A phase I trial of enzalutamide plus selective glucocorticoid receptor modulator relacorilant in patients with metastatic castration resistant prostate cancer.

PURPOSE: Majority of patients with metastatic prostate cancer who receive androgen deprivation therapy and androgen receptor (AR) signaling inhibitors progress. Activation of the glucocorticoid receptor (GR) is associated with ARSI-resistance. This single-arm phase I trial assessed safety and pharmacokinetic feasibility of combined AR antagonist (enzalutamide) and selective GR modulator (relacorilant) in metastatic castration-resistant prostate cancer (mCRPC) patients. PATIENTS AND METHODS: This was a phase I trial (NCT03674814) of relacorilant and enzalutamide in refractory mCRPC patients enrolled using 6+3 design. Enzalutamide dose was kept constant at 120 mg/day with escalating doses of relacorilant based on safety and pharmacokinetic measures in cohorts of ≥ 6 patients. Primary objective was safety and establishment of pharmacologically active doses. Secondary objectives were related to antitumor activity. RESULTS: Thirty-five mCRPC patients were enrolled. Twenty-three were accrued across 3 dose cohorts in the dose escalation phase and twelve enrolled at the recommended phase 2 dose. The combination was generally well-tolerated and safe and achieved desirable enzalutamide pharmacokinetics. RP2D of 120 mg/day + 150 mg/day respectively was established. Median time on study was 2.2 months with 4 patients remaining on study for longer than 11 months. Four of twelve evaluable patients had a PSA partial response. CONCLUSIONS: This is the first prospective trial combining an AR antagonist and a non-steroidal selective GR modulator. The combination was safe and well tolerated with PSA response and prolonged disease control observed in a limited subset of patients. Further prospective trials are justified to evaluate efficacy and identify predictive biomarkers of response.

Bladder-Preserving Trimodality Therapy With Capecitabine.

INTRODUCTION: Many patients with muscle-invasive bladder cancer are poor candidates for radical cystectomy or trimodality therapy with maximal transurethral resection of bladder tumor (TURBT) and chemoradiotherapy with cisplatin or mitomycin C. Given the benefit of chemotherapy in bladder-preserving therapy, less-intense concurrent chemotherapy regimens are needed. This study reports on efficacy and toxicity for patients treated with trimodality therapy using single-agent concurrent capecitabine. MATERIALS AND METHODS: Patients deemed ineligible for radical cystectomy or standard chemoradiotherapy by a multidisciplinary tumor board and patients who refused cystectomy were included. Following TURBT, patients received twice-daily capecitabine (goal dose 825 mg/m2) concurrent with radiotherapy to the bladder +/- pelvis depending on nodal staging and patient risk factors. Toxicity was evaluated prospectively in weekly on-treatment visits and follow-up visits by the treating physicians. Descriptive statistics are provided. Overall, progression-free, cancer-specific, distant metastasis-free, and bladder recurrence-free survival were estimated using the Kaplan-Meier method. RESULTS: Twenty-seven consecutive patients met criteria for inclusion from 2013 to 2023. The median age was 79 with 9 patients staged cT3-4a and 7 staged cN1-3. The rate of complete response in the bladder and pelvis was 93%. Overall, progression-free, cancer-specific, distant metastasis-free, and bladder recurrence-free survival at 2 years were estimated as 81%, 65%, 91%, 75%, and 92%, respectively. There were 2 bladder recurrences, both noninvasive. There were 7 grade 3 acute hematologic or metabolic events but no other grade 3+ toxicities. CONCLUSION: Maximal TURBT followed by radiotherapy with concurrent capecitabine offers a high rate of bladder control and low rates of acute and late toxicity.

PROMISE Registry: A prostate cancer registry of outcomes and germline mutations for improved survival and treatment effectiveness.

