Current first line treatment options in patients with metastatic urothelial carcinoma unfit to receive cisplatin containing chemotherapy include PD-1/L1 inhibitors and carboplatin containing ...chemotherapy. However, the optimal sequencing of these therapies remains unclear.
We conducted a multicenter retrospective analysis. Consecutive cisplatin ineligible patients with metastatic urothelial carcinoma treated with first line carboplatin containing chemotherapy followed sequentially by second line PD-1/L1 inhibitor, or the reverse order, were included. Patient demographics, objective response, time to treatment failure for first line and second line therapy, interval between end of first line and initiation of second line treatment (Interval
) and overall survival were collected. Multivariate analysis was conducted to examine the association of sequencing on overall survival.
In this multicenter retrospective study we identified 146 cisplatin ineligible patients with metastatic urothelial carcinoma treated with first line PD-1/L1 inhibitor therapy followed by second line carboplatin containing chemotherapy (group 1, 43) or the reverse sequence (group 2, 103). In the overall cohort median age was 72, 76% were men and 18% had liver metastasis. In both groups objective response rates were higher with carboplatin containing chemotherapy (45.6% first line, 44.2% second line) compared to PD-1/L1 inhibitors (9.3% first line, 21.3% second line). On multivariate analysis treatment sequence was not associated with overall survival (HR 1.05, p=0.85). Site of metastasis was the only factor significantly associated with overall survival (p=0.002).
In this biomarker unselected cohort of cisplatin ineligible patients with metastatic urothelial carcinoma, PD-1/L1 inhibitor followed by carboplatin containing chemotherapy and the reverse sequence had comparable overall survival.
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447
Background: ER models were previously developed to characterize the relationship between C exposure and efficacy endpoints in RCC pts in the phase III METEOR study (J Clin Oncol 34, ...2016 suppl; abstr 2565). Higher C exposure correlated with decreased tumor size and improved progression-free survival and objective response rate. Model-based predictions showed that C would be effective at the 60 mg starting dose evaluated in METEOR as well as dose levels of 40 and 20 mg resulting from dose reduction. In the current study, ER models were developed to characterize the relationship between C exposure and safety endpoints in RCC pts. Methods: The ER analysis included 318 RCC pts who had received at least one C dose and had at least one measurable C concentration. Time-to-event Cox proportional hazard ER models were developed to characterize the relationship between various individual predicted C exposure measures and the likelihood of dose modification and 6 specific adverse events (AEs): fatigue/asthenia, palmar-plantar erythrodysesthesia (PPE), nausea/vomiting, diarrhea, hypertension, and stomatitis. Results: A statistically significant relationship was identified between individual predicted C clearance (CL/F) and the rate of dose modification (p <0.0001), with the risk of dose modification decreasing with increasing CL/F. An increase in average C concentration was associated with increased risk of fatigue/asthenia (Grade ≥3), PPE (Grade ≥1), hypertension (systolic blood pressure BP >160 mmHg or diastolic BP >100 mmHg), and diarrhea (Grade ≥3). The predicted hazard ratios for these AEs were 2.01, 2.21, 1.85, and 1.78, respectively, based on the predicted steady-stage average C concentration for a 60 mg dose relative to a 20 mg dose. Statistically significant ER relationships were not identified for nausea/vomiting (Grade ≥3) or stomatitis (Grade ≥3). Conclusions: Based on the ER analysis, higher C exposures resulting from lower C CL/F are predicted to increase the dose modification rate. Reduced C exposures resulting from dose reduction are predicted to decrease the risk of fatigue/asthenia, PPE, hypertension, and diarrhea while maintaining clinical benefit. Clinical trial information: NCT01865747.
