BGJ398, a potent and selective pan-FGFR antagonist, was prospectively evaluated in patients with metastatic urothelial carcinoma bearing a diverse array of
alterations. Patients (
= 67) who were ...unable to receive platinum chemotherapy were enrolled. The majority (70.1%) had received two or more prior antineoplastic therapies. BGJ398 was administered orally at 125 mg/day on a 3 weeks on, 1 week off schedule until unacceptable toxicity or progression. The primary endpoint was the response rate. Among 67 patients treated, an overall response rate of 25.4% was observed and an additional 38.8% of patients had disease stabilization, translating to a disease control rate of 64.2%. The most common treatment-emergent toxicities were hyperphosphatemia, elevated creatinine, fatigue, constipation, and decreased appetite. Further examination of BGJ398 in this disease setting is warranted.
BJG398 is active in patients with alterations in
, resulting in both reductions in tumor volume and stabilization of disease. Our data highlight putative mechanisms of resistance to the agent, which may be useful in following disease status.
.
Patients with bladder cancer with clinical lymph node involvement (cN+) are at high risk for distant metastases, but are potentially curable. Such patients are excluded from neoadjuvant chemotherapy ...trials and pooled with patients with distant metastases in first-line chemotherapy trials not suited to define the role of combined-modality therapy. To address this evidence void, we performed a comparative effectiveness analysis.
We included cTanyN1-3M0 bladder cancer patients from the National Cancer Data Base (2003-2012) treated with chemotherapy and/or cystectomy. We used multistate survival analysis, allowing for delayed entry, to assess overall survival (OS) according to various treatment strategies. Effectiveness was estimated with multivariable adjustment for tumor-, patient-, and facility-level characteristics.
Among 1,739 patients (cN1, 48%; cN2, 45%; cN3, 7%), 1,104 underwent cystectomy and 635 were treated with chemotherapy alone. Of the cystectomy patients, 363 received preoperative and 328 received adjuvant chemotherapy. The crude 5-year OS for chemotherapy alone, cystectomy alone, preoperative chemotherapy followed by cystectomy, and cystectomy followed by adjuvant chemotherapy was 14% (95% CI, 11% to 17%), 19% (95% CI, 15% to 24%), 31% (95% CI, 25% to 38%), and 26% (95% CI, 21% to 34%), respectively. Compared with cystectomy alone, preoperative chemotherapy was associated with a significant improvement in OS (hazard ratio, 0.80; 95% CI, 0.66 to 0.97). Adjuvant chemotherapy was also associated with a significant improvement in survival compared with cystectomy alone. The survival of patients treated with chemotherapy alone was worse than those treated with cystectomy alone.
A subset of patients with cN+ bladder cancer achieves long-term survival. Combined-modality therapy, with chemotherapy and cystectomy, is associated with the best outcomes.
Several anti-programmed death-1 (anti-PD-1) and anti-programmed death ligand-1 (anti-PD-L1) antibodies have been approved by regulatory authorities for treatment of platinum-resistant metastatic ...urothelial cancer (mUC). The impact of these therapies on survival, and comparability of PD-1 versus PD-L1 blockade are unknown.
To determine the restricted mean survival time (RMST) of patients with platinum-resistant mUC treated with PD-1/PD-L1 inhibitors and to compare RMSTs in patients treated with PD-1 versus PD-L1 inhibitors.
We searched for phase 1, 2, and 3 clinical trials that assessed PD-1 or PD-L1 inhibition for patients with platinum-resistant mUC. Literature review and study selection, data abstraction, and risk of bias assessment were performed by two reviewers. Survival data were reconstructed using an algorithm that derives individual time-to-event data from published Kaplan-Meier curves. The RMST with 95% confidence interval (CIs) was calculated.
From 836 references, six clinical trials were included. Survival data were reconstructed for 1315 and 736 patients treated with PD-1/PD-L1 inhibitors and chemotherapy, respectively. The RMSTs with PD-1/PD-L1 blockade up to 12 and 18mo of follow-up were 7.8mo (95% CI 7.6, 8.1) and 10mo (95% CI 9.7, 10.5), respectively. A network meta-analysis of two randomized trials revealed no significant difference in the RMST up to 18mo with PD-1 versus PD-L1 blockade (1.0mo; 95% CI −0.5, 2.3mo). Using reconstructed survival data from all six trials, the RMSTs with PD-1 versus PD-L1 blockade up to 12 and 18mo follow-up were 7.8mo (95% CI 7.7, 8.2) versus 7.8mo (95% CI 7.5, 8.2) and 10.1mo (95% CI 9.6, 10.7) versus 10mo (95% CI 9.5, 10.6), respectively.
