Impact of smoking status on clinical outcomes in patients with metastatic renal cell carcinoma treated with first-line immune checkpoint inhibitor-based regimens.

BACKGROUND: Current tobacco smoking is independently associated with decreased overall survival (OS) among patients with metastatic renal cell carcinoma (mRCC) treated with targeted monotherapy (VEGF-TKI). Herein, we assess the influence of smoking status on the outcomes of patients with mRCC treated with the current first-line standard of care of immune checkpoint inhibitor (ICI)-based regimens. MATERIALS AND METHODS: Real-world data from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) were collected retrospectively. Patients with mRCC who received either dual ICI therapy or ICI with VEGF-TKI in the first-line setting were included and were categorized as current, former, or nonsmokers. The primary outcomes were OS, time to treatment failure (TTF), and objective response rate (ORR). OS and TTF were compared between groups using the log-rank test and multivariable Cox regression models. ORR was assessed between the 3 groups using a multivariable logistic regression model. RESULTS: A total of 989 eligible patients were included in the analysis, with 438 (44.3%) nonsmokers, 415 (42%) former, and 136 (13.7%) current smokers. Former smokers were older and included more males, while other baseline characteristics were comparable between groups. Median follow-up for OS was 21.2 months. In the univariate analysis, a significant difference between groups was observed for OS (P = .027) but not for TTF (P = .9), with current smokers having the worse 2-year OS rate (62.8% vs 70.8% and 73.1% in never and former smokers, respectively). After adjusting for potential confounders, no significant differences in OS or TTF were observed among the 3 groups. However, former smokers demonstrated a higher ORR compared to never smokers (OR 1.45, P = .02). CONCLUSION: Smoking status does not appear to independently influence the clinical outcomes to first-line ICI-based regimens in patients with mRCC. Nonetheless, patient counseling on tobacco cessation remains a crucial aspect of managing patients with mRCC, as it significantly reduces all-cause mortality.

Outcomes of Patients with Brain Metastases from Renal Cell Carcinoma Receiving First-line Therapies: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

Patients with brain metastases (BrM) from renal cell carcinoma and their outcomes are not well characterized owing to frequent exclusion of this population from clinical trials. We analyzed data for patients with or without BrM using the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). A total of 389/4799 patients (8.1%) had BrM on initiation of systemic therapy. First-line immuno-oncology (IO)-based combination therapy was associated with longer median overall survival (OS; 32.7 mo, 95% confidence interval [CI] 22.3-not reached) versus tyrosine kinase inhibitor monotherapy (20.6 mo, 95% CI 15.7-24.5; p = 0.019), as were intensive focal therapies with stereotactic radiotherapy or neurosurgery (31.4 mo, 95% CI 22.3-37.5) versus whole-brain radiotherapy alone or no focal therapy (16.5 mo, 95% CI 10.2-21.1; p = 0.028). On multivariable analysis, IO-based regimens (HR 0.49, 95% CI 0.25-0.97; p = 0.040) and stereotactic radiotherapy or neurosurgery (HR 0.48, 95% CI 0.29-0.78; p = 0.003) were independently associated with longer OS, as was IMDC favorable or intermediate risk (HR 0.40, 95% CI 0.24-0.66; p < 0.001). Intensive systemic and focal therapies were associated with better prognosis in this population. Further studies should explore the clinical effectiveness of multimodal strategies. PATIENT SUMMARY: In a large group of patients with advanced kidney cancer, we found that 8.1% had brain metastases when starting systemic therapy. Patients with brain metastases had significantly poorer prognosis than those without brain metastases. Receipt of combination immunotherapy, stereotactic radiotherapy, or neurosurgery was associated with longer overall survival.

Real-world Assessment of Clinical Outcomes in Patients with Metastatic Renal Cell Carcinoma with or Without Sarcomatoid Features Treated with First-line Systemic Therapies.