BACKGROUND: Recently approved treatments and updates to genetic testing recommendations for prostate cancer have created a need for correlated analyses of patient outcomes data via germline genetic mutation status. Genetic registries address these gaps by identifying candidates for recently approved targeted treatments, expanding clinical trial data examining specific gene mutations, and understanding effects of targeted treatments in the real-world setting. METHODS: The PROMISE Registry is a 20-year (5-year recruitment, 15-year follow-up), US-wide, prospective genetic registry for prostate cancer patients. Five thousand patients will be screened through an online at-home germline testing to identify and enroll 500 patients with germline mutations, including: pathogenic or likely pathogenic variants and variants of uncertain significance in genes of interest. Patients will be followed for 15 years and clinical data with real time patient reported outcomes will be collected. Eligible patients will enter long-term follow-up (6-month PRO surveys and medical record retrieval). As a virtual study with patient self-enrollment, the PROMISE Registry may fill gaps in genetics services in underserved areas and for patients within sufficient insurance coverage. RESULTS: The PROMISE Registry opened in May 2021. 2114 patients have enrolled to date across 48 US states and 23 recruiting sites. 202 patients have met criteria for long-term follow-up. PROMISE is on target with the study's goal of 5000 patients screened and 500 patients eligible for long-term follow-up by 2026. CONCLUSIONS: The PROMISE Registry is a novel, prospective, germline registry that will collect long-term patient outcomes data to address current gaps in understanding resulting from recently FDA-approved treatments and updates to genetic testing recommendations for prostate cancer. Through inclusion of a broad nationwide sample, including underserved patients and those unaffiliated with major academic centers, the PROMISE Registry aims to provide access to germline genetic testing and to collect data to understand disease characteristics and treatment responses across the disease spectrum for prostate cancer with rare germline genetic variants.

Optimizing the doses of cancer drugs after usual dose finding.

Since the middle of the 20th century, oncology's dose-finding paradigm has been oriented toward identifying a drug's maximum tolerated dose, which is then carried forward into phase 2 and 3 trials and clinical practice. For most modern precision medicines, however, maximum tolerated dose is far greater than the minimum dose needed to achieve maximal benefit, leading to unnecessary side effects. Regulatory change may decrease maximum tolerated dose's predominance by enforcing dose optimization of new drugs. Dozens of already approved cancer drugs require re-evaluation, however, introducing a new methodologic and ethical challenge in cancer clinical trials. In this article, we assess the history and current landscape of cancer drug dose finding. We provide a set of strategic priorities for postapproval dose optimization trials of the future. We discuss ethical considerations for postapproval dose optimization trial design and review three major design strategies for these unique trials that would both adhere to ethical standards and benefit patients and funders. We close with a discussion of financial and reporting considerations in the realm of dose optimization. Taken together, we provide a comprehensive, bird's eye view of the postapproval dose optimization trial landscape and offer our thoughts on the next steps required of methodologies and regulatory and funding regimes.

Enrollment Barriers for Molecular Targeted Trials.

This quality improvement study examines the difficulties of patient accrual among patients with cancer and SETD2 variants.

A Phase II Study of sEphB4-HSA in Metastatic Castration-Resistant Prostate Cancer.