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326
Background: TCGA molecular sybtyping is established in metastatic urothelial bladder cancer (UBC). It remains unclear if it is of prognostic importance with chemotherapy in ...metastatic UBC. Data into immune therapy suggests TCGA subtyping is predictive to response. Methods: Archival formalin-fixed paraffin embedded (FFPE) tissue were analysed from 170 patients that had consented into a clinical trial (NCT00949455) after first line chemotherapy for metastatic disease. Gene expression levels were quantified by NanoString technology. Molecular subtypes were assigned according to The Cancer Genome Atlas (TCGA) subtypes. Clinical information was available for all patients and analysis on individual genes were explored. Results: 170 patients were analysed, 75% male. 107 (64%) patients received cisplatin based first-line chemotherapy, with 36% receiving carboplatin based regimen. Median overall survival (OS) was 15.73 months 95% CI: 13.87-17.58, and median progression free survival (PFS) was 10.71 months 95% CI: 8.97-12.45. Samples were initially clustered into luminal (n=109) and basal (n=61) subtypes. Response to first line chemotherapy occurred in all subtypes but was shown to be significantly higher in the luminal subtype versus the basal subtype 58% vs 20%, p=0.01. PFS was superior in luminal subtypes 11.8 months vs 8.9 months, p=0.005. Exploratory analysis showed that luminal II subtype had the best outcome for OS 20.3 months, p=0.03 compared to the other subtypes. Outcomes with other genes including immune markers were explored. TCGA outcomes can be summarised in the table. Conclusions: In metastatic urothelial cancer, TCGA subclassifying influences outcome of patients post chemotherapy. Table: see text
•There is a rise in incidence of urothelial carcinoma (UC) in the Emerging Markets (EM) region.•There is paucity of literature on frequency of patient eligibility and ineligibility for platinum-based ...chemotherapy from the EM region.•Common challenges for management of UC in EM includes cost of the therapies and lack of local guidelines or clinical guidance.•There is a low rate of participation in clinical trials from EM countries and LMICs in general as opposed to high income countries.
Urothelial carcinoma (UC) is the 10th most common cancer globally with an almost 4 times higher prevalence in men. The main risk factors for development of urothelial carcinoma are advanced age, smoking, arsenic contamination, exposure to carcinogens. Metastatic urothelial carcinoma (mUC) has overall poor prognosis with a 5-year overall survival rate of only < 5%. The standard of care comprises of platinum-based chemotherapy, but the responses are often not sustained. A working group was established with an objective to discuss the most recent clinical data on the genitourinary tumors of interest and comprised of experts across Latin America, Emerging Asia (except China, Japan, and South Korea), Africa, and the Middle East (known as Emerging Markets or EM). There is an evident disparity in terms of uneven mortality and incidence rate distribution among various regions. There is a lack and/or insufficient data on epidemiology, treatment, and outcomes in the EM. The lack of registries impacts the healthcare decisions and the lower incidence from the region might not be reflective of the true disease burden. The treatment outcomes of mUC can be improved by understanding the current disease burden and treatment approach of mUC and identifying the gaps and challenges associated with management. Hence, a literature review was developed to summarize the current disease burden and treatment approach of mUC across EM. The review also highlights the unmet needs for mUC management in EM and suggests a way forward to improve the current situation in order to better serve the patients.
Sipuleucel-T is an autologous cellular immunotherapy approved in the US for patients with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). This ...significant advance for mCRPC treatment provides healthcare professionals with another effective therapy to extend survival. As an immunotherapy, sipuleucel-T possesses specific characteristics differentiating it from traditional therapies. At a roundtable meeting of experts, sipuleucel-T data were discussed, focusing on interpretation and clinical implications. Important differences between immunotherapies and traditional therapies were explored, e.g., mode of action, outcomes, data consistency and robustness, timing of sipuleucel-T treatment, and future perspectives in areas such as short-term markers of long-term benefit.