BACKGROUND AND OBJECTIVE: Metastatic renal cell carcinoma (mRCC) patients have been reported to have better outcomes when treated with immunotherapies (IO) compared to targeted therapies (TT). This study aims to evaluate the impact of first-line systemic therapies on survival of mRCC patients with or without sarcomatoid features using real-world data. METHODS: Metastatic RCC patients of International mRCC Database Consortium (IMDC) intermediate or high risk, diagnosed from January 2011 to December 2022, treated with first-line systemic therapies, and with histological documentation of the presence or absence of sarcomatoid features in nephrectomy specimens were identified using the Canadian Kidney Cancer information system. Patients were classified by initial treatment: (1) targeted therapy (TT) used alone or (2) immunotherapy (IO)-based systemic therapies used in combination of either IO-IO or IO-TT. The inverse probability of treatment weighting using propensity scores was used to balance for covariates. Cox proportional hazard models were used to assess the impact of initial treatment received on overall survival (OS). KEY FINDINGS AND LIMITATIONS: Of the 1202 eligible patients, 791 were treated with TT and 411 with IO combinations. Of the patients, 76% were male, and the majority (91%) had a nephrectomy before systemic therapy. In nonsarcomatoid patients (639 TT and 320 IO patients), treatment with IO was associated with improved OS compared with patients treated with TT (median of 72 vs 48 mo, hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.50-0.80, objective response rate [ORR] of 38.5% for IO and 23.5% for TT). In sarcomatoid patients (152 TT and 91 IO patients), treatment with IO was associated with improved OS (median of 48 vs 18 mo, HR 0.41, 95% CI 0.26-0.64, ORR of 49.5% for IO and 13.8% for TT). Similar results were observed in patients with synchronous metastatic disease only. CONCLUSIONS AND CLINICAL IMPLICATIONS: IO treatment was associated with improved survival in mRCC patients. The magnitude of benefit is increased in patients with sarcomatoid mRCC, consequently, identifying the sarcomatoid status early on could help healthcare providers make a better treatment decision. PATIENT SUMMARY: Metastatic renal cell carcinoma (mRCC) patients of International mRCC Database Consortium intermediate and high risk, diagnosed from January 2011 to December 2022, treated with first-line systemic therapies, and with histological documentation of the presence or absence of sarcomatoid features in nephrectomy specimens were identified using the Canadian Kidney Cancer information system (CKCis). In this study, treatment with immunotherapy was associated to an improved survival and response rates for mRCC patients with and without sarcomatoid features. The magnitude of benefit is increased in patients with sarcomatoid mRCC.

Characterization of Patients with Metastatic Renal Cell Carcinoma Undergoing Deferred, Upfront, or No Cytoreductive Nephrectomy in the Era of Combination Immunotherapy: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

BACKGROUND: The role of cytoreductive nephrectomy (CN) has not yet been well characterized in the era of combination immunotherapy. OBJECTIVE: To evaluate characteristics and outcomes for patients with metastatic renal cell carcinoma (mRCC) who received immuno-oncology (IO)-based combination therapy according to CN status. DESIGN, SETTING, AND PARTICIPANTS: Using the International mRCC Database Consortium (IMDC), patients with mRCC who received frontline IO-based combinations were included. Upfront CN was defined as CN up to 3 mo before diagnosis of metastatic disease but before systemic therapy initiation. Deferred CN was defined as CN after systemic therapy initiation. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS) from initiation of systemic therapy was estimated via Cox proportional-hazards regression. A 12-mo landmark time and a time-varying covariate for CN status were used to mitigate potential bias. RESULTS AND LIMITATIONS: Of the 385 patients eligible for landmark analysis, 24, 182, and 179 underwent deferred CN, upfront CN, and no CN, respectively. Patients in the no CN subgroup were older (63 yr vs 57 yr in the deferred CN subgroup and 60 yr in the upfront CN subgroup; p = 0.001) and a higher proportion had bone metastases (44% vs 26% in the deferred CN subgroup and 23% in the upfront CN subgroup; p < 0.001). A lower proportion of patients in the upfront CN subgroup had IMDC poor risk (23% vs 43% in the no CN subgroup and 47% in the deferred CN subgroup; p < 0.001). On multivariable analysis, CN receipt was an independent favorable prognostic factor (hazard ratio 0.45, 95% confidence interval 0.26-0.78; p = 0.005). The study is limited by the lack of randomization and its retrospective nature. CONCLUSIONS: Despite changes in practice patterns with the advent of novel therapeutic agents, CN may still serve as an effective surgical intervention in carefully selected patients. PATIENT SUMMARY: For patients with metastatic kidney cancer, surgery to remove the primary tumor was traditionally the treatment of choice, but immunotherapy drugs are now another option for these patients. We analyzed data for contemporary patients with metastatic kidney cancer who received combination immunotherapy as their first treatment. We found that in selected patients receiving immunotherapy, surgery to remove the primary tumor as well can result in better prognosis.

