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Since the establishment of neoadjuvant chemotherapy as the standard of care for patients with muscle invasive bladder cancer, the pathologic absence of disease, denoted pT0, was found to be predictive of improved overall survival. Accordingly, it has been used in clinical trials as an optimal surrogate outcome measure, even in contemporary nonchemotherapeutic interventions. We review the role of pT0 as a catalyst for change in trial design and its suitability to facilitate more efficient and timely results. In addition, we explore the present and future of cT0, the clinical absence of disease, in defining treatment response and enabling bladder-sparing management options.The use of pT0 as a surrogate has provided initial results for the efficacy of immunotherapy in the neoadjuvant space. In combination with molecular markers, pT0 has improved our ability to identify treatment responders and its clinical counterpart, cT0, has been integrated into multiple trials to redefine postneoadjuvant chemotherapy management algorithms.The use of pT0 as a surrogate endpoint in bladder cancer trials has improved clinical trial design, defined efficacy of emerging therapeutics, and has the potential to redefine the postneoadjuvant treatment management for patients seeking bladder-sparing options.

OBJECTIVES To determine whether patients with carcinoma invading bladder muscle (MIBC) and ureteric obstruction can safely receive cisplatin-based neoadjuvant chemotherapy (C-NAC), and to determine whether such patients require relief of obstruction with a ureteric stent or percutaneous nephrostomy prior to beginning C-NAC. PATIENTS AND METHODS We performed a single-institution retrospective analysis of MIBC patients receiving C-NAC and falling into three groups: no ureteric obstruction (NO); relieved ureteric obstruction (RO); and unrelieved ureteric obstruction (URO). To address whether patients with obstruction can safely receive C-NAC, we compared patients with NO to those with RO, with the primary outcome of premature chemotherapy discontinuation. To investigate whether patients with obstruction should have the obstruction relieved prior to NAC, we compared RO to URO patients using a primary composite outcome of grade ≥ 3 adverse events, premature chemotherapy discontinuation, dose reduction, or dose interruption. The primary outcomes were compared using multivariable logistic regression. Sensitivity analyses were performed for the RO vs URO comparison, in which patients with only mild degrees of obstruction were excluded from the URO group. RESULTS A total of 193 patients with NO, 49 with RO, and 35 with URO were analysed. There were no statistically significant differences between those with NO and those with RO in chemotherapy discontinuation (15% vs 22%; P = 0.3) or any secondary outcome. There was no statistically significant difference between those with RO and URO in the primary composite outcome (51% vs 53%; P = 1) or any secondary outcome. CONCLUSION Patients with ureteric obstruction can safely receive C-NAC. Relief of obstruction was not associated with increased safety of C-NAC delivery.

The VESPER trial demonstrated improved progression-free (PFS) and (preliminarily) overall survival (OS) with six cycles of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVACx6) versus four cycles of gemcitabine and cisplatin (GCx4) before radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC), but with increased toxicity. This study compares the cost-effectiveness of these regimens.A cost-effectiveness analysis of neoadjuvant ddMVACx6 and GCx4 was performed using a decision-analytic Markov model with 5-year, 10-year, and lifetime horizons. Probabilities were derived from reported VESPER data. Utility values were obtained from the literature. Primary outcomes were effectiveness measured in quality-adjusted life years (QALY) and incremental cost-effectiveness ratio (ICER) with a willingness to pay threshold of $100,000 per QALY. One-way and probabilistic sensitivity analyses were performed to evaluate the robustness of the model.At 5 years, ddMVACx6 improved QALYs by 0.30 at an additional cost of $16,100, rendering it cost-effective relative to GCx4 (ICER: $53,284/QALY). Additionally, probabilistic sensitivity analysis found ddMVACx6 to be cost-effective in 79% and 81% of microsimulations at10-year and lifetime horizons, respectively. One-way sensitivity analysis demonstrated a minimum difference in 5-year progression of 0.9% and progression mortality of 0.7% between ddMVACx6 and GCx4 was necessary for ddMVACx6 to remain cost-effective.Neoadjuvant ddMVACx6 was more cost-effective than GCx4 for MIBC. These data, together with the improved PFS and (albeit preliminary) OS noted in VESPER, support use of this regimen in appropriate candidates for neoadjuvant chemotherapy before RC.We performed a benefit-to-cost analysis using evidence from a randomized controlled trial that compared two different chemotherapy treatments before bladder removal for bladder cancer that had invaded into the bladder muscle. Despite being more expensive and having a greater likelihood of toxicity, six cycles of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin was more cost-effective (or had higher value) than four cycles of gemcitabine and cisplatin.