INTRODUCTION: Ephrin receptors and their membrane-localized ligands induce bidirectional signaling and facilitate tumor-stroma interactions. Blocking the EphB4-EphrinB2 pathway, which can be accomplished by soluble EphB4 conjugated to human serum albumin (sEphB4-HSA), promotes cell death in preclinical models of aggressive prostate cancer. We hypothesized that targeting the EphB4-EphrinB2 pathway may serve as a therapeutic target in the treatment of metastatic castration resistant prostate cancer (mCRPC). PATIENTS AND METHODS: We conducted a single arm, phase II trial in patients with progressive mCRPC who had received no more than 3 prior therapies for mCRPC. sEphB4-HSA 1000 mg IV was administered every 2 weeks, extending to 3 weeks starting from cycle 7. The primary endpoint was confirmed prostate specific antigen (PSA) response rate. We employed a Simon 2-stage Minimax design with 15 patients in the first stage and 10 additional patients in the second stage. RESULTS: Fourteen eligible patients enrolled in the study with median age of 73.5 years (range: 52-83) and median baseline PSA of 65.11 ng/mL (range: 7.77-2850 ng/mL). Most patients received 3 prior therapies for mCRPC. The median treatment duration with sEphB4-HSA was 6.5 weeks (range: 2-35 weeks). Three patients experienced a serious adverse event potentially related to therapy, including 1 patient with a grade 5 event (cerebral vascular accident) possibly related to the study drug. No patient had a confirmed PSA response, and the study was stopped for futility. Thirteen patients had PSA progression. The median time to PSA progression was 28 days (90% CI: 28-42 days), and median time to radiologic progression was 55 days (90% CI: 54-72 days). Of 3 patients with measurable disease, 2 had stable disease and one had progressive disease. CONCLUSION: In patients with mCRPC who progressed on prior second generation AR-targeted therapy, sEphB4-HSA monotherapy had no discernable anti-tumor activity.

Efficacy and Safety of Telaglenastat Plus Cabozantinib vs Placebo Plus Cabozantinib in Patients With Advanced Renal Cell Carcinoma: The CANTATA Randomized Clinical Trial.

Importance: Dysregulated metabolism is a hallmark of renal cell carcinoma (RCC). Glutaminase is a key enzyme that fuels tumor growth by converting glutamine to glutamate. Telaglenastat is an investigational, first-in-class, selective, oral glutaminase inhibitor that blocks glutamine utilization and downstream pathways. Preclinically, telaglenastat synergized with cabozantinib, a VEGFR2/MET/AXL inhibitor, in RCC models. Objective: To compare the efficacy and safety of telaglenastat plus cabozantinib (Tela + Cabo) vs placebo plus cabozantinib (Pbo + Cabo). Design, Setting, and Participants: CANTATA was a randomized, placebo-controlled, double-blind, pivotal trial conducted at sites in the US, Europe, Australia, and New Zealand. Eligible patients had metastatic clear-cell RCC following progression on 1 to 2 prior lines of therapy, including 1 or more antiangiogenic therapies or nivolumab plus ipilimumab. The data cutoff date was August 31, 2020. Data analysis was performed from December 2020 to February 2021. Interventions: Patients were randomized 1:1 to receive oral cabozantinib (60 mg daily) with either telaglenastat (800 mg twice daily) or placebo until disease progression or unacceptable toxicity. Main Outcomes and Measures: The primary end point was progression-free survival (Response Evaluation Criteria in Solid Tumors version 1.1) assessed by blinded independent radiology review. Results: A total of 444 patients were randomized: 221 to Tela + Cabo (median [range] age, 61 [21-81] years; 47 [21%] women and 174 [79%] men) and 223 to Pbo + Cabo (median [range] age, 62 [29-83] years; 68 [30%] women and 155 [70%] men). A total of 276 (62%) patients had received prior immune checkpoint inhibitors, including 128 with prior nivolumab plus ipilimumab, 93 of whom had not received prior antiangiogenic therapy. Median progression-free survival was 9.2 months for Tela + Cabo vs 9.3 months for Pbo + Cabo (HR, 0.94; 95% CI, 0.74-1.21; P = .65). Overall response rates were 31% (69 of 221) with Tela + Cabo vs 28% (62 of 223) with Pbo + Cabo. Treatment-emergent adverse event (TEAE) rates were similar between arms. Grade 3 to 4 TEAEs occurred in 160 patients (71%) with Tela + Cabo and 172 patients (79%) with Pbo + Cabo and included hypertension (38 patients [17%] vs 40 patients [18%]) and diarrhea (34 patients [15%] vs 29 patients [13%]). Cabozantinib was discontinued due to AEs in 23 patients (10%) receiving Tela + Cabo and 33 patients (15%) receiving Pbo + Cabo. Conclusions and Relevance: In this randomized clinical trial, telaglenastat did not improve the efficacy of cabozantinib in metastatic RCC. Tela + Cabo was well tolerated with AEs consistent with the known risks of both agents. Trial Registration: ClinicalTrials.gov Identifier: NCT03428217.