Perioperative systemic therapy in renal cell carcinoma.

PURPOSE OF REVIEW: Renal cell carcinoma (RCC) is the most common kidney neoplasm. Localized RCC can be cured with nephrectomy. However, a proportion of patients will recur with incurable distant metastatic disease. There is a clear need for treatments to reduce the risk of RCC recurrence and thus improve survival. This review describes the landscape of perioperative therapy for RCC, focusing on more recent trials involving immune checkpoint inhibitors (ICIs). RECENT FINDINGS: ICIs have significantly changed outcomes in advanced RCC. Four trials investigating the role of perioperative ICI for RCC are now reported. Only one trial utilizing adjuvant pembrolizumab (Keynote-564) has shown a disease-free survival benefit in resected RCC. SUMMARY: Patients with resected RCC should be counselled on their risk of recurrence and the potential option of adjuvant pembrolizumab, recognizing that overall survival data are not yet available.

Adjuvant therapy for renal cell carcinoma: 2023 Canadian Kidney Cancer Forum consensus statement.

INTRODUCTION: Several recent randomized trials evaluated the impact of adjuvant immune checkpoint inhibitor (ICI)-based therapy on post-surgical outcomes in renal cell carcinoma (RCC), with disparate results. The objective of this consensus statement is to provide data-driven guidance regarding the use of ICIs after complete resection of clear-cell RCC in a Canadian context. METHODS: An expert panel of genitourinary medical oncologists, urologic oncologists, and radiation oncologists with expertise in RCC management was convened in a dedicated session during the 2022 Canadian Kidney Cancer Forum in Toronto, Canada. Topic statements on the management of patients after surgery for RCC, including counselling, risk stratification, indications for medical oncology referral, appropriate followup, eligibility and management for adjuvant ICIs, as well as treatment options for patients with recurrence who received adjuvant immunotherapy, were discussed. Participants were asked to vote if they agreed or disagreed with each statement. Consensus was achieved if greater than 75% of participants agreed with the topic statement. RESULTS: A total of 22 RCC experts voted on 14 statements. Consensus was achieved on all topic statements. The panel felt patients with clear-cell RCC at increased risk of recurrence after surgery, as per the Keynote-564 group definitions, should be counselled about recurrence risk by a urologist, should be informed about the potential role of adjuvant ICI systemic therapy, and be offered referral to discuss risks and benefits with a medical oncologist. The panel felt that one year of pembrolizumab is currently the only regimen that should be considered if adjuvant therapy is selected. Panelists emphasized current opinions are based on disease-free survival given the available results. Significant uncertainty regarding the benefit and harms of adjuvant therapy remains, primarily due to a lack of consistent benefit observed across similar trials of adjuvant ICI-based therapies and immature overall survival (OS) data. CONCLUSIONS: This consensus document provides guidance from Canadian RCC experts regarding the potential role of ICI-based adjuvant systemic therapy after surgery. This rapidly evolving field requires frequent evidence-based re-evaluation.

Impact of the COVID-19 Pandemic on Medical Oncology Workload: A Provincial Review.

(1) Background: Cancer is the leading cause of death in Canada, with significant resource limitation impacting the delivery of cancer care nationwide. The onset of the COVID-19 pandemic forced additional resource restriction and diversion, further impacting care delivery. Our intention is to analyze the impact COVID-19 on a provincial medical oncology workload and bring attention to the limitations of the current workload metric for oncologists. (2) Methods: All medical oncology patient encounters were extracted and compared, collected by year and encounter type, from April 2014 through March 2022. (3) Results: There was an increase in all patient encounters by an average of 9.5% per year, including during the strictest COVID-19 restrictions. There was an increase in virtual care encounters from 37.9% to 52.1%. (4) Conclusions: Medical Oncology workloads have increased over time and estimates suggest growing demand. Little data exist to inform workforce requirements and actual workload is not captured by the current metric. Though volume of new consults continues to increase, COVID-19 has highlighted additional changes in the delivery of care, likely with lasting impact, little of which are included in the current workload metric.

Outcomes for International Metastatic Renal Cell Carcinoma Database Consortium Prognostic Groups in Contemporary First-line Combination Therapies for Metastatic Renal Cell Carcinoma.