Our RMST estimates may be used as benchmarks to contextualize survival outcomes and inform future trial design with PD-1/PD-L1 inhibitors. PD-1 versus PD-L1 blockade in patients with mUC yields comparable survival outcomes.
In this study, we found that outcomes for patients with metastatic bladder cancer treated with programmed death-1 and programmed death ligand-1 inhibitors, who received prior platinum-based chemotherapy, were similar.
Restricted mean survival time estimates may be used to benchmark survival outcomes and inform future trial design.Programmed death-1 and programmed death ligand-1 blockade in patients with platinum-resistant metastatic urothelial cancer yield comparable survival outcomes.
Prostate cancer treatment has substantial effects on sexual health and function. Sexual function is a vital aspect of human health and a critical component of cancer survivorship, and understanding ...the potential effects of different treatment modalities on sexual health is crucial. Existing research has extensively described the effects of treatment on male erectile tissues necessary for heterosexual intercourse; however, evidence regarding their effects on sexual health and function in sexual and gender minority populations is minimal. These groups include sexual minority - gay and bisexual - men, and transgender women or trans feminine people in general. Such unique effects in these groups might include altered sexual function in relation to receptive anal and neovaginal intercourse and changes to patients' role-in-sex. Sexual dysfunctions following prostate cancer treatment affecting quality of life in sexual minority men include climacturia, anejaculation, decreased penile length, erectile dysfunction, and problematic receptive anal intercourse, including anodyspareunia and altered pleasurable sensation. Notably, clinical trials investigating sexual outcomes after prostate cancer treatment do not collect sexual orientation and gender identity demographic data or outcomes specific to members of these populations, which perpetuates the uncertainty regarding optimal management. Providing clinicians with a solid evidence base is essential to communicate recommendations and tailor interventions for sexual and gender minority patients with prostate cancer.
Abstract
Background
In the phase III SPARC trial, satraplatin, an oral platinum analogue, demonstrated anticancer activity in men with metastatic castration-resistant prostate cancer (mCRPC). Repeat ...biopsies are uncommon in mCRPC, limiting the feasibility of tissue–based biomarkers. This phase II study sought to evaluate the feasibility and utility of blood–based biomarkers to identify platinum–sensitive mCRPC.
Methods
Patients with mCRPC who had progressed on docetaxel were enrolled at a single center from 2011 to 2013. Subjects received satraplatin 80 mg/m2 by mouth daily on days 1-5 and prednisone 5 mg PO twice daily, on a 35-day cycle. Serial peripheral blood samples were collected for biomarker assessment.
Results
Thirteen docetaxel-refractory mCRPC patients were enrolled, with a median age of 69 years (range 54-77 years) and median PSA of 71.7 ng/mL (range 0.04-3057). Four of 13 patients (31%) responded to satraplatin (defined as a PSA decline of ≥30%). Responders demonstrated improved time to disease progression (206 vs. 35 days, HR 0.26, 95% CI, 0.02-0.24, P = .003). A 6-gene peripheral blood RNA signature and serum tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were assessed as biomarkers, but neither was significantly associated with response to satraplatin.
Conclusion
In this small series, one-third of mCRPC patients responded to platinum–based chemotherapy. Peripheral blood biomarker measurement is feasible in mCRPC, though the biomarkers we investigated were not associated with platinum response. Other biomarkers, such as DNA damage repair mutations, should be evaluated.
Repeat biopsies are uncommon in metastatic castration–resistant prostate cancer (CRPC), limiting the feasibility of tissue–based biomarkers. This article evaluates the feasibility and utility of blood–based biomarkers to identify platinum–sensitive mCRPC.