Advanced Renal Cell Carcinoma; Adverse Events; Nivolumab Carcinoma de células renales avanzado; Eventos adversos; Nivolumab Carcinoma de cèl·lules renals avançat; Esdeveniments adversos; Nivolumab Background and Objectives Novel immunotherapy-based combination treatments have drastically improved clinical outcomes for previously untreated patients with advanced/metastatic renal cell carcinoma (aRCC). This study aimed to assess the temporal trends in grade 3/4 adverse event (AE) rates and associated costs of nivolumab plus cabozantinib combination therapy versus sunitinib monotherapy in previously untreated patients with aRCC. Methods Individual patient data from the CheckMate 9ER trial (nivolumab plus cabozantinib: N = 320; sunitinib: N = 320) were used to calculate the proportion of patients experiencing grade 3/4 AEs. AE unit costs were obtained from the United States (US) 2017 Healthcare Cost and Utilization Project (HCUP) and inflated to 2020 US dollars. Per-patient-per-month (PPPM) all-cause and treatment-related grade 3/4 AE costs over 18-months, temporal trends, and top drivers of AE costs were evaluated in both treatment arms. Results Overall, the proportion of patients experiencing grade 3/4 AEs decreased over time, with the highest rates observed in the first 3 months for the nivolumab plus cabozantinib and sunitinib arms. Compared with sunitinib, nivolumab plus cabozantinib was associated with consistently lower average all-cause AE costs PPPM [month 3: $2021 vs. $3097 (p < 0.05); month 6: $1653 vs. $2418 (p < 0.05); month 12: $1450 vs. $1935 (p > 0.05); month 18: $1337 vs. $1755 (p > 0.05)]. Over 18 months, metabolism and nutrition disorders ($244), laboratory abnormalities ($182), and general disorders and administration site conditions ($122) were the costliest all-cause PPPM AE categories in the nivolumab plus cabozantinib arm, and laboratory abnormalities ($443), blood and lymphatic system disorders ($254), and metabolism and nutrition disorders ($177) were the costliest in the sunitinib arm. Trends of treatment-related AE costs were consistent with all-cause AE costs. Conclusions Nivolumab plus cabozantinib was associated with lower costs of grade 3/4 AE management PPPM than sunitinib, which accumulated over the 18-month study period.

499 Background: In EV-103 Cohort K (NCT03288545), EV and P in combination (EV+P) showed encouraging antitumor activity and a manageable safety profile when used as 1L therapy in patients (pts) w/ la/mUC who are ineligible for cisplatin, a population w/ high unmet need. Here we report results of an analysis of prespecified Cohort K subgroups known to be associated w/ poor outcomes. Methods: Pts who are cisplatin-ineligible w/ previously untreated la/mUC were randomized 1:1 to EV (1.25 mg/kg) as monotherapy on Days 1 and 8 or in combination w/ P (200 mg) on Day 1 of 3-week cycles. Primary endpoint is cORR per RECIST v1.1 by blinded independent central review w/ no formal statistical comparison between arms. Secondary endpoints included duration of response and safety (e.g. treatment-related adverse events, TRAEs). The cORR analysis was performed in prespecified subgroups including age, ECOG PS, liver metastasis, PD-L1 expression status, metastatic disease site at baseline, and primary disease site of origin. Results: 149 pts were treated: EV+P n=76; EV n=73; cORRs across key subgroups for both EV+P and EV monotherapy are shown in the table. For EV+P overall cohort, cORR (95%CI): 64.5% (52.7, 75.1); median DOR was not reached. cORRs were consistent across subgroups for EV+P including those w/ ECOG PS score of 1-2: 62.8% (46.7, 77.0) and presence of liver metastasis: 53.8% (25.1, 80.8). Among TRAEs of special interest in the EV+P arm, skin reactions occurred in n=51 (67.1%); peripheral neuropathy occurred in n=46 (60.5%). For EV+P, 68.4% of pts had TRAEs leading to interruption of either EV or P; 48.7% of pts had TRAEs leading to EV dose reduction. Median duration of EV+P treatment was 11 cycles. Conclusions: EV+P showed promising cORR in 1L cisplatin-ineligible pts w/ la/mUC; activity was consistently observed across a range of pre-specified subgroups including those with poor prognosis. EV+P TRAEs were manageable w/ close monitoring and appropriate dose modifications w/ a meaningful duration of treatment. EV+P has the potential to address high unmet needs in 1L la/mUC and MIBC and is being further evaluated in 3 Phase 3 trials (NCT04223856, NCT04700124, NCT03924895). Clinical trial information: NCT03288545 . [Table: see text]

438 Background: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by cystectomy or chemoradiation is the standard of care for urothelial carcinoma (UC) patients with MIBC. Both cystectomy and chemoradiation have short and long-term toxicity and QOL implications. Mutations in DNA damage repair/response genes are associated with pathologic downstaging after NAC. We hypothesized that a combination of biomarker selection and clinical staging would identify patients prospectively for a cystectomy or chemoradiation avoidance algorithm. Methods: We conducted a single-arm, phase II, non-inferiority trial (NCT02710734) to evaluate a risk-adapted approach for MIBC. Patients with cT2-T3N0M0 UC underwent NAC with accelerated MVAC. Pre-NAC TURBT specimens were sequenced (Caris) for mutations in ATM, ERCC2, FANCC or RB1. Patients with ≥ 1 mutations and no clinical evidence of disease by restaging TUR, urine cytology and imaging post-NAC began pre-defined active surveillance (AS). Remaining patients underwent bladder-directed therapy. The primary endpoint was metastasis-free survival (MFS) at 2 years for the entire cohort. The risk-adapted approach would be declared non-inferior to the standard of care if the lower bound of an exact 1-sided 95% CI for MFS was > 64%. The study required 70 patients with a 4.5% type I error and 81.6% power. Results: 71 (ITT) patients were enrolled over 33 months at four academic centers. Median age was 70 years (47-83), 74% were male, 92% Caucasian, 81% ECOG PS 0 and 79% cT2. 90% completed 3 cycles of MVAC with 17% grade 3-4 TRAEs. In the ITT population, 33 (46%) had a relevant mutation and 26 (37%) began AS. With a median follow-up of 41 months, 47 patients (66%) are metastasis-free (CI 54%-77%). The 2-year MFS for the ITT patients (primary endpoint) was 72% (lower bound exact 1-sided 95% CI=62%). On post hoc analysis, the 2-year MFS was 65% in the AS group (CI 44%-83%) and 76% (CI 60%-87%) in the remaining patients (P=0.42). In the AS group, 18 patients (69%) had some UC recurrence, 8 had a cystectomy, 2 chemoradiation, and 13 (50%) are metastasis-free with an intact bladder. Of the 10 patients (38%) on AS who developed metastatic disease, 9 recurred with localized disease first. The 2-year OS is 83% (CI 72%-90%) and 89% (CI 68%-96%) in the ITT and AS groups, respectively. Associations between mutation presence and MFS or UC recurrence were not observed. Conclusions: The 72% 2-year MFS rate in this MIBC cohort treated with a risk-adapted approach did not satisfy the pre-specified non-inferiority condition. 38% of AS patients developed metastatic disease, with most patients first recurring locally in the bladder. With a median follow-up of 41 months, although 50% of AS patients have been able to avoid cystectomy without metastatic disease, further refinement of this approach is necessary. Clinical trial information: NCT02710734 .