BACKGROUND: The combination of immuno-oncology (IO) agents ipilimumab and nivolumab (IPI-NIVO) and vascular endothelial growth factor targeted therapies (VEGF-TT) combined with IO (IO-VEGF) are current standard of care first-line treatments for metastatic renal cell carcinoma (mRCC). OBJECTIVE: To establish real-world clinical benchmarks for IO combination therapies based on the International mRCC Database Consortium (IMDC) criteria. DESIGN, SETTING, AND PARTICIPANTS: Patients with mRCC who received first-line IPI-NIVO, IO-VEGF, or VEGF-TT from 2002 to 2021 were identified using the IMDC database and stratified according to IMDC risk groups. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS), time to next treatment (TTNT), and treatment duration (TD) were calculated using the Kaplan-Meier method and compared between IMDC risk groups within each treatment cohort by the log-rank test. The overall response rate (ORR) was calculated by physician assessment of the best overall response. The primary outcome was OS at 18 mo. RESULTS AND LIMITATIONS: In total, 728 patients received IPI-NIVO, 282 IO-VEGF, and 7163 VEGF-TT. The median follow-up times for patients remaining alive were 14.3 mo for IPI-NIVO, 14.9 mo IO-VEGF, and 34.4 mo for VEGF-TT. OS at 18 mo for favorable, intermediate, and poor risk was, respectively, 90%, 78%, and 50% for those receiving IPI-NIVO; 93%, 83%, and 74% for IO-VEGF; and 84%, 64%, and 28% for VEGF-TT. ORRs in favorable-, intermediate-, and poor-risk groups were 41.3%, 40.6%, and 33.0% for those receiving IPI-NIVO; 60.3%, 56.8%, and 40.9% for IO-VEGF; and 39.3%, 33.5%, and 20.9% for VEGF-TT, respectively. The IMDC model stratified patients into statistically distinct risk groups for the three endpoints of OS, TTNT, and TD within each treatment cohort. Limitations of this study were the retrospective design and short follow-up. CONCLUSIONS: This study demonstrated that the IMDC model continues to risk stratify patients with mRCC treated with contemporary first-line IO combination therapies and provided real-world survival benchmarks. PATIENT SUMMARY: The International Metastatic Renal Cell Carcinoma Database Consortium model continues to stratify patients with metastatic renal cell carcinoma receiving modern combination treatments in the real-world setting.

Accuracy of germ cell tumor histology and stage within a Canadian cancer registry.

INTRODUCTION: Cancer registries are the mainstay for Canadian population-based cancer statistics. Data are collected in provincial and territorial registries, including the Nova Scotia Cancer Registry (NS CR). The goal of this study was to determine the accuracy of NS CR data for germ cell tumors (GCT). METHODS: This analysis included all NS CR patients diagnosed with GCT from 2006-2015. The date and method of diagnosis, primary site, histology, and stage were recorded from the NS CR and compared to each patient's chart. Any discrepancies between the two sources were reviewed and reasons behind the discrepancies recorded. RESULTS: A total of 229 patients made up the study cohort. Using NS CR data, 57.6% had seminoma, 34.5% non-seminoma (NSG CT), and 7.9% other. Discrepancies in pathology were noted in 16 patients (7.0%). Using NS CR staging data (available in 185 cases), 71.9% had stage I, 12.4% stage II, 11.9% stage III, and 3.8% other. Discrepancies in stage were noted in 32 patients (17.3%) with NS CR data downstaging eight patients (4.3%) and upstaging 21 patients (11.4%). The site of the primary GCT was discrepant in 12 patients (5.2%). The date of diagnosis was accurate within one week for all patients except one. CONCLUSIONS: Higher-level NS CR data, such as date of diagnosis and overall pathological diagnosis, appear relatively accurate; however, there are inaccuracies in histological subtype and stage. This study raises awareness of these gaps and highlights key areas for improvement in educating registry personnel who interpret and enter data about the uniqueness of GCT pathology, staging, and interpretation of tumor markers.

Uncommon case of metastatic prostate cancer developing cutaneous metastasis.

We report a case of a man in his early 70s with a known history of prostate adenocarcinoma who presented with an undiagnosed skin lesion on his right lower lateral neck 6 years after his metastatic cancer diagnosis. The painless lesion was pink, lobulated and soft. The differential diagnosis included both primary and metastatic tumours. On resection, the histology and immunohistochemical profile of the lesion were consistent with metastatic prostate cancer. He has been managed with multiple lines of therapy since then due to progressive disease. In the 18 months, since his resection, however, he has had no clinical evidence of recurrent cutaneous metastases.