Evaluation of Provider Preferences in First-Line Metastatic Renal Cell Carcinoma: Comparison Between Dual Immunotherapy vs. Immunotherapy/Tyrosine Kinase Inhibitors.

INTRODUCTION: Dual immunotherapy (ipilimumab/nivolumab, IO/IO) and immunotherapy/tyrosine kinase inhibitor (IO/TKI) combinations (e.g. pembrolizumab/axitinib) are approved for the first-line treatment of intermediate/poor risk metastatic renal cell carcinoma (RCC), but there is limited comparative data between these two options. We sought to understand how oncologists decide between IO/IO vs. IO/TKI. METHODS: We sent a 10-question electronic survey centered on a patient scenario of intermediate/poor risk metastatic RCC to 294 academic/disease-focused and general oncologists in the US. RESULTS: We received 105 responses (36% response rate): 61% (64) of providers chose IO/IO, 39% (41) chose IO/TKI. 78% (82) of oncologists were academic or disease-focused, 22% (23) were general. Academic/disease-focused oncologists were significantly more likely to choose IO/IO (56/82, 68%) than general oncologists (8/23, 35%), P = .004. Among those who chose IO/IO, the perceived main issue with IO/TKI was: long-term toxicities - 31% (20), short-term toxicities - 28% (18), less effective - 28% (18), less convenient - 8% (5). Among those who chose IO/TKI, the perceived main issue with IO/IO was: short-term toxicities - 43% (17), less effective - 28% (11), long-term toxicities - 15% (6), and risk of death - 10% (4). 88% (92) of providers would be comfortable enrolling patients into a phase III trial comparing IO/IO vs. IO/TKI. We found no associations between therapy chosen by a provider and participation as PI in a trial of IO/IO or IO/TKI, or receipt of outside funding from an IO/IO or IO/TKI company. CONCLUSION: In response to a patient scenario of intermediate/poor risk metastatic RCC, 61% of providers chose IO/IO, 39% chose IO/TKI. There was a significant association between type of practice and choice of therapy, with academic/disease-focused oncologists more likely to choose IO/IO. The majority of oncologists would be comfortable enrolling patients into a phase III trial comparing IO/IO vs. IO/TKI.

Phase I/II Trial of Enzalutamide and Mifepristone, a Glucocorticoid Receptor Antagonist, for Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: Although androgen deprivation therapy (ADT) and androgen receptor (AR) signaling inhibitors are effective in metastatic prostate cancer, resistance occurs in most patients. This phase I/II trial assessed the safety, pharmacokinetic impact, and efficacy of the glucocorticoid receptor (GR) antagonist mifepristone in combination with enzalutamide for castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: One hundred and six patients with CRPC were accrued. Phase I subjects were treated with enzalutamide monotherapy at 160 mg per day for 28 days to allow steady-state accumulation. Patients then entered the dose escalation combination portion of the study. In phase II, patients were randomized 1:1 to either receive enzalutamide alone or enzalutamide plus mifepristone. The primary endpoint was PSA progression-free survival (PFS), with radiographic PFS, and PSA response rate (RR) as key secondary endpoints. Circulating tumor cells were collected before randomization for exploratory translational biomarker studies. RESULTS: We determined a 25% dose reduction in enzalutamide, when added to mifepristone, resulted in equivalent drug levels compared with full-dose enzalutamide and was well tolerated. However, the addition of mifepristone to enzalutamide following a 12-week enzalutamide lead-in did not delay time to PSA, radiographic or clinical PFS. The trial was terminated early due to futility. CONCLUSIONS: This is the first prospective trial of dual AR-GR antagonism in CRPC. Enzalutamide combined with mifepristone was safe and well tolerated but did not meet its primary endpoint. The development of more specific GR antagonists combined with AR antagonists, potentially studied in an earlier disease state, should be explored.

