Outcome and biomarker analysis from a multi-centre phase 2 study of ipilimumab in combination with carboplatin and etoposide (ICE) as first line therapy for extensive stage small cell lung cancer.

BACKGROUND: To evaluate safety and efficacy of ipilimumab combined with standard first-line chemotherapy for patients with extensive stage SCLC. METHODS: Chemotherapy-naïve extensive stage SCLC patients were treated with carboplatin and etoposide up to six cycles. Ipilimumab 10 mg/kg was given on day 1 of cycles 3-6 and every 12 weeks. Response was assessed by RECIST v1.0 and immune related response criteria (irRC). The primary endpoint was 1-year progression-free survival (PFS) according to RECIST. Secondary endpoints included PFS by irRC (irPFS) and overall survival (OS). Autoantibody serum levels were evaluated and correlated with clinical outcomes. RESULTS: 42 patients were enrolled between September 2011-April 2014, 39 evaluable for safety and 38 for efficacy. 6/38 patients (15.8% [95% 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 irPFS was 7.3 months (95% CI: 5.5-8.8). Median OS was 17.0 months (95% CI: 7.9-24.3). In patients evaluable for response, 21/29 patients (72.4%) achieved an objective response by RECIST and 28/33 (84.8%) by irRC. All patients experienced at least one adverse event; 35/39 (89.7%) patients developed at least one toxicity ≥ Grade 3; in 27 (69.2%) this was related to ipilimumab. Five deaths were reported to be related to ipilimumab. The positivity of an autoimmune profile at baseline was associated with improved outcomes and severe neurological toxicity. CONCLUSION: 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

Imaging Modality and Frequency in Surveillance of Stage I Seminoma Testicular Cancer: Results From a Randomized, Phase III, Noninferiority Trial (TRISST)

PURPOSE: Survival in stage I seminoma is almost 100%. Computed tomography (CT) surveillance is an international standard of care, avoiding adjuvant therapy. In this young population, minimizing irradiation is vital. The Trial of Imaging and Surveillance in Seminoma Testis (TRISST) assessed whether magnetic resonance images (MRIs) or a reduced scan schedule could be used without an unacceptable increase in advanced relapses. METHODS: A phase III, noninferiority, factorial trial. Eligible participants had undergone orchiectomy for stage I seminoma with no adjuvant therapy planned. Random assignment was to seven CTs (6, 12, 18, 24, 36, 48, and 60 months); seven MRIs (same schedule); three CTs (6, 18, and 36 months); or three MRIs. The primary outcome was 6-year incidence of Royal Marsden Hospital stage ≥ IIC relapse (> 5 cm), aiming to exclude increases ≥ 5.7% (from 5.7% to 11.4%) with MRI (v CT) or three scans (v 7); target N = 660, all contributing to both comparisons. Secondary outcomes include relapse ≥ 3 cm, disease-free survival, and overall survival. Intention-to-treat and per-protocol analyses were performed. RESULTS: Six hundred sixty-nine patients enrolled (35 UK centers, 2008-2014); mean tumor size was 2.9 cm, and 358 (54%) were low risk (< 4 cm, no rete testis invasion). With a median follow-up of 72 months, 82 (12%) relapsed. Stage ≥ IIC relapse was rare (10 events). Although statistically noninferior, more events occurred with three scans (nine, 2.8%) versus seven scans (one, 0.3%): 2.5% absolute increase, 90% CI (1.0 to 4.1). Only 4/9 could have potentially been detected earlier with seven scans. Noninferiority of MRI versus CT was also shown; fewer events occurred with MRI (two [0.6%] v eight [2.6%]), 1.9% decrease (-3.5 to -0.3). Per-protocol analyses confirmed noninferiority. Five-year survival was 99%, with no tumor-related deaths. CONCLUSION: Surveillance is a safe management approach-advanced relapse is rare, salvage treatment successful, and outcomes excellent, regardless of imaging frequency or modality. MRI can be recommended to reduce irradiation; and no adverse impact on long-term outcomes was seen with a reduced schedule

COAST (Cisplatin Ototoxicity Attenuated by Aspirin Trial): A phase II double blind, randomised controlled trial to establish if aspirin reduces cisplatin induced hearing loss