Outcomes of Radiation Therapy Plus Immunotherapy in Metastatic Renal Cell Carcinoma: Results From the Canadian Kidney Cancer Information System.

Purpose: With the integration of immunotherapy (IO) agents in the management of metastatic renal cell carcinoma (mRCC), there has been interest in the combined use with radiation therapy (RT). However, real world data are limited. The purpose of this study was to evaluate outcomes in patients with mRCC receiving both RT and IO compared with IO alone. Methods and Materials: Data were collected from Canadian Kidney Cancer Information System from January 2011 to September 2019 across 14 academic centers. Patients with mRCC who received IO as first- or second-line therapy were included. RT was categorized as radical dose or palliative dose. Kaplan-Meier estimates were reported for overall survival (OS) and time to treatment failure. Cox proportional hazard models were used adjusted for age and International Metastatic RCC Database Consortium risk categories. Results: In total, 505 patients were included in the study: 179 received RT + IO and 326 received IO alone. Two-year OS for the RT + IO group was 55.0% compared with 66.4% in the IO alone cohort (adjusted hazard ratio [aHR], 1.38; P = .07). At 2 years, 12.2% of the RT + IO patients remained on therapy versus 30.9% in the IO alone group (aHR, 1.30; P = .02). For patients receiving first-line therapy, 2-year OS in the RT + IO group was 56.4% versus 78.4% in the IO alone arm, though this difference was not statistically significant (aHR, 1.23; P = .56). For patients receiving radical dose and palliative dose, 2-year OS was 57.0% and 53.9%, respectively (aHR, 0.86; P = .63). Conclusions: In this descriptive analysis, more than one-third of patients with mRCC received RT and demonstrated inferior outcomes compared with IO alone. Potential explanations include greater presence of adverse metastatic sites in those receiving RT. Prospective clinical trials evaluating potential benefits of RT in an IO era remain an important need.

Outcomes of patients with advanced non-clear cell renal cell carcinoma treated with first-line immune checkpoint inhibitor therapy.

BACKGROUND: Immune checkpoint inhibitors (ICI) have demonstrated impressive activity in metastatic clear-cell renal cell carcinoma (ccRCC) and have become standard treatment options for patients with advanced disease. Data supporting the effectiveness of ICI-based therapy in advanced non-clear cell RCC (nccRCC) is more limited. METHODS: We performed a retrospective analysis using the International Metastatic RCC Database Consortium (IMDC) to evaluate the outcomes of patients with advanced nccRCC. Patients were classified into three groups based on first-line therapy: ICI-based therapy (monotherapy or combination), vascular endothelial growth factor (VEGF) inhibitor monotherapy, or mammalian target of rapamycin (mTOR) inhibitor monotherapy. The primary outcome was overall survival (OS). Secondary outcomes were time to treatment failure (TTF) and objective response rate (ORR). We used the Kaplan-Meier method to compare OS and TTF between treatment groups and Cox proportional hazards models to adjust for prognostic covariates. RESULTS: We identified a total of 1145 patients with metastatic nccRCC. The most common subtype was papillary RCC (54.9%). For first-line therapy, 74.3% received VEGF monotherapy, 15% received mTOR monotherapy, and 10.7% received ICI-based therapy. Median OS in the ICI group was 28.6 months, versus 16.4 months in the VEGF group and 12.2 months in the mTOR group. Median TTF in the ICI group was 6.9 months, versus 5.0 months in the VEGF group and 3.9 months in the mTOR group. ORR was 27.2% in the ICI group, 14.5% in the VEGF group, and 9% in the mTOR group. After adjusting for the IMDC risk group, histological subtype, and age, the hazard ratio for OS was 0.57 (95% CI 0.42-0.78, p < 0.0001) for ICI versus VEGF and 0.50 (95% CI 0.36-0.71, p < 0.0001) for ICI versus mTOR. CONCLUSIONS: In advanced nccRCC, first-line ICI-based treatment appears to be associated with improved OS compared to VEGF and mTOR targeted therapy. These results should be confirmed in prospective randomised trials.

Imaging Response to Contemporary Immuno-oncology Combination Therapies in Patients With Metastatic Renal Cell Carcinoma.