There are few data on outcomes for patients with metastatic urothelial carcinoma (MUC) who receive chemotherapy (CT) after progression on immune checkpoint inhibitors (ICIs). We carried out a ...retrospective single-centre analysis of MUC patients who progressed after ICI and then received CT. Patients fell into two groups: CT-naive (no prior-CT) and CT-pretreated (platinum-based CT followed by ICI on progression). The response rate (RR), progression-free survival (PFS), and duration of response (DOR) were assessed. A total of 29 patients received CT following progression on ICI. The median follow-up was 17.0mo (interquartile range 9.1–20.5mo). In the CT-naive group (n=17), 53% had a partial response, 18% had stable disease, and 29% had progressive disease. In the CT-pretreated group (n=12) 17% had a partial response, 67% had stable disease, and 16% had progressive disease. The median PFS was 6.4mo (95% confidence interval CI 3.8–9.1) in the CT-naive and 4.4mo (95% CI 1.5–7.3) in the CT-pretreated group. The median DOR was 8.1mo (range 5.1–11.1) among the ten patients with a response to CT after ICI in both groups. Some 38% of patients in the CT-naive and 17% in the CT-pretreated group had dose reductions on post-ICI CT. CT and ICI can be sequenced after previous chemotherapy exposure, although this does not induce long-term durable remissions in most patients.
We looked at outcomes for patients with metastatic bladder cancer who received chemotherapy after the cancer got worse while on immunotherapy. We found that patients can be safely treated with further chemotherapy. However, the positive effects of chemotherapy will not be durable in the majority of patients.
Chemotherapy and immune checkpoint inhibition can be sequenced in metastatic urothelial carcinoma even after previous chemotherapy exposure. Patients can be safely treated with further chemotherapy. However, the positive effects of chemotherapy will not be durable in the majority of patients.
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TPS4595
Background: Lenvatinib (LEN) is a multikinase inhibitor of vascular endothelial growth factor (VEGF) receptor 1–3, fibroblast growth factor receptor 1–4, platelet-derived growth ...factor receptor alpha, and RET and KIT. Based on a phase 2 study (Motzer et al. Lancet Oncol 2015), LEN was approved in combination with everolimus (EVE) for treatment of metastatic RCC following 1 prior VEGF-targeted therapy. A phase 1b/2 study of LEN in combination with pembrolizumab (PEM) in pts with RCC LEN is also underway. We report the design of a multicenter, open-label, phase 3 trial of LEN plus EVE or PEM vs sunitinib (SUN; a standard therapy for RCC) as first-line treatment for advanced RCC. Methods: Pts aged ≥ 18 years with confirmed advanced RCC diagnosis, ≥ 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Karnofsky Performance Status ≥ 70, controlled blood pressure, and adequate blood coagulation, renal, hepatic, and bone marrow function are eligible. Pts will be randomized 1:1:1 to receive LEN 18 mg/day + EVE 5 mg/day, LEN 20 mg/day + PEM 200 mg every 3 weeks, or SUN 50 mg/day (on a schedule of 4 weeks on treatment followed by 2 weeks off) until disease progression, unacceptable toxicity, withdrawal of consent, or study end. The primary endpoint is to show superiority of LEN+EVE or LEN+PEM over single-agent SUN as first-line treatment for advanced RCC in improving progression-free survival (PFS). Secondary endpoints include comparison of objective response rate, overall survival, PFS on next-line therapy, health-related quality of life, and safety and tolerability in pts receiving LEN+EVE or LEN+PEM vs SUN. Exploratory endpoints include PFS in the LEN+PEM arm using immune-related RECIST, comparison of duration of response, disease control rate, and clinical benefit rate in pts treated with LEN+EVE or LEN+PEM vs SUN, and analysis of the relationship between blood biomarkers and outcome. No interim analysis is planned for efficacy or futility. Enrollment of 735 pts is planned to achieve 90% power at 2-sided α = 0.05 to detect a difference in ≥ 1 of the primary comparisons. Clinical trial information: NCT02811861.