377 Background: Metformin impacts immune response in several ways. It protects CD8 TILs from apoptotic death, downregulates CD39 and CD73, reduces MDSC activity and suppresses the transcription of PD1 thus enhancing CD8+ T cell antitumor activity (Ma et al, 2000, Nature). There is limited data on the immunologic impact of metformin treatment in hormone sensitive prostate cancer. Methods: We conducted an open label, randomized, phase II trial of bicalutamide with or without metformin of patients with high risk, biochemically recurrent prostate cancer (NCT02614859). Patients were randomized 1:2 to observation for an initial 8 weeks or metformin 1000 mg twice daily. Bicalutamide 50 mg/day was added after 8 weeks to both arms. The study discontinued accrual after interim analysis indicated no difference in PSA at 32 weeks between the two arms; however, metformin monotherapy for 8 weeks induced modest PSA declines observed in 40% of patients. Here we report immune responses in a subgroup of patients (N=12), including systemic cytokine levels and 158 circulating immune cell subsets after 8 weeks of metformin monotherapy. Results: Twelve patients treated at the NCI were analyzed. After 8 weeks, the metformin arm showed increased pDCs and lower Tregs compared to baseline. Significant differences in the percent change of immune parameters after 8 weeks of metformin monotherapy compared to 8 weeks of observation are summarized. Conclusions: Metformin has been shown to reduce markers of immune exhaustion in hormone sensitive prostate cancer which is supported by a greater reduction of PD-1+ and Tim3+ NK cells. Additional immune changes included increases in activated subpopulations of natural killer (NK) cells, which have been reported as a potential predictive biomarker of prolonged treatment response to hormone therapy in prostate cancer (Pasero et al, Oncotarget, 2015). Clinical trial information: NCT02614859 . [Table: see text]

The majority of germ cell tumors (GCT) arise from the testicles and are often self-diagnosed. Extra-gonadal germ cell tumors (EGGCT) are rare and vary greatly in their clinical presentations. This case report describes a 24-year-old male with an unusual presentation for an EGGCT.

The therapeutic landscape for advanced urothelial carcinoma (mUC) has changed significantly since studies establishing superiority of cisplatin as first-line therapy were conducted. Most patients who are eligible now receive either maintenance or second-line immune checkpoint inhibitors (ICI) and data comparing first-line platinum chemotherapy agents in this setting is limited.The objective of this study was to determine the impact of first-line platinum chemotherapy agent on survival for patients who receive second-line ICI. This is a retrospective cohort study of real-world data, performed from January 1, 2015, to March 21, 2021, included patients with a diagnosis of metastatic or locally advanced urothelial carcinoma. Exposure of interest was first-line platinum-doublet chemotherapy (gemcitabine and/or cisplatin or gemcitabine and/or carboplatin) followed by single-agent second-line ICI. The primary endpoint was overall survival from start of second-line therapy.2,042 patients received either gemcitabine and cisplatin (gem/cis) or gemcitabine and carboplatin (gem/carbo) as first-line therapy. The primary analysis of 890 patients who received second-line single-agent ICI had a median follow-up was 24.2 months from initiation of second-line therapy. Important differences in baseline demographics and/or clinical factors between groups were age, performance status, incidence of upper tract disease, and cisplatin eligibility. Unadjusted overall survival (OS) calculated from start of second-line therapy was longer in patients who received gem/cis compared to gem/carbo followed by ICI (median 9.3 vs. 8.8 months, P = 0.0009). However, OS adjusted for covariates was not significantly different with a hazard ratio (HR) of 0.94 (95% CI, 0.79-1.13; P = 0.50). A separate time-varying covariate model also showed no association between OS and first-line gem/cis (HR 1.00 [95% CI, 0.84-1.19]) while receiving second-line ICI.Survival time on ICI in the second-line setting is the same regardless of choice of prior platinum agent (cisplatin vs. carboplatin) suggesting against specific synergy for one of these agents with ICI. However, a significantly greater proportion of patients in a landmark analysis had long-term benefit with cisplatin strongly supporting it is as the preferred first-line platinum agent.