Importance: The association between treatment with first-line immuno-oncology (IO) combination therapies and physician-assessed objective imaging response among patients with metastatic renal cell carcinoma (mRCC) remains uncharacterized. Objective: To compare the likelihood of objective imaging response (ie, complete or partial response) to first-line IO combination ipilimumab-nivolumab (IOIO) therapy vs approved IO with vascular endothelial growth factor inhibitor (IOVE) combination therapies among patients with mRCC. Design, Setting, and Participants: This multicenter international cohort study was nested in routine clinical practice. A data set from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) was used to identify consecutive patients with mRCC who received treatment with IO combination therapies between May 30, 2013, and September 9, 2021. A total of 899 patients with a histologically confirmed diagnosis of mRCC who received treatment with a first-line IOVE or IOIO regimen and had evaluable responses were included. Exposures: Best overall response to first-line IO combination therapy based on Response Evaluation Criteria in Solid Tumors, version 1.1. Main Outcomes and Measures: The primary outcome was the difference in treating physician-assessed objective imaging response based on the type of first-line IO combination therapy received. Secondary outcomes included the identification of baseline characteristics positively associated with objective imaging response and the association of objective imaging response with overall survival. Results: Among 1085 patients with mRCC who received first-line IO combination therapies, 899 patients (median age, 62.8 years [IQR, 55.9-69.2 years]; 666 male [74.2%]) had evaluable responses. A total of 794 patients had information available on IMDC risk classification; of those, 127 patients (16.0%) had favorable risk, 442 (55.7%) had intermediate risk, and 225 (28.3%) had poor risk. With regard to best overall response among all participants, 37 patients (4.1%) had complete response, 344 (38.3%) had partial response, 315 (35.0%) had stable disease, and 203 (22.6%) had progressive disease. Corresponding median overall survival was not estimable (95% CI, 53.3 months to not estimable) among patients with complete response, 55.9 months (95% CI, 44.1 months to not estimable) among patients with partial response, 48.1 months (95% CI, 33.4 months to not estimable) among patients with stable disease, and 13.0 months (95% CI, 8.4-18.1 months) among patients with progressive disease (log rank P < .001). Treatment with IOVE therapy was found to be independently associated with an increased likelihood of obtaining response (OR, 1.89; 95% CI, 1.26-2.81; P = .002) compared with IOIO therapy. The presence of lung metastases (odds ratio [OR], 1.49; 95% CI, 1.01-2.20), receipt of cytoreductive nephrectomy (OR, 1.59; 95% CI, 1.04-2.43), and favorable IMDC risk (OR, 1.93; 95% CI, 1.10-3.39) were independently associated with an increased likelihood of response. Conclusions and Relevance: In this study, treatment with IOVE therapy was associated with significantly increased odds of objective imaging response compared with IOIO therapy. The presence of lung metastases, receipt of cytoreductive nephrectomy, and favorable IMDC risk were associated with increased odds of experiencing objective imaging response. These findings may help inform treatment selection, especially in clinical contexts associated with high-volume multisite metastatic disease, in which obtaining objective imaging response is important.

Delivering Chemotherapy to a Metastatic Poor Risk Testicular Cancer Patient on Hemodialysis.

A standard curative intent approach of chemotherapy treatment for metastatic testicular cancer has been well established. However, there is little guidance for patients undergoing hemodialysis (HD) who require chemotherapy for this disease. Thus, we describe our treatment approach and rationale for a patient on HD with poor risk metastatic nonseminomatous germ cell tumor involving the testicle, lymph nodes, liver, and bone. After orchiectomy, five cycles of cisplatin and modified dose etoposide were delivered and strategically timed with HD. Treatment was complicated by significant neuropathy. Surgical resection of two liver lesions was performed after chemotherapy. Ten years post-chemotherapy, he remains free of clinical, biochemical, or radiological recurrence. While our patient remains free of disease after this treatment, the optimal chemotherapy and dialysis dose and schedule to maximize cure and minimize toxicity remains unknown.

Utilization and Safety of Ipilimumab Plus Nivolumab in a Real-World Cohort of Metastatic Renal Cell Carcinoma Patients.