Biomarker-Based Phase II Study of Sapanisertib (TAK-228): An mTORC1/2 Inhibitor in Patients With Refractory Metastatic Renal Cell Carcinoma.

PURPOSE: Sapanisertib is a kinase inhibitor that inhibits both mammalian target of rapamycin complex 1 (mTORC1) and mTORC2. In this multicenter, single-arm phase II trial, we evaluated the efficacy of sapanisertib in patients with treatment-refractory metastatic renal cell carcinoma (mRCC; NCT03097328). METHODS: Patients with mRCC of any histology progressing through standard therapy (including prior mTOR inhibitors) had baseline biopsy and received sapanisertib 30 mg by mouth once weekly until unacceptable toxicity or disease progression. The primary end point was objective response rate by RECIST 1.1. Tissue biomarkers of mTOR pathway activation were explored. RESULTS: We enrolled 38 patients with mRCC (clear cell = 28; variant histology = 10) between August 2017 and November 2019. Twenty-four (63%) had received ≥ 3 prior lines of therapy; 17 (45%) had received prior rapalog therapy. The median follow-up was 10.4 (range 1-27.4) months. Objective response rate was two of 38 (5.3%; 90% CI, 1 to 15.6); the median progression-free survival (PFS) was 2.5 months (95% CI, 1.8 to 3.7). Twelve patients (32%) developed treatment-related grade 3 adverse events, with no grade 4 or 5 toxicities. Alterations in the mTOR pathway genes were seen in 5 of 29 evaluable patients (MTOR n = 1, PTEN n = 3, and TSC1 n = 1) with no association with response or PFS. Diminished or loss of PTEN expression by immunohistochemistry was seen in 8 of 21 patients and trended toward shorter PFS compared with intact PTEN (median 1.9 v 3.7 months; hazard ratio 2.5; 95% CI, 0.9 to 6.7; P = .055). CONCLUSION: Sapanisertib had minimal activity in treatment-refractory mRCC independent of mTOR pathway alterations. Additional therapeutic strategies are needed for patients with refractory mRCC.

NF2-mutated Renal Carcinomas Have Common Morphologic Features Which Overlap With Biphasic Hyalinizing Psammomatous Renal Cell Carcinoma: A Comprehensive Study of 14 Cases.

Genetic alterations involving NF2 occur at low frequencies in renal cell carcinoma across all of the major histologic subtypes and have been associated with adverse outcomes. To better characterize tumors harboring these alterations, we identified 14 cases with NF2 mutations that had been previously diagnosed as papillary renal cell carcinoma; renal cell carcinoma, unclassified; or translocation associated renal cell carcinoma. These tumors were characterized by a tubulopapillary architecture, sclerotic stroma, microscopic coagulative necrosis, and psammomatous calcifications. All the cases displayed eosinophilic cytology as well as a high nuclear grade (World Health Organization/International Society of Urological Pathology [WHO/ISUP] grade 3 to 4) in all but 1 case. A subset of cases shared features with the recently described biphasic hyalinizing psammomatous renal cell carcinoma. Next-generation sequencing demonstrated mutations involving NF2 gene in all cases. In 10 cases, this was paired with the loss of chromosome 22. Additional mutations involving PBRM1 were found in 5 cases that were associated with a more solid growth pattern. Eight patients presented with metastatic disease including all 5 with PBRM1 mutations. Despite the aggressive disease course seen in many of the patients in our series, 2 patients exhibited a dramatic response to immunotherapy. Our results support the existence of a distinct group of cases of renal cell carcinoma characterized by distinct although admittedly nonspecific morphology, an aggressive disease course, and NF2 mutations, often paired with the loss of chromosome 22.

A Prospective Multicenter Evaluation of Initial Treatment Choice in Metastatic Renal Cell Carcinoma Prior to the Immunotherapy Era: The MaRCC Registry Experience.

INTRODUCTION: The Metastatic Renal Cell Carcinoma (MaRCC) Registry provides prospective data on real-world treatment patterns and outcomes in patients with metastatic renal cell carcinoma (mRCC). METHODS AND MATERIALS: Patients with mRCC and no prior systemic therapy were enrolled at academic and community sites. End of study data collection was in March 2019. Outcomes included overall survival (OS). A survey of treating physicians assessed reasons for treatment initiations and discontinuations. RESULTS: Overall, 376 patients with mRCC initiated first-line therapy; 171 (45.5%) received pazopanib, 75 (19.9%) sunitinib, and 74 (19.7%) participated in a clinical trial. Median (95% confidence interval) OS was longest in the clinical trial group (50.3 [35.8-not reached] months) versus pazopanib (39.0 [29.7-50.9] months) and sunitinib 26.2 [19.9-61.5] months). Non-clear cell RCC (21.5% of patients) was associated with worse median OS than clear cell RCC (18.0 vs. 47.3 months). Differences in baseline characteristics, treatment starting dose, and relative dose exposure among treatment groups suggest selection bias. Survey results revealed a de-emphasis on quality of life, toxicity, and patient preference compared with efficacy in treatment selection. CONCLUSION: The MaRCC Registry gives insights into real-world first-line treatment selection, outcomes, and physician rationale regarding initial treatment selection prior to the immunotherapy era. Differences in outcomes between clinical trial and off-study patients reflect the difficulty in translating trial results to real-world patients, and emphasize the need to broaden clinical trial eligibility. Physician emphasis on efficacy over quality of life and toxicity suggests more data and education are needed regarding these endpoints.

Comparison of out-of-pocket costs and adherence between the two arms of the prospective, randomized abiraterone food effect trial.

PURPOSE: Abiraterone acetate, prescribed for metastatic prostate cancer, has enhanced absorption with food. This effect was exploited in a randomized trial which showed noninferiority of PSA decline for 250 mg abiraterone with a low-fat meal (LOW) compared to 1,000 mg abiraterone fasting (STD). Drug was obtained via patient insurance. Patient out-of-pocket costs and adherence were surveyed. METHODS: Trial participants were randomized to STD or LOW, and surveys of adherence and out-of-pocket costs were administered at baseline and just before coming off study (follow-up). RESULTS: Out-of-pocket costs were available from 20 of 36 STD and 21 of 36 LOW patients. Median out-of-pocket costs for a month of drug were $0 (LOW) and $5 (STD); mean costs were $43.61 (LOW) and $393.83 (STD). The two groups did not differ significantly (p = 0.421). Maximum out-of-pocket cost was $1,000 (LOW) and $4,000 (STD). Monthly out-of-pocket costs > $500 were found in 1 LOW and 5 STD patients. For adherence, only 11 STD and 19 LOW patients had questionnaires completed at both baseline and follow-up. STD adherence was 98.18% at baseline and 91.69% at follow-up, differing significantly (p = 0.0078). LOW adherence was 96.52% at baseline and 97.86% at follow-up, not differing significantly (p = 0.3511). Adherence did not correlate with demographics. At follow-up, increasing adherence correlated significantly with decreasing dose (p = 0.013; rho = - 0.458). CONCLUSIONS: Out-of-pocket costs did not differ significantly in this limited analysis. Adherence was significantly different in STD as the trial progressed, which was not found in LOW. TRIAL REGISTRATION: ClinicalTrials.gov NCT01543776; registered March 5, 2012.

Tissue based biomarkers in non-clear cell RCC: Correlative analysis from the ASPEN clinical trial.

