Pre-therapy mRNA expression of TNF is associated with regimen-related gastrointestinal toxicity in patients with esophageal cancer: a pilot study

Author version made available following 12 month embargo from date of publication (27 March 2015) in accordance with publisher copyright policy.Purpose Esophageal cancer has a high mortality rate, and its multimodality treatment is often associated with significant rates of severe toxicity. Effort is needed to uncover ways to maximize effectiveness of therapy through identification of predictive markers of response and toxicity. As such, the aim of this study was to identify genes predictive of chemoradiotherapy-induced gastrointestinal toxicity using an immune pathway-targeted approach. Methods Adults with esophageal cancer treated with chemotherapy consisting of 5-fluorouracil and cisplatin and 45–50 Gy radiation were recruited to the study. Pre-therapy-collected whole blood was analyzed for relative expression of immune genes using real-time polymerase chain reaction (RT-PCR). Gene expression was compared between patients who experienced severe regimen-related gastrointestinal toxicity vs. those experiencing mild to moderate toxicity. Results Blood from 31 patients were analyzed by RT-PCR. Out of 84 immune genes investigated, TNF was significantly elevated (2.05-fold, p = 0.025) in the toxic group (n = 12) compared to the non-toxic group (n = 19). Nausea and vomiting was the most commonly documented severe toxicity. No associations between toxicity and response, age, sex, histology, or treatment were evident. Conclusions This study supports evidence of TNF as a predictive biomarker in regimen-related gastrointestinal toxicity. Confirming these findings in a larger cohort is warranted

Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial

Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab-a human IgG1 VEGFR-2 antagonist-or placebo in this patient population

New systemic treatment options for metastatic renal-cell carcinoma in the era of targeted therapies

Advances in understanding the biology and genetics of renal-cell carcinomas have led to the development of novel targeted therapies for the treatment of metastatic renal-cell cancer. Previously the systemic approaches were limited to cytokine therapies that were modest in their clinical benefits and at the expense of significant toxicities. Investigational treatments with allogeneic bone marrow transplantation were equally toxic and resulted in significant morbidity and mortality. The development of targeted therapy has revolutionized the treatment of metastatic renal-cell cancer with more meaningful outcomes. This review aims to provide a detailed discussion of the clinical benefits of targeted therapies such as sunitinib, sorafenib, temsirolimus, everolimus, bevacizumab, and some of the newer agents in clinical trial development. The efficacy of these compounds in terms of response, survival and clinical benefit are explored as well as their toxicities. The role of surgery in metastatic renal-cell carcinoma is reviewed in the context of cytoreductive therapy and resection of solitary and oligometastatic disease. Ongoing studies in the adjuvant setting following curative resection are also reviewed. The availability of targeted therapies has led to their rapid adoption as frontline therapy over traditional cytokine therapy, thus bringing more optimistic and hopeful therapeutic options in a condition where historically, systemic treatments have been relatively unsatisfactory and disappointing

Overall survival of men with metachronous metastatic hormone-sensitive prostate cancer treated with enzalutamide and androgen deprivation therapy

Men who initially present with localized prostate cancer and later develop metachronous metastases have a better prognosis than men with de novo metastatic disease and often have a low burden of disease on conventional imaging. Some have disease amenable to metastasis-directed therapy for lymph node or bone metastases, a strategy used by some because no documented overall survival (OS) benefit of combination systemic therapy in this setting. We report data for patients prospectively classified as “M0” at initial diagnosis from the interim analysis of the ENZAMET trial, with 34 mo of median follow-up for survivors. A total of 312 (28%) of the 1125 enrolled patients were classified as M0 at diagnosis, and 205 (66%) of the 312 patients had low-volume disease at study entry as per the CHAARTED criteria. The hazard ratio for OS, that is, HR(OS), was 0.56 (95% confidence interval [CI]: 0.29–1.06) with the addition of enzalutamide for all patients with metachronous metastatic hormone-sensitive prostate cancer, and for the low-volume subset the HR(OS) was 0.40 (95% CI: 0.16–0.97). The 3-yr OS was 83% without and 89% with enzalutamide for all patients with metachronous metastases, and 83% and 92%, respectively, for the low-volume subset. Intensification of hormonal therapy should strongly be considered for these men. Patient summary: Many men present with prostate cancer that has spread to distant sites beyond the prostate gland years after their initial diagnosis and treatment, while others have distant spread at the time the cancer is diagnosed. On average, men whose cancer comes back years after the initial diagnosis often survive much longer than men whose cancer has been found to spread to distant sites when it is first diagnosed. In this report, we demonstrate strong evidence for the first time that the survival of men whose cancer comes back years later is improved when drugs such as enzalutamide or apalutamide are added to testosterone suppression in this setting

Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET) : an international, open-label, randomised, phase 3 trial