The therapeutic landscape for metastatic renal cell carcinoma has rapidly evolved over the years, and we are now in an era of combination therapy strategies employing immune checkpoint blockade and anti-angiogenesis targeted therapy. Since 2018, we have gained regulatory approval for four distinct combination therapies, all with survival benefits, and with guideline recommendation for use in the front-line setting. As such, treatment selection has become increasingly complex with a myriad of treatment choices but little high-level head-to-head data to guide treatment selection. Heterogeneity in tumor biology further complicates treatment selection as tumors vary in behavior and treatment responsiveness. Ongoing development of biomarkers will certainly assist in this setting, and validation of predictive markers represents an unmet need. In their absence, we highlight features of disease and nuances to datasets from landmark prospective clinical trials to help inform treatment selection. There is growing evidence to support deferring upfront systemic therapy in some patients, with opportunities for active surveillance or metastasis-directed therapy. In others, upfront systemic therapy is warranted and necessitates thoughtful consideration of multiple clinicopathologic parameters to inform optimal patient-centered decision making.

Objective: Pembrolizumab/axitinib significantly prolonged overall survival (OS) and progression-free survival (PFS) and increased objective response rate versus sunitinib in the phase III trial KEYNOTE-426 among previously untreated patients with advanced renal cell carcinoma (RCC). This study assessed the cost-effectiveness of pembrolizumab/axitinib versus other first-line treatments of advanced RCC from a US public healthcare payer perspective. Methods: A partitioned survival model with three states (progression-free, progressed, death) evaluated lifetime costs and quality-adjusted life-years (QALYs) for pembrolizumab/axitinib and other first-line regimens: sunitinib, pazopanib, and avelumab/axitinib in the overall population; and sunitinib, cabozantinib, and nivolumab/ipilimumab in the subgroup with intermediate/poor prognostic risk. Costs of treatments, adverse events, and medical resources were estimated. OS, PFS, and treatment duration were extrapolated using parametric models fitted to KEYNOTE-426 data and hazard ratios from network meta-analyses. Utilities were derived through mixed-effects regressions of KEYNOTE-426 EuroQol-5 Dimensions-3 Levels data. Results: In the overall population, pembrolizumab/axitinib was associated with incremental cost-effectiveness ratios (ICERs) of $95,725/QALY versus sunitinib and $128,210/QALY versus pazopanib, and was dominant (lower cost, higher effectiveness) versus avelumab/axitinib, with incremental QALY gains of 2.73, 2.40, and 1.80 versus these therapies, respectively. In the intermediate/poor-risk subgroup, base-case ICERs for pembrolizumab/axitinib were $101,030/QALY versus sunitinib, $6,989/QALY versus cabozantinib, and $130,934/QALY versus nivolumab/ipilimumab, with incremental QALY gains of 2.62, 1.78, and 1.06 versus these therapies. Conclusions: In this economic evaluation, pembrolizumab/axitinib was associated with higher life expectancy and QALYs and, based on typical willingness-to-pay thresholds of $150,000-$180,000/QALY, was found cost-effective versus other first-line treatments for advanced RCC in the US.

Inguinal lymphadenectomy remains under performed in patients with invasive penile cancer. Using a large national cancer registry we assessed temporal trends in inguinal lymphadenectomy performance and evaluated the impact of the procedure on survival in patients in whom inguinal lymphadenectomy was an absolute indication (T1b-4 N0/x-1) according to NCCNWe queried the National Cancer Database for all cases of nonmetastatic, T1b-4 N0/x-1 squamous cell carcinoma of the penis from 2004 to 2014. Multivariable logistic regression models adjusting for patient, demographic, and clinicopathological characteristics were used to examine the association between available covariates and receipt of inguinal lymphadenectomy. Cox proportional hazards regression analysis was then done to assess the impact of clinical and pathological variables on overall survival. Propensity score weighted analysis was performed to assess the effect of inguinal lymphadenectomy on overall survival.A total of 2,224 patients met analysis criteria, of whom 606 (27.2%) underwent inguinal lymphadenectomy. Following adjustment the procedure was more likely in younger patients, those who presented with palpable adenopathy (cN1), those treated at an academic facility and those with a more contemporary diagnosis. On survival analysis controlling for all known and measured confounders inguinal lymphadenectomy was associated with improved overall survival (HR 0.79, 95% CI 0.74-0.84, p0.001).At hospitals that report to the National Cancer Database the overall rate of inguinal lymphadenectomy in patients with invasive penile cancer was only 27.2%. Inguinal lymphadenectomy was associated with increased overall survival, justifying the procedure as an important quality metric for performance reporting in patients with invasive penile cancer.