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TPS541
Background: Cabozantinib (CABO) is an oral receptor tyrosine kinase inhibitor of MET, VEGFR, and TAM family receptors (TYRO3, AXL, and MER). It is approved for patients (pts) ...with RCC after prior therapy with antiangiogenic therapy, and has demonstrated clinical activity in UC. In clinical studies, CABO exposure increased circulating CD8+ T cells and reduced immune-suppressive monocytes and Tregs. In preclinical tumor models, CABO increased MHC class 1 expression on tumor cells and reduced myeloid-derived suppressor cells. CABO may facilitate an immune-permissive tumor environment and may enhance response to immune checkpoint inhibitors. Atezolizumab (ATEZO), an anti-PD-L1 mAb, is approved for: locally advanced/metastatic UC in pts who are cisplatin-ineligible or have disease progression during/following platinum-containing chemo; pts with metastatic NSCLC and disease progression during/following platinum-containing chemo. We present the study design of an ongoing phase 1b study combining CABO with ATEZO in pts with locally advanced/metastatic UC or RCC. Methods: This multicenter, phase 1b, open-label study aims to assess safety, tolerability, preliminary efficacy, and pharmacokinetics of CABO in combination with ATEZO (NCT03170960). The study will enroll pts with advanced UC (bladder, renal pelvis, ureter, urethra) or RCC. It consists of two stages: dose escalation and expansion. In the dose-escalation stage (3+3 design), a recommended CABO dose for the combination will be established. In the expansion stage, four tumor-specific cohorts will be enrolled: 1) pts with UC who have progressed on/after platinum-containing chemo; 2) chemo-naïve pts with UC who are cisplatin ineligible; 3) chemo-naïve pts with UC who are cisplatin eligible; and 4) untreated pts with RCC with clear cell histology; the primary objective is to determine the objective response rate in each cohort. Exploratory objectives include correlation of tumor and plasma biomarkers, and changes in immune cell profiles with clinical outcome. The study has been initiated and enrollment target is 120 pts across the 4 expansion cohorts. Clinical trial information: NCT03170960.
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419
Background: RAM + DOC in RANGE (NCT02426125) improved progression free survival (hazard ratio HR = 0.757) with a higher objective response rate (24.5% vs 14%) and an acceptable ...safety profile (Petrylak, et al Lancet 2017). QoL was a secondary objective. Methods: Patients (pts) whose UC progressed following platinum-based therapy were randomized to receive RAM (10 mg/kg) + DOC (75 mg/m
2
) or P + DOC on Day 1 of a 21-day cycle. Treatment continued until disease progression or unacceptable toxicity with a maximum of 10 cycles for DOC. Pts completed the EORTC QLQ-C30 (v3) prior to each cycle & at the 30-day follow up visit. QoL scales were analyzed for: 1) rates of improved/stable scores (compared with Fisher’s exact test) & 2) time to sustained deterioration (TtD), defined as randomization to first worsening with no subsequent non-worsened assessment (compared with unstratified log-rank test). A ≥10 point change (on 100-point scale) was deemed clinically meaningful. Results: 530 pts were randomized. 254/263 (97%) RAM-DOC & 260/267 (97%) P-DOC pts provided baseline (BL) QoL data & ≥85% for post-BL, on-therapy assessments. Median number of cycles was 4 for RAM-DOC & 3 for P-DOC. Mean BL scores were similar between arms & indicated greatest impairment for global QoL, fatigue, pain, & insomnia. For all scales, rates of improved/stable scores were not different, except for pain at Cycles 4 & 7 where rates were higher for RAM-DOC (p < 0.05). Relative to other QoL scales, pain generally had highest rates of improved scores in both arms (14-25% for RAM-DOC & 8-24% for P-DOC for Cycles 1-4). In a post hoc analysis, Cycles 1-4 rates of improved pain scores were 31-32% for RAM-DOC & 14-26% for P-DOC in tumor responders, but 17-29% for RAM-DOC & 16-28% for P-DOC in pts with stable disease. For TtD, 14/15 QoL scales had HRs < 1, indicating similar or numerically longer TtD in QoL for RAM-DOC (HRs 0.67- 1.06; all 95% confidence intervals included 1). Conclusions: The addition of RAM to DOC for platinum-refractory UC pts did not adversely impact QoL relative to P-DOC. Trends in improved TtD and improved rates of pain associated with tumor response favored RAM-DOC. Clinical trial information: NCT02426125.
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