INTRODUCTION: Ipilimumab plus nivolumab was associated with a survival benefit in a phase III clinical trial of first-line treatment for metastatic renal cell carcinoma (mRCC). In this study, mRCC patients from the Canadian Kidney Cancer Information System (CKCis) database who received first-line ipilimumab plus nivolumab were analyzed to determine the safety and outcomes in a real-world setting. PATIENTS AND METHODS: Patients who received ipilimumab plus nivolumab as first-line therapy for mRCC in CKCis, were identified, and the amount of treatment received, discontinuation rates, and reasons for discontinuing treatment were determined. Toxicity data, including type and grade, were collected. Efficacy outcomes of interest included overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). RESULTS: The cohort included 195 patients, the majority with clear cell histology (74%). All 4 cycles of ipilimumab plus nivolumab were administered in 124 patients (64%). Progressive disease (n = 87; 45%) and toxicity (n = 36; 18%) were the most common causes for discontinuing treatment. Several patients (n = 18) did not receive all 4 doses of ipilimumab but received single agent nivolumab. The estimated median OS was 54.5 months (95% CI, 17.7 - NE) and 12-month OS was 72.2% (95% CI, 65.0 - 79.3). Median PFS was 7.4 months (95% CI 5.3 - 10.2) and ORR was 42.5%. Patients who received all 4 cycles of ipilimumab plus nivolumab had better ORR (50% vs. 28%) and a longer PFS and OS than those who received less than 4 cycles (P < .0001). Ninety-five AEs were documented in 72 patients who required dose reduction/change, with colitis being the most frequent. CONCLUSION: In this real-world cohort of treatment-naïve mRCC patients, outcomes, and safety were comparable to previously reported clinical trial data.

Outcomes of Cytoreductive Nephrectomy for Patients with Metastatic Renal Cell Carcinoma: Real World Data from Canadian Centers.

BACKGROUND: Treatment options for metastatic renal cell carcinoma (mRCC) include cytoreductive nephrectomy (CN) and systemic therapy (ST). Results from the CARMENA and SURTIME trials suggest that CN before ST may not be the optimal treatment strategy for mRCC. OBJECTIVE: To use real-world data to evaluate and compare outcomes for patients with mRCC who underwent CN before, after, or without ST to those patients who only received ST. DESIGN, SETTING, AND PARTICIPANTS: The Canadian Kidney Cancer information system (CKCis) database was used to identify patients diagnosed with mRCC between January 2011 and April 2020. Only patients with synchronous disease, treated within 12 mo from their initial RCC diagnosis, with International Metastatic Renal Cell Carcinoma Database Consortium intermediate/high risk, and confirmed RCC histology were included. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patients were classified into four groups according to the initial treatment received for mRCC. Inverse probability of treatment weighting using propensity scores was used to balance the treatment groups. Cox proportional hazards models were used to assess the impact of CN after adjusting for potential confounding variables in the weighted cohorts. RESULTS AND LIMITATIONS: A total of 788 patients were included in the study cohort. Of these 383 patients underwent CN before ST, 73 underwent CN after ST, 80 underwent CN only, and 252 patients received ST only. The median patient age was 63 yr and 73% of the cohort were men. In weighted analysis, the groups undergoing CN before ST (hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.52-0.82) and CN after ST (HR 0.41, 95% CI 0.28-0.60) both had better survival compared to the ST only group. No survival benefit was observed for CN only compared to ST only, or for CN before ST compared to CN after ST. CONCLUSIONS: We evaluated the association between different sequences of treatment with CN and survival in patients with mRCC using CKCis real world data. The results demonstrate that the selected patients who undergo CN, whether performed before or after ST, have an associated improvement in survival. PATIENT SUMMARY: Two of the treatment options for metastatic kidney cancer are surgery and systemic therapy (chemotherapy or immunotherapy). We used data from the Canadian Kidney Cancer information system to determine whether there are differences in survival according to the sequencing of these treatments. Patients who had both surgery and systemic therapy, regardless of which treatment was first, had better survival than patients who only received systemic therapy.

Characterization and Management of Treatment-emergent Hepatic Toxicity in Patients with Advanced Renal Cell Carcinoma Receiving First-line Pembrolizumab plus Axitinib. Results from the KEYNOTE-426 Trial.