265 Background: Adherence to oral chemotherapy (OC) is a critical factor in achieving optimal oncologic outcomes. Correct dosing, education, and symptom management are essential to maximizing adherence. As part of the 2020 Quality Oncology Practice Initiative Certification Program Fox Chase Cancer Center (FCCC), a NCCN Comprehensive Cancer Center, learned that only 33% of patients on OC had a documented OC plan, 7% were assessed for adherence, and 0% had documentation reflecting efforts to address non-adherence. Methods: Our goal was to create and implement an electronic medical record (EMR) tool (Oral Chemo Smart Form) to address the variance and deficiencies in monitoring adherence to OC. The Smart Form (SF) was designed to include fields to document the OC plan (drug, indication, dose, schedule, duration of cycle, initial start/end date) as well as provide a standard for documentation of education, management of toxicity and non-adherence. We integrated the SF into nursing, pharmacy, and physician workflows to capitalize on shared EMR tools. A series of Plan-Do-Study-Act cycles were conducted over 8 weeks within pilot clinics. Weekly review of the SF and feedback forms generated real-time progress reports which were serially appraised and shared with stakeholders. Results: Two oncologists (piloted in Genitourinary and Breast Cancer clinics), two pharmacists, and several nurses used the SF March 15, 2021 to May 7, 2021. Over these 8 weeks, 223 patients on OC were seen in clinic. If the OC was dispensed from FCCC, pharmacists were to complete the SF at the time of initial OC prescription, 7 days after dispensing, and with each refill. Pharmacists also identified patients receiving OC through a specialty pharmacy and routed a message to clinic nurses via an EMR message pool. The message became the trigger for nurses to call patients within two weeks to troubleshoot dispensing issues and/or complete the SF. Oncologists were to complete the SF with each clinic visit for a patient on OC. Feedback from the clinical and pharmacy teams motivated changes in the content fields of the SF and workflow. Ultimately, 45% of patients on OC had the SF completed. An OC plan was documented in 41% of patients, compared to 33% at baseline; 87% had an administration schedule compared to 81%. There was an increase in the number of patients contacted following start of OC, 35% from 4%. Medication adherence was assessed in 35% of patients, up from 7%. Documented discussions addressing medication adherence increased to 78%, from 0%. Conclusions: Introduction of the Oral Chemo SF in pilot clinics improved documented OC plans and administration schedules. Its use introduced a standard process for monitoring safety, assessing and addressing non-adherence, while troubleshooting specialty pharmacy dispensing issues. The SF will be implemented throughout FCCC and further evaluated with efforts focused on adopting and streamlining this as standard work.

305 Background: Nivolumab plus ipilimumab (NIVO+IPI), a first-in-class combination immunotherapy, was approved by the US Food and Drug Administration in April 2018 for the treatment of intermediate- or poor-risk advanced renal cell carcinoma (RCC), and the treatment paradigm has changed dramatically over the past few years. This real-world study examined treatment patterns and sequences, treatment response, safety, and survival outcomes with this novel first-line (1L) combination therapy among patients diagnosed with metastatic RCC (mRCC) in a community oncology practice setting. Methods: A retrospective analysis of the US Oncology Network’s iKnowMed medical data examined adult patients with an International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognosis of intermediate- or poor-risk clear cell mRCC who received 1L NIVO+IPI between April 1, 2018, and March 31, 2020. Baseline demographic and clinical characteristics, treatment patterns, and treatment sequence were examined descriptively. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), time to treatment discontinuation (TTD), and time to treatment response (TTR) were analyzed using the Kaplan–Meier method. Treatment-related adverse events (TRAEs) and healthcare resource utilization were also analyzed. Results: A total of 193 adults with stage IV mRCC treated with 1L NIVO+IPI were identified. Median age (range) was 63 (30.0–89.0) years, 73.1% were male, 69.4% were white, 56.7% were IMDC intermediate risk, and 60.6% had a documented Eastern Cooperative Oncology Group performance status of 0 or 1. Median follow-up time (range) was 9.7 (0.1–24.7) months. Median PFS (95% CI) was 17.1 (12.6–21.2) months, and the 1-year landmark PFS rate was 58.3% (50.4–65.4). At 12 months, the OS rate (95% CI) was 75.4% (67.8–81.4). The ORR (95% CI) was 43.2% (34.6–52.1) among patients with a response assessment; the median TTR (range) was 2.8 (0.3–4.1) months and median DoR was not reached. Median TTD (95% CI) was 5.8 (4.5–7.5) months. Among the 63 (31.3%) patients who received second-line therapy, 50.8% received cabozantinib and 12.7% received pazopanib. TRAEs were reported in 47.2% of patients—the most frequently reported were fatigue (13.5%), rash (10.4%), diarrhea (6.7%), nausea (6.2%), colitis (3.6%), and pruritus (3.6%). The treatment-related hospitalization rate was 5.5% and the emergency department visit rate was 3.1%. Conclusions: This real-world study supports the clinical efficacy of 1L NIVO+IPI for patients with mRCC. Our findings also suggest that the NIVO+IPI combination was generally well tolerated in the real-world setting, with low rates of adverse events and healthcare resource utilization.

Background The programmed death 1 (PD-1) checkpoint inhibitors (CKIs) can lead to immune-related adverse events (irAEs). We sought to evaluate whether the development of irAEs correlates with treatment response in non-melanoma malignancies. Materials and Methods We conducted a retrospective study of patients who received anti-PD-1 CKI monotherapy at Fox Chase Cancer Center. Endpoints included overall response rate (ORR), time to next therapy or death (TTNTD), and overall survival (OS). Fisher's exact tests and logistic regression models were used to determine the association between irAE incidence and ORR, and Kaplan-Meier curves with log-rank tests and Cox regression models were used for the comparison of TTNTD and OS. Results Between November 2011 and November 2016, 160 patients were treated with >1 dose of an anti-PD-1 CKI. Seventy-three (46%) were treated on a clinical trial. Immune-related adverse events were noted in 64 patients (40%), with steroids required in 36 (23%). Of the 142 patients evaluable for clinical response, 28 patients (20%) achieved a partial response at first scan. An association between irAEs and ORR was seen in clinical trial patients (p = .007), but not in non-trial patients (p = .13). When controlling for clinical trial participation and cancer type using multivariate analysis, low-grade irAEs had higher ORR (p = .017) and longer TTNTD (p = .008). No association between irAE incidence and OS was seen (p = .827). Immune-related adverse events that required steroid treatment were marginally associated with increased TTNTD (p = .05, hazard ratio 0.62) but were not associated with OS (p = .13). Conclusion We demonstrate several positive associations between the development of irAEs and clinical outcomes in non-melanoma patients treated with PD-1 CKIs, for which further validation is required.