Background: The interim analysis of the ENZAMET trial of testosterone suppression plus either enzalutamide or standard nonsteroidal antiandrogen therapy showed an early overall survival benefit with enzalutamide. Here, we report the planned primary overall survival analysis, with the aim of defining the benefit of enzalutamide treatment in different prognostic subgroups (synchronous and metachronous high-volume or low-volume disease) and in those who received concurrent docetaxel. Methods: ENZAMET is an international, open-label, randomised, phase 3 trial conducted at 83 sites (including clinics, hospitals, and university centres) in Australia, Canada, Ireland, New Zealand, the UK, and the USA. Eligible participants were males aged 18 years or older with metastatic, hormone-sensitive prostate adenocarcinoma evident on CT or bone scanning with 99mTc and an Eastern Cooperative Oncology Group performance status score of 0–2. Participants were randomly assigned (1:1), using a centralised web-based system and stratified by volume of disease, planned use of concurrent docetaxel and bone antiresorptive therapy, comorbidities, and study site, to receive testosterone suppression plus oral enzalutamide (160 mg once per day) or a weaker standard oral non-steroidal antiandrogen (bicalutamide, nilutamide, or flutamide; control group) until clinical disease progression or prohibitive toxicity. Testosterone suppression was allowed up to 12 weeks before randomisation and for up to 24 months as adjuvant therapy. Concurrent docetaxel (75 mg/m2 intravenously) was allowed for up to six cycles once every 3 weeks, at the discretion of participants and physicians. The primary endpoint was overall survival in the intention-to-treat population. This planned analysis was triggered by reaching 470 deaths. This study is registered with ClinicalTrials.gov, NCT02446405, ANZCTR, ACTRN12614000110684, and EudraCT, 2014-003190-42. Findings: Between March 31, 2014, and March 24, 2017, 1125 participants were randomly assigned to receive non-steroidal antiandrogen (n=562; control group) or enzalutamide (n=563). The median age was 69 years (IQR 63–74). This analysis was triggered on Jan 19, 2022, and an updated survival status identified a total of 476 (42%) deaths. After a median follow-up of 68 months (IQR 67–69), the median overall survival was not reached (hazard ratio 0·70 [95% CI 0·58–0·84]; p<0·0001), with 5-year overall survival of 57% (0·53–0·61) in the control group and 67% (0·63–0·70) in the enzalutamide group. Overall survival benefits with enzalutamide were consistent across predefined prognostic subgroups and planned use of concurrent docetaxel. The most common grade 3–4 adverse events were febrile neutropenia associated with docetaxel use (33 [6%] of 558 in the control group vs 37 [6%] of 563 in the enzalutamide group), fatigue (four [1%] vs 33 [6%]), and hypertension (31 [6%] vs 59 [10%]). The incidence of grade 1–3 memory impairment was 25 (4%) versus 75 (13%). No deaths were attributed to study treatment. Interpretation: The addition of enzalutamide to standard of care showed sustained improvement in overall survival for patients with metastatic hormone-sensitive prostate cancer and should be considered as a treatment option for eligible patients. Funding: Astellas Pharma

[177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP) : a randomised, open-label, phase 2 trial

Background: Lutetium-177 [177Lu]Lu-PSMA-617 is a radiolabelled small molecule that delivers β radiation to cells expressing prostate-specific membrane antigen (PSMA), with activity and safety in patients with metastatic castration-resistant prostate cancer. We aimed to compare [177Lu]Lu-PSMA-617 with cabazitaxel in patients with metastatic castration-resistant prostate cancer. Methods: We did this multicentre, unblinded, randomised phase 2 trial at 11 centres in Australia. We recruited men with metastatic castration-resistant prostate cancer for whom cabazitaxel was considered the next appropriate standard treatment. Participants were required to have adequate renal, haematological, and liver function, and an Eastern Cooperative Oncology Group performance status of 0–2. Previous treatment with androgen receptor-directed therapy was allowed. Men underwent gallium-68 [68Ga]Ga-PSMA-11 and 2-flourine-18[18F]fluoro-2-deoxy-D-glucose (FDG) PET-CT scans. PET eligibility criteria for the trial were PSMA-positive disease, and no sites of metastatic disease with discordant FDG-positive and PSMA-negative findings. Men were randomly assigned (1:1) to [177Lu]Lu-PSMA-617 (6·0–8·5 GBq intravenously every 6 weeks for up to six cycles) or cabazitaxel (20 mg/m2 intravenously every 3 weeks for up to ten cycles). The primary endpoint was prostate-specific antigen (PSA) response defined by a reduction of at least 50% from baseline. This trial is registered with ClinicalTrials.gov, NCT03392428. Findings: Between Feb 6, 2018, and Sept 3, 2019, we screened 291 men, of whom 200 were eligible on PET imaging. Study treatment was received by 98 (99%) of 99 men randomly assigned to [177Lu]Lu-PSMA-617 versus 85 (84%) of 101 randomly assigned to cabazitaxel. PSA responses were more frequent among men in the [177Lu]Lu-PSMA-617 group than in the cabazitaxel group (65 vs 37 PSA responses; 66% vs 37% by intention to treat; difference 29% (95% CI 16–42; p<0·0001; and 66% vs 44% by treatment received; difference 23% [9–37]; p=0·0016). Grade 3–4 adverse events occurred in 32 (33%) of 98 men in the [177Lu]Lu-PSMA-617 group versus 45 (53%) of 85 men in the cabazitaxel group. No deaths were attributed to [177Lu]Lu-PSMA-617. Interpretation: [177Lu]Lu-PSMA-617 compared with cabazitaxel in men with metastatic castration-resistant prostate cancer led to a higher PSA response and fewer grade 3 or 4 adverse events. [177Lu]Lu-PSMA-617 is a new effective class of therapy and a potential alternative to cabazitaxel. Funding: Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, The Distinguished Gentleman's Ride, It's a Bloke Thing, and CAN4CANCER

Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial

Background: Ramucirumab—an IgG1 vascular endothelial growth factor receptor 2 antagonist—plus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial. Methods: We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m2 (60 mg/m2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues. Findings: Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7·4 months (IQR 3·5–13·9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4·1 months [95% CI 3·3–4·8] vs 2·8 months [2·6–2·9]; HR 0·696 [95% CI 0·573–0·845]; p=0·0002). Median overall survival was 9·4 months (95% CI 7·9–11·4) in the ramucirumab group versus 7·9 months (7·0–9·3) in the placebo group (stratified HR 0·887 [95% CI 0·724–1·086]; p=0·25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group. Interpretation: Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population. Funding: Eli Lilly and Company