-up of 23 months, the median progression-free survival and OS were 2.8 and 6.1 months, respectively; the 1-year and 2-year OS rates were 31 and 14.8%, respectively. The 2-year OS was significantly lower for patients with poorer PS (P<0.0001), low albumin concentrations (P<0.0001), the presence of brain metastases (P=0.007) and lactate dehydrogenase levels more than two times the upper limit of normal (P<0.0001) at baseline. These baseline characteristics are negative predictors of benefit from ipilimumab and should be taken into consideration before prescription.

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

ABSTRACT 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.

Recombinant Factor VIIa in the Management of Pulmonary Hemorrhage Associated With Metastatic Choriocarcinoma

A 25-year-old man presented in September 2005 with relapsed metastatic germ cell tumor and a rapidly rising serum human beta chorionic gonadotropin (HCG; from 10,000 to 40,000 U/L over the preceding 10 days). He had been diagnosed 18 months earlier with International Germ Cell Cancer Collaborative Group (IGCCCG) poor prognosis extragonadal retroperitoneal metastatic germ cell cancer. He had presented then with lower back pain, hemoptysis, and weight loss. A computed tomography (CT) scan of the brain, chest, abdomen,andpelvis hadshowna large retroperitoneal mass with a left hydronephrosis, multiple pulmonary deposits, and multiple brain metastases. Blood markers showed HCG 522,442 U/L, alphafetoprotein 5 KU/L, and lactate dehydrogenase 1,500 U/L. Testicular examination and ultrasound were unremarkable.

Treatment outcome and patterns of relapse following adjuvant carboplatin for stage I testicular seminomatous germ-cell tumour: results from a 17-year UK experience

BACKGROUND Following inguinal orchidectomy, management options for patients with stage I seminoma include initial surveillance or treatment with adjuvant radiotherapy or chemotherapy. The anticipated relapse rate for patients followed by surveillance alone is ∼15%, with adjuvant treatment this risk is reduced to ∼4%-5% at 5 years. After carboplatin treatment, follow-up strategies vary and there are no validated, predictive markers of relapse. PATIENTS AND METHODS We conducted a retrospective analysis of all patients presenting with stage I seminoma who received a single cycle of adjuvant carboplatin in South Central England between 1996 and 2013. We report on outcome and the results of univariate and multivariate analysis evaluating possible risk factors for post carboplatin relapse. RESULTS A total of 517 eligible patients were identified. All underwent nuclear medicine estimation of glomerular filtration rate before treatment with carboplatin (dosed at area under the curve × 7). With a median follow-up of 47.2 months (range 0.4-214 months), 21/517 patients have relapsed resulting in a 5-year estimated relapse-free survival of 95.0% (95% confidence interval 92.8% to 97.3%). Median time to relapse was 22.7 months (range 12.5-109.5 months). Relapse beyond 3 years was rare (4/517; 0.8%). Twenty of 21 (95%) relapsed patients had retroperitoneal lymph node metastases. The majority (16/21; 76%) of patients had elevated tumour markers at relapse. Twenty of 517 (3.9%) patients developed a new contralateral testicular germ-cell cancer. There were no seminoma-related deaths. Tumour size was the only variable significantly associated with an increased risk of relapse. CONCLUSIONS Overall results for this large cohort of patients confirm an excellent prognosis for these patients with outcomes equivalent to those seen in prospective clinical trials. Increasing tumour size alone appears to be associated with an increased risk of post chemotherapy relapse.

Infliximab for IPILIMUMAB-Related Colitis-Letter.

Ipilimumab, an anticytotoxic T-lymphocyte–associated protein (CTLA)-4 antibody, was approved in 2011 by the FDA for the treatment of advanced melanoma ([1, 2][1]). Our study aimed to evaluate the impact of immunosuppressants used for the treatment of immune-related adverse events (irAE) on outcome

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.

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.

Clinical outcomes following neoadjuvant cisplatin-based chemotherapy for bladder cancer in elderly compared with younger patients

Bladder cancer is a disease of the elderly. Older patients might potentially be undertreated due to assumptions about benefit versus risk. Our objective was to determine outcomes in older patients receiving neoadjuvant chemotherapy for muscle-invasive bladder cancer (MIBC). We hypothesised that appropriately selected elderly patients (≥70 years) with MIBC could have similar clinical outcomes, and be safely treated, with standard neoadjuvant chemotherapy prior to definitive cystectomy or radiotherapy. We utilised a single institution case series analysis of patients with T2-4a N0 M0 transitional cell carcinoma of the bladder treated with cisplatin-based neoadjuvant chemotherapy between 2005 and 2011. Eighty-three patients were eligible. Median age was 68 (range 48-80), 33 patients (40%) were ≥70 years. Overall survival at 3 years was 65.8% (≥70) and 63.2% (<70) (P = 0.653), relapse-free survival at 3 years was 61.6% and 54.8% respectively (P = 0.471). The rates going forward to definitive local therapy (87.9% ≥ 70 and 84.0% < 70) and the pathological complete response rate (31.3% ≥ 70 and 40% < 70) were similar. Disease relapse rate was also similar (63.6% ≥ 70 vs. 60% < 70, P = 0.906). Elderly patients with good functional status and limited comorbidities diagnosed with MIBC receiving standard neoadjuvant chemotherapy followed by cystectomy or radiotherapy can have similar clinical outcomes as their younger counterparts. Prospective studies evaluating the optimum curative management in this elderly population are 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.