Neoadjuvant cisplatin-based chemotherapy (NAC; 70 mg/m2) is standard of care for muscle-invasive bladder carcinoma (MIBC). Many patients (pts) cannot receive cisplatin because of renal impairment, and administration of cisplatin 35 mg/m2 on day 1 + 8 or 1 + 2 (i.e., split schedule) is a commonly used alternative. In this retrospective analysis, we compared complete (pT0) and partial (

Level 1 evidence supports cisplatin-based neoadjuvant chemotherapy (NAC) in muscle-invasive urothelial bladder cancer (MIUBC). Recent data from small prospective trials with neoadjuvant immune checkpoint inhibitors are encouraging, but long-term follow-up is required. Randomized trials have failed to accrue a sufficient number of patients and have not demonstrated a survival benefit with adjuvant chemotherapy in MIUBC, but for those with high-risk features at surgery, adjuvant cisplatin-based therapy is appropriate. In upper tract urothelial carcinoma, several retrospective trials and one recent phase 2 prospective trial support the use of NAC, and a randomized trial with adjuvant chemotherapy demonstrated improved disease- and metastasis-free survival and a trend toward improved overall survival.

Immunotherapy with checkpoint inhibitors has arrived and begun to change the landscape of clinical oncology, including for patients with renal cell carcinoma. Specifically, drugs targeting the programmed death 1 and cytotoxic T-lymphocyte associated antigen pathways have demonstrated remarkable responses for patients in clinical trials. In this article, we review the most recent available data for immune checkpoint inhibitors for patients with renal cell carcinoma. We discuss potential strategies for rational combination therapies in these patients, some of which are currently being studied, and address important future considerations for use of these novel agents in the years to come.

The management of advanced clear cell renal cell carcinoma (RCC) has evolved over the past decade with the introduction of targeted therapies and immune checkpoint inhibitors. Recently, studies of dual checkpoint inhibition and of vascular endothelial growth factor (VEGF) inhibition combined with checkpoint inhibition have shown promising results, adding newer options to the treatment armamentarium for advanced RCC. Specifically, therapies combining checkpoint inhibitors of different classes and combining VEGF inhibitors with checkpoint inhibitors have gained much interest, and results from studies of several other combinations are awaited. These and previously approved treatments offer multiple options to patients with advanced RCC. In this review, we discuss the efficacy and safety results from the pivotal trials of these therapies, how the trial data can guide selection of the most appropriate therapy, and how to consider sequencing therapies in the care of patients with advanced RCC.

Purpose This study sought to define and identify drivers of trends in cost and use of targeted therapeutics among privately insured nonelderly patients with cancer receiving chemotherapy between 2001 and 2011. Methods We classified oncology drugs as targeted oral anticancer medications, targeted intravenous anticancer medications, and all others. Using the LifeLink Health Plan Claims Database, we studied and disaggregated trends in use and in insurance and out-of-pocket payments per patient per month and during the first year of chemotherapy. Results We found a large increase in the use of targeted intravenous anticancer medications and a gradual increase in targeted oral anticancer medications; targeted therapies accounted for 63% of all chemotherapy expenditures in 2011. Insurance payments per patient per month and in the first year of chemotherapy for targeted oral anticancer medications more than doubled in 10 years, surpassing payments for targeted intravenous anticancer medications, which remained fairly constant throughout. Substitution toward targeted therapies and growth in drug prices both at launch and postlaunch contributed to payer spending growth. Out-of-pocket spending for targeted oral anticancer medications was ≤ half of the amount for targeted intravenous anticancer medications. Conclusion Targeted therapies now dominate anticancer drug spending. More aggressive management of pharmacy benefits for targeted oral anticancer medications and payment reform for injectable drugs hold promise. Restraining the rapid rise in spending will require more than current oral drug parity laws, such as value-based insurance that makes the benefits and costs transparent and involves the patient directly in the choice of treatment.

Autosomal dominant polycystic kidney disease (ADPKD) is a progressive inherited disorder in which renal tissue is gradually replaced with fluid-filled cysts, giving rise to chronic kidney disease (CKD) and progressive loss of renal function. ADPKD is also associated with liver ductal cysts, hypertension, chronic pain and extra-renal problems such as cerebral aneurysms. Intriguingly, improved understanding of the signalling and pathological derangements characteristic of ADPKD has revealed marked similarities to those of solid tumours, even though the gross presentation of tumours and the greater morbidity and mortality associated with tumour invasion and metastasis would initially suggest entirely different disease processes. The commonalities between ADPKD and cancer are provocative, particularly in the context of recent preclinical and clinical studies of ADPKD that have shown promise with drugs that were originally developed for cancer. The potential therapeutic benefit of such repurposing has led us to review in detail the pathological features of ADPKD through the lens of the defined, classic hallmarks of cancer. In addition, we have evaluated features typical of ADPKD, and determined whether evidence supports the presence of such features in cancer cells. This analysis, which places pathological processes in the context of defined signalling pathways and approved signalling inhibitors, highlights potential avenues for further research and therapeutic exploitation in both diseases.