BackgroundCisplatin has the highest ototoxic potential of platinum containing drugs leaving 50% of patients with a permanent and irreversible hearing-loss, and associated reduction in quality of life. There are no preventative treatment strategies to minimise this common side-effect. Both cisplatin and gentamicin are thought to damage hearing through a common mechanism involving reactive oxygen species in the inner ear. Aspirin has been shown to minimise gentamicin induced ototoxicity. We tested the hypothesis that aspirin could reduce ototoxicity from cisplatin based chemotherapy.Method94 patients were recruited into a phase II, double blind, placebo controlled, 2-arm trial, and randomised 1:1 from multiple tumour-sites (head and neck, thoracic, bladder, germ cell) in the U.K. Patients underwent pure tone audiometry (PTA) before, and following their final cisplatin dose at 7 and 90 days. Patients received aspirin 975mg tid and omeprazole 20 mg od, or placebos; from the day before, to 2 days after their cisplatin dose, for each cisplatin cycle. The primary endpoint was total hearing difference, comparing pre- and post-cisplatin PTA at 6 and 8kHz in both ears.ResultsAlthough aspirin was well-tolerated, it did not protect protect hearing in patients receiving cisplatin [mean difference 9.38 60% CI (-1.45, 20.22) one sided p-value of 0.233 in favour of placebo 71% (56/79) patients demonstrated hearing loss following cisplatin administration (median loss of 35db IQR 0-90 range -85 to 180, mean 42.4 SD 56.3). The extent of hearing-loss was not associated with cisplatin dose, age or hearing loss at presentation. Patients undergoing treatment for head and neck malignancy experienced the biggest hearing loss.ConclusionAspirin was well-tolerated but did not protect hearing suggesting that cisplatin and gentamicin may have distinct ototoxic mechanisms or that cisplatin is more ototoxic, requiring larger protective doses. Cisplatin induced ototoxicity results in significant morbidity and further research is required to prevent it.<br/

COAST (Cisplatin Ototoxicity Attenuated by Aspirin Trial): A phase II double blind, randomised controlled trial to establish if aspirin reduces cisplatin induced hearing loss

BackgroundCisplatin has the highest ototoxic potential of platinum containing drugs leaving 50% of patients with a permanent and irreversible hearing-loss, and associated reduction in quality of life. There are no preventative treatment strategies to minimise this common side-effect. Both cisplatin and gentamicin are thought to damage hearing through a common mechanism involving reactive oxygen species in the inner ear. Aspirin has been shown to minimise gentamicin induced ototoxicity. We tested the hypothesis that aspirin could reduce ototoxicity from cisplatin based chemotherapy.Method94 patients were recruited into a phase II, double blind, placebo controlled, 2-arm trial, and randomised 1:1 from multiple tumour-sites (head and neck, thoracic, bladder, germ cell) in the U.K. Patients underwent pure tone audiometry (PTA) before, and following their final cisplatin dose at 7 and 90 days. Patients received aspirin 975mg tid and omeprazole 20 mg od, or placebos; from the day before, to 2 days after their cisplatin dose, for each cisplatin cycle. The primary endpoint was total hearing difference, comparing pre- and post-cisplatin PTA at 6 and 8kHz in both ears.ResultsAlthough aspirin was well-tolerated, it did not protect protect hearing in patients receiving cisplatin [mean difference 9.38 60% CI (-1.45, 20.22) one sided p-value of 0.233 in favour of placebo 71% (56/79) patients demonstrated hearing loss following cisplatin administration (median loss of 35db IQR 0-90 range -85 to 180, mean 42.4 SD 56.3). The extent of hearing-loss was not associated with cisplatin dose, age or hearing loss at presentation. Patients undergoing treatment for head and neck malignancy experienced the biggest hearing loss.ConclusionAspirin was well-tolerated but did not protect hearing suggesting that cisplatin and gentamicin may have distinct ototoxic mechanisms or that cisplatin is more ototoxic, requiring larger protective doses. Cisplatin induced ototoxicity results in significant morbidity and further research is required to prevent it.<br/

Molecular Targeted Agents for Gastric Cancer: A Step Forward Towards Personalized Therapy

Gastric cancer (GC) represents a major cancer burden worldwide, and remains the second leading cause of cancer-related death. Due to its insidious nature, presentation is usually late and often carries a poor prognosis. Despite having improved treatment modalities over the last decade, for most patients only modest improvements have been seen in overall survival. Recent progress in understanding the molecular biology of GC and its signaling pathways, offers the hope of clinically significant promising advances for selected groups of patients. Patients with Her-2 overexpression or amplification have experienced benefit from the integration of monoclonal antibodies such as trastuzumab to the standard chemotherapy. Additionally, drugs targeting angiogenesis (bevacizumab, sorafenib, sunitinib) are under investigation and other targeted agents such as mTOR inhibitors, anti c-MET, polo-like kinase 1 inhibitors are in preclinical or early clinical development. Patient selection and the development of reliable biomarkers to accurately select patients most likely to benefit from these tailored therapies is now key. Future trials should focus on these advances to optimize the treatment for GC patients. This article will review recent progress and current status of targeted agents in GC