BACKGROUND: Pembrolizumab plus axitinib improved efficacy over sunitinib in treatment-naive advanced renal cell carcinoma in the KEYNOTE-426 (NCT02853331) study. However, a relatively high incidence of grade 3/4 aminotransferase elevations was observed. OBJECTIVE: To further characterize treatment-emergent aminotransferase elevations in patients treated with pembrolizumab-axitinib. DESIGN, SETTING, AND PARTICIPANTS: Patients enrolled in KEYNOTE-426 were included in this study. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Three Standardized MedDRA Queries for potential hepatic disorders were used to identify patients for the hepatic event analysis subpopulation (HEAS). Alanine aminotransferase events were characterized for time to onset, time to recovery, corticosteroid use, and rechallenge with study treatment(s). RESULTS AND LIMITATIONS: The HEAS comprised 189/429 (44%) pembrolizumab-axitinib patients and 128/425 (30%) sunitinib patients. Grade 3/4 hepatic adverse events were more common in the combination arm: 22% (94/429) versus 7% (29/425); 3% (13/429) discontinued the combination due to hepatic adverse events. In the pembrolizumab-axitinib arm, 125/426 patients (29%) had alanine aminotransferase (ALT) ≥3× upper limit of normal (ULN), with median time to onset of 84 d (range, 7-840 d). Among patients with ALT ≥3× ULN, 120/125 (96%) recovered to <3× ULN following study treatment interruption/discontinuation, with a median time to recovery of 15 d (3-176 d): 68/120 (57%) received corticosteroids. One hundred patients were rechallenged with one or both study treatment(s): 45/100 (45%) had ALT ≥3× ULN recurrence, and all 45 recovered to ALT <3× ULN following study treatment interruption/discontinuation. No fatal hepatic events occurred. CONCLUSIONS: A higher incidence of grade 3/4 aminotransferase elevations occurs with pembrolizumab-axitinib. These events should be carefully evaluated and managed with prompt study treatment interruption or discontinuation, with or without corticosteroid treatment. The decision to rechallenge with one or both drugs should be based on severity of event and thorough causality assessment. PATIENT SUMMARY: Renal cell carcinoma patients receiving pembrolizumab-axitinib are at a higher risk of liver enzyme elevations, which could be reversed with appropriate management.

Outcomes of patients with solid tumour malignancies treated with first-line immuno-oncology agents who do not meet eligibility criteria for clinical trials.

BACKGROUND: Immuno-oncology (IO)-based therapies have been approved based on randomised clinical trials, yet a significant proportion of real-world patients are not represented in these trials. We sought to compare the outcomes of trial-ineligible vs. -eligible patients with advanced solid tumours treated with first-line (1L) IO therapy. PATIENTS AND METHODS: Using the International Metastatic Renal Cell Carcinoma (RCC) Database Consortium and the Alberta Immunotherapy Database, patients with advanced RCC, non-small-cell lung cancer (NSCLC) or melanoma treated with 1L PD-(L)1 inhibition-based therapy were included. Trial eligibility was retrospectively determined as per commonly used exclusion criteria. The outcomes of interest were overall survival (OS), overall response rate (ORR), treatment duration (TD) and time to next treatment (TTNT). RESULTS: A total of 395 of 1241 (32%) patients were deemed trial-ineligible. The main reasons for ineligibility based on preselected exclusion criteria were Karnofsky performance status <70%/Eastern Cooperative Oncology Group performance status >1 (40%, 158 of 395), brain metastases (32%, 126 of 395), haemoglobin < 9 g/dL (16%, 63 of 395) and estimated glomerular filtration rate <40 mL/min (15%, 61 of 395). Between the ineligible vs. eligible groups, the median OS, ORR, median TD and median TTNT were 10.2 vs. 39.7 months (p < 0.01), 36% vs. 47% (p < 0.01), 2.7 vs. 6.9 months (p < 0.01) and 6.0 vs. 16.8 months (p < 0.01), respectively. Subgroup analyses showed statistically significant inferior OS, TD and TTNT for trial-ineligible vs. -eligible patients across all tumour types. Adjusted hazard ratios for death in RCC, NSCLC and melanoma were 1.84 (95% confidence interval [CI] 1.22-2.77), 2.21 (95% CI 1.58-3.11) and 1.82 (95% CI 1.21-2.74), respectively.. CONCLUSIONS: Thirty-two percent of real-world patients treated with contemporary 1L IO-based therapies were ineligible for clinical trials. Although one-third of the trial-ineligible patients responded to treatment, the overall trial-ineligible population had inferior outcomes than trial-eligible patients. These data may guide patient counselling and temper expectations of benefit.