Over the last 15 years, a paradigm shift in oncology has led to the approval of dozens of targeted oral anti-cancer medications (OAMs), which have become the standard of care for certain cancers. While more convenient for patients than infused drugs, the possibility of non-adherence and the frequently high costs of targeted OAMs have proven controversial. Our objective was to perform the first comprehensive review of cost-effectiveness analyses (CEAs) of targeted OAMs. A literature search in PubMed, The Cochrane Library, and the Health Technology Assessment (HTA) reports published by the National Institute for Health Research HTA Programme in the UK was performed, covering articles published in the 5 years prior to 30 September 2013. Our inclusion criteria were peer-reviewed English-language full-text original research articles with a primary focus on CEA related to targeted OAMs. We categorized these articles by treatment setting (i.e. cancer site/type, line of therapy, and treatment and comparator) and synthesized information from the articles into summary tables. We identified 41 CEAs covering nine of the 18 targeted OAMs approved by the US FDA as of December 2012. These medications were studied in seven cancers, most often as second-line therapy for advanced-stage patients. In over half of treatment settings where a targeted OAM was compared with treatment that was not a targeted OAM, targeted OAMs were considered cost effective. Limitations in interpreting these findings include the risk of bias due to author conflicts of interest, cross-country variation, and difficulties in generalizing clinical trial evidence to community practice. Several types of cost-effectiveness studies remain under-represented in the literature on targeted OAMs, including those for follow-on indications approved after the initial indication for a drug and for off-label indications, head-to-head comparisons of targeted OAMs with other targeted OAMs and targeted intravenous therapies, and studies that adopt a perspective other than the payer’s. Keeping up with the increasing number of approved targeted OAMs will also prove an important challenge for economic evaluation.

We report on a 34-yr-old man with no medical history who presented in September 2014 with night sweats, fevers, bilateral pulmonary masses, extensive bony disease, and a left renal mass of 4.3 cm 4.1 cm. A lung biopsy showed poorly differentiated carcinoma with rhabdoid features consistent with high-grade renal cell carcinoma (RCC). Therapy with carboplatin and gemcitabine was initiated for palliative reasons, but a subsequent biopsy of the renal mass revealed papillary RCC with sarcomatoid and rhabdoid features. Genomic profiling revealed alterations in FAT1, as well as a number of variants of unknown significance (VUS) including DICER1, FANCL, SPTA1 and WISP3; most interestingly, a PBRM1 VUS was noted. After a brief clinical improvement on cytotoxic chemotherapy, the patient’s disease progressed and sunitinib was initiated at first alone and then with gemcitabine. Unfortunately, rapid progression once again occurred. ByMarch 2015 the patient was on 30 mg of long-acting morphine twice daily, as well as a short-acting narcotic for breakthrough pain. His performance statuswas rapidly declining and subcutaneous lesions were appearing. At that point we decided to treat the patient with the anti-programmed cell death protein 1 (PD-1) antibody nivolumab, as it was felt that no other standard therapy targeting vascular endothelial growth factor (VEGF) or mammalian target of rapamycin would be helpful given the rapidly progressive nature of his disease. At 3 wk after a single dose of nivolumab at 0.3 mg/kg, the patient felt dramatically better, with dissipation of all pain and discontinuation of all narcotics, improvement in laboratory values and energy, and disappearance of all subcutaneous lesions. After three doses of nivolumab, the patient’s hemoglobin increased from 10.5 to 14.3 g/dl, thrombocytosis resolved from 489 to 190 k/ml, and C-reactive protein decreased from 67.8 mg/dl in October 2014 to 0.7 mg/dl. Radiographic studies with magnetic resonance imaging and computed tomography before and after nivolumab demonstrated significant improvement in pulmonary, subcutaneous, and bony lesions (Fig. 1). No adverse reactions to nivolumab have occurred so far and the patient is working full time. Immunotherapy is rapidly being integrated into oncology practice and is poised to alter the therapeutic landscape for a variety of malignancies [1]. In RCC, single-agent and combination checkpoint inhibitor trials are either completed or under way, with promising results already published or presented [2]. Importantly, thus far all checkpoint inhibitor trials in RCC have required at least some clear cell component for enrollment [3], and patients with pure non–clear cell (NCC) histology have been excluded. In the patient described here, a PBRM1 variantwas noted. PBRM1 is a tumor suppressor gene that is mutated in approximately 40–50% of clear cell RCCs [4], but was only noted in 3% of papillary RCC patients in one analysis [5]. Thus, although no VHL alteration was reported and no response to a VEGF inhibitor was observed, it is possible that the patient has an aggressive form of clear cell RCC and not papillary RCC as histologically determined. Nevertheless, he would not have been eligible for any current clinical trial and the papillary histology was confirmed by two separate institutions. Previous analysis of tumor samples from 50 patients with papillary RCC demonstrated PD-1 ligand (PD-L1) positivity ranging from 10% to 60% depending on whether tumor cells or immune infiltrating cells were evaluated [6]. Other NCC subtypes such as chromophobe and translocation Xp11.2 type also express PD-L1. In clear cell RCC and other tumor types, although PD-L1 positivity is not required for a response, it appears to lead to a higher likelihood of benefit from anti-PD-1 therapy. Given the PDL1 expression in NCC RCC and clinical observations such as EU RO P E AN URO L OG Y 6 8 ( 2 0 1 5 ) 9 1 2 – 9 1 5

Bone complications are a frequent co-occurrence with prostate cancer (PCa). Androgen deprivation therapy, the mainstay of treatment in both castration-sensitive (CSPC) and castration-resistant PCa (CRPC), leads to a loss of bone mineral density and subsequent possible osteoporotic fractures. In men with metastatic CRPC (mCRPC), skeletalrelated events (SREs), commonly defined as pathologic fractures, spinal cord compressions, or a need for palliative local bone therapy, are common ( 50% without treatment [1]) because of the osteotropism of PCa. SREs are associated with increased pain and cost, as well as decreased quality of life and survival [2]. Over the last two decades a number of bone-targeted therapies (BTTs) have been developed, tested, and approved for use in men with PCa. These generally fall into three categories: radiopharmaceuticals, bisphosphonates, and a monoclonal antibody against receptor activator of nuclear factor kB ligand (RANKL), the latter two of which are osteoclast inhibitors [2]. The radiopharmaceuticals strontium-89 and samarium-153 are sometimes used to palliate pain, but do not improve survival; however, the recently approved alpha-emitting agent radium-223 both improves overall survival (OS) and increases time to first SRE. Bisphosphonates such as zoledronic acid have been extensively studied in PCa and work by attaching to the bony surface and preventing osteoclast-mediated bone resorption and arresting osteoclast development. InmCRPC, zoledronic acid decreases SRE incidence, prolongs time to first SRE, and decreases pain [1]. Denosumab, a RANKL inhibitor, was approved because of its superiority to zoledronic acid in preventing SREs in a phase 3 trial of

DOI: 10.1200/JCO.2012.48.2059 The inbox of my work e-mail was neatly organized into folders—an attempt to keep some semblance of control over my life as a hematology-oncology fellow in a busy academic medical center. Recently, with my training near its end and with the knowledge that I would be leaving the university, I decided to clean out the thousands of emails I had accumulated. At first, I found this easy, clicking the “Delete” button again and again with a growing sense of satisfaction and accomplishment...until I reached the “Patient e-mails” folder. I found myself staring at hundreds of e-mails with familiar names. No different than tombstones at a cemetery, these e-mails were neatly lined up, organized by date and a few subject words. I clicked the “From” button, rearranging the e-mails by sender, and suddenly, the stories returned. KV (cholangiocarcinoma): questions about pain, diarrhea, shingles, mouth sores, Ativan; then silence. BD (pancreatic cancer): e-mails about nausea, weight loss, rearranging Monday’s chemotherapy appointment, lab results, fatigue; silence. EH (lung cancer): an inquiry about an appointment time, an episode of confusion, a fall, pain, hospitalization; silence. MP (renal cell carcinoma): low blood counts, a note of thanks, a Happy New Year greeting, a request for a second opinion, pain; silence. What happened in the space of those silences? I realized that, for the most part, I never kept in touch with my patients once chemotherapy stopped working, instead handing off care responsibility to my hospice and palliative care colleagues. As I read through those e-mails and recalled my relationships with those patients, I wondered if this well-meaning transition, although in many ways appropriate, should be reexamined for its effects on patients, doctors, and the doctor-patient relationship. My eyes returned to two particular patients— L.B. and M.M.—and I couldn’t help but smile but thinking about them. L.B. was a bright, well-respected physician with a horrible cancer. He came to our hospital for a second opinion and stayed under our care as we enrolled him onto a clinical trial. It was the first time I had taken care of another physician for an extended period of time, and I got to know L.B. well. I met his family and talked to him about his practice and the challenges of transitioning away from it prematurely. I fielded many of his calls and e-mails, and he was kind enough to allow me to be his primary oncologist. In return, I allowed him as much control as possible in his care. L.B. did well at first, with the tumor shrinking and pain abating, which allowed him to travel. He continued to chair national meetings and to bring gifts of fruit baskets for all of us in the clinic. But inevitably, as he and I had known from the start would happen, his cancer began to grow once again, and soon a permanent abdominal drain was required. A new course of chemotherapy was useless and then came weight loss, fatigue, thrush, blood clots, and pain. We met and spoke about hospice. He agreed that it was time, and we made a referral. He jokingly said that he would not bother me so much anymore, because the hospice doctor would take over. That was the last time we spoke until I received an e-mail from his wife informing me of his death at home, followed several weeks later by a card from his family thanking me for his care. At the same time, I was taking care of M.M., a recently retired school teacher, avid golfer, fisherman, and tennis player. His cancer, originally diagnosed as localized and treated with liver surgery, had returned and was no longer curable. M.M. was stoic, calm, and accepting of his diagnosis. His wife was obviously in love with M.M. and shocked and confused about their new predicament. She told me during our first meeting that they were looking for a doctor who would be with them “throughout his illness,” until the end. I promised that I would do just that. And indeed I watched him go through months of chemotherapy as well as yoga, acupuncture, daily tennis, and numerous fishing trips (we joked that he fished more in one year than most people do in a lifetime). Eventually, his cancer, too, progressed. As I was trying to manage M.M.’s pain and arrange for initiation of palliative radiation, I left for vacation. On my return, I found that M.M. had been referred to palliative care by one of our nurses and JOURNAL OF CLINICAL ONCOLOGY A R T O F O N C O L O G Y VOLUME 31 NUMBER 12 APRIL 2