Biomarkers are needed in patients with non-clear cell renal cell carcinomas (NC-RCC), particularly papillary renal cell carcinoma, in order to inform on initial treatment selection and identify potentially novel targets for therapy. We enrolled 108 patients in ASPEN, an international randomized open-label phase 2 trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC treated with the mTOR inhibitor everolimus (n=57) or the vascular endothelial growth factor (VEGF) receptor inhibitor sunitinib (n=51), stratified by MSKCC risk and histology. The primary endpoint was overall survival (OS) and secondary efficacy endpoints for this exploratory biomarker analysis were radiographic progression-free survival (rPFS) defined by intention-to-treat using the RECIST 1.1 criteria and radiographic response rates. Tissue biomarkers (n=78) of mTOR pathway activation (phospho-S6 and -Akt, c-kit) and VEGF pathway activation (HIF-1α, c-MET) were prospectively explored in tumor tissue by immunohistochemistry prior to treatment and associated with clinical outcomes. We found that S6 activation was more common in poor risk NC-RCC tumors and S6/Akt activation was associated with worse PFS and OS outcomes with both everolimus and sunitinib, while c-kit was commonly expressed in chromophobe tumors and associated with improved outcomes with both agents. C-MET was commonly expressed in papillary tumors and was associated with lower rates of radiographic response but did not predict PFS for either agent. In multivariable analysis, both pAkt and c-kit were statistically significant prognostic biomarkers of OS. No predictive biomarkers of treatment response were identified for clinical outcomes. Most biomarker subgroups had improved outcomes with sunitinib as compared to everolimus.

Randomized Phase III Trial of Gemcitabine and Cisplatin With Bevacizumab or Placebo in Patients With Advanced Urothelial Carcinoma: Results of CALGB 90601 (Alliance).

PURPOSE: The combination of gemcitabine and cisplatin (GC) is a standard therapy for metastatic urothelial carcinoma. Based on data that angiogenesis plays a role in urothelial carcinoma growth and progression, a randomized placebo-controlled trial was performed with the primary objective of testing whether patients treated with GC and bevacizumab (GCB) have superior overall survival (OS) than patients treated with GC and placebo (GCP). PATIENTS AND METHODS: Between July 2009 and December 2014, 506 patients with metastatic urothelial carcinoma without prior chemotherapy for metastatic disease and no neoadjuvant or adjuvant chemotherapy within 12 months were randomly assigned to receive either GCB or GCP. The primary end point was OS, with secondary end points of progression-free survival, objective response, and toxicity. RESULTS: With a median follow-up of 76.3 months among alive patients, the median OS was 14.5 months for patients treated with GCB and 14.3 months for patients treated with GCP (hazard ratio for death = 0.87; 95% CI, 0.72 to 1.05; two-sided stratified log-rank P = .14). The median progression-free survival was 8.0 months for GCB and 6.7 months for GCP (hazard ratio = 0.77; 95% CI, 0.63 to 0.95; P = .016). The proportion of patients with grade 3 or greater adverse events did not differ significantly between both arms, although increased bevacizumab-related toxicities such as hypertension and proteinuria occurred in the bevacizumab-treated arm. CONCLUSION: The addition of bevacizumab to GC did not result in improved OS. The observed median OS of about 14 months is consistent with prior phase III trials of cisplatin-based chemotherapy.

Active surveillance of metastatic renal cell carcinoma: Results from a prospective observational study (MaRCC).

BACKGROUND: Systemic therapy (ST) can be deferred in patients who have metastatic renal cell carcinoma (mRCC) and slow-growing metastases. Currently, this subset of patients managed with active surveillance (AS) is not well described in the literature. METHODS: This was a prospective observational study of patients with mRCC across 46 US community and academic centers. The objective was to describe baseline characteristics and demographics of patients with mRCC initially managed by AS, reasons for AS, and patient outcomes. Descriptive statistics were used to characterize demographics, baseline characteristics, and patient-related outcomes. Wilcoxon 2-sample rank-sum tests and χ2 tests were used to assess differences between ST and AS cohorts in continuous and categorical variables, respectively. Kaplan-Meier survival curves were used to assess survival. RESULTS: Of 504 patients, mRCC was initially managed by AS (n = 143) or ST (n = 305); 56 patients were excluded from the analysis. Disease was present in 69% of patients who received AS, whereas the remaining 31% had no evidence of disease. At data cutoff, 72 of 143 patients (50%) in the AS cohort had not received ST. The median overall survival was not reached (95% CI, 122 months to not estimable) in patients who received AS versus 30 months (95% CI, 25-44 months) in those who received ST. Quality of life at baseline was significantly better in patients who were managed with AS versus ST. CONCLUSIONS: AS occurs frequently (32%) in real-world clinical practice and appears to be a safe and appropriate alternative to immediate ST in selected patients.

Efficacy and Safety of Atezolizumab Plus Bevacizumab Following Disease Progression on Atezolizumab or Sunitinib Monotherapy in Patients with Metastatic Renal Cell Carcinoma in IMmotion150: A Randomized Phase 2 Clinical Trial.

BACKGROUND: The use of immune checkpoint inhibitors combined with vascular endothelial growth factor (VEGF)-targeted therapy as second-line treatment for metastatic clear cell renal cancer (mRCC) has not been evaluated prospectively. OBJECTIVE: To evaluate the efficacy and safety of atezolizumab + bevacizumab following disease progression on atezolizumab or sunitinib monotherapy in patients with mRCC. DESIGN, SETTING, AND PARTICIPANTS: IMmotion150 was a multicenter, randomized, open-label, phase 2 study of patients with untreated mRCC. Patients randomized to the atezolizumab or sunitinib arm who had investigator-assessed progression as per RECIST 1.1 could be treated with second-line atezolizumab + bevacizumab. INTERVENTION: Patients received atezolizumab 1200 mg intravenously (IV) plus bevacizumab 15 mg/kg IV every 3 wk following disease progression on either atezolizumab or sunitinib monotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The secondary endpoints analyzed during the second-line part of IMmotion150 included objective response rate (ORR), progression-free survival (PFS), and safety. PFS was examined using Kaplan-Meier methods. RESULTS AND LIMITATIONS: Fifty-nine patients in the atezolizumab arm and 78 in the sunitinib arm were eligible, and 103 initiated second-line atezolizumab + bevacizumab (atezolizumab arm, n = 44; sunitinib arm, n = 59). ORR (95% confidence interval [CI]) was 27% (19-37%). The median PFS (95% CI) from the start of second line was 8.7 (5.6-13.7) mo. The median event follow-up duration was 19.4 (12.9-21.9) mo among the 25 patients without a PFS event. Eighty-six (83%) patients had treatment-related adverse events; 31 of 103 (30%) had grade 3/4 events. Limitations were the small sample size and selection for progressors. CONCLUSIONS: The atezolizumab + bevacizumab combination had activity and was tolerable in patients with progression on atezolizumab or sunitinib. Further studies are needed to investigate sequencing strategies in mRCC. PATIENT SUMMARY: Patients with advanced kidney cancer whose disease had worsened during treatment with atezolizumab or sunitinib began second-line treatment with atezolizumab + bevacizumab. Tumors shrank in more than one-quarter of patients treated with this combination, and side effects were manageable.

Steroid-refractory dermatologic and pulmonary toxicity in a patient on rituximab treated with pembrolizumab for progressive urothelial carcinoma: a case report.

BACKGROUND: Increasingly widespread use of programmed cell death protein 1 (PD-1) immune checkpoint inhibitors (ICIs) for treatment of a variety of progressive malignancies continues to reveal a range of immune-related adverse events (irAEs), necessitating immunosuppressive therapy for management. While a single course of systemic corticosteroids may be sufficient for many irAEs, no clear standard-of-care guidelines exist for steroid-refractory cases. We present an unusual case of a patient who developed several steroid-refractory novel irAEs on pembrolizumab despite ongoing B cell-directed immunosuppressive therapy with rituximab, who ultimately noted resolution of symptoms with tacrolimus, a T-cell-directed immunosuppressant. CASE PRESENTATION: This 72-year-old Caucasian man with