Targeted cancer therapies, which act on specific cancer-associated molecular targets, are predominantly inhibitors of oncogenic kinases. While these drugs have achieved some clinical success, the ...inactivation of kinase signaling via stimulation of endogenous phosphatases has received minimal attention as an alternative targeted approach. Here, we have demonstrated that activation of the tumor suppressor protein phosphatase 2A (PP2A), a negative regulator of multiple oncogenic signaling proteins, is a promising therapeutic approach for the treatment of cancers. Our group previously developed a series of orally bioavailable small molecule activators of PP2A, termed SMAPs. We now report that SMAP treatment inhibited the growth of KRAS-mutant lung cancers in mouse xenografts and transgenic models. Mechanistically, we found that SMAPs act by binding to the PP2A Aα scaffold subunit to drive conformational changes in PP2A. These results show that PP2A can be activated in cancer cells to inhibit proliferation. Our strategy of reactivating endogenous PP2A may be applicable to the treatment of other diseases and represents an advancement toward the development of small molecule activators of tumor suppressor proteins.
Highlights • We identified 684 precision cancer medicine trials from ClinicalTrials.gov. • 38 unique genomic alterations were identified for enrollment. • These trials were more likely to involve ...breast, colorectal and skin cancers. • The proportion of these trials increased from 3% in 2006 to 16% in 2013.
Summary Background Survival for patients with castration-resistant prostate cancer is highly variable. We assessed the effectiveness of a whole-blood RNA transcript-based model as a prognostic ...biomarker in castration-resistant prostate cancer. Methods Peripheral blood was prospectively collected from 62 men with castration-resistant prostate cancer on various treatment regimens who were enrolled in a training set at the Dana-Farber Cancer Institute (Boston, MA, USA) from August, 2006, to June, 2008, and from 140 patients with castration-resistant prostate cancer in a validation set from Memorial Sloan-Kettering Cancer Center (New York, NY, USA) from August, 2006, to February, 2009. A panel of 168 inflammation-related and prostate cancer-related genes was assessed with optimised quantitative PCR to assess biomarkers predictive of survival. Findings A six-gene model (consisting of ABL2, SEMA4D, ITGAL , and C1QA, TIMP1, CDKN1A ) separated patients with castration-resistant prostate cancer into two risk groups: a low-risk group with a median survival of more than 34·9 months (median survival was not reached) and a high-risk group with a median survival of 7·8 months (95% CI 1·8–13·9; p<0·0001). The prognostic utility of the six-gene model was validated in an independent cohort. This model was associated with a significantly higher area under the curve compared with a clinicopathological model (0·90 95% CI 0·78–0·96 vs 0·65 0·52–0·78; p=0·0067). Interpretation Transcriptional profiling of whole blood yields crucial prognostic information about men with castration-resistant prostate cancer. The six-gene model suggests possible dysregulation of the immune system, a finding that warrants further study. Funding Source MDX.
The phase 3 CheckMate 274 trial demonstrated superiority of adjuvant nivolumab over placebo after radical surgery in patients with high-risk muscle-invasive urothelial carcinoma. However, the ...efficacy and safety of adjuvant nivolumab in Japanese patients with muscle-invasive urothelial carcinoma have not been clarified.
Patients with muscle-invasive urothelial carcinoma were randomized to adjuvant nivolumab 240 mg or placebo (every 2 weeks via intravenous infusion) up to 120 days after radical surgery in CheckMate 274.
Of 49 patients in the Japanese subgroup, 27 and 22 patients were randomized to nivolumab and placebo, respectively. Eleven and 8 patients, respectively, had tumor PD-L1 expression level of 1% or more. The median disease-free survival times in the nivolumab and placebo groups were 29.67 months (95% confidence interval 7.79-not reached) and 9.72 months (95% confidence interval 4.73-not reached), respectively (hazard ratio 0.77, 95% confidence interval 0.35-1.69). The corresponding values in patients with tumor PD-L1 expression level of 1% or more were 29.67 months (95% confidence interval 2.63-not reached) and 25.95 months (95% confidence interval 5.59-not reached) (hazard ratio 1.10, 95% confidence interval 0.31-3.92), respectively. Treatment-related adverse events of Grade 3-4 occurred in 25.9 and 13.6% of patients in the nivolumab and placebo groups, respectively. The most common treatment-related adverse events in the nivolumab group were lipase increased, amylase increased and diarrhea. The changes in quality of life scores from baseline over time were similar in both groups.
The efficacy and safety results in the Japanese subgroup were consistent with the overall population of CheckMate 274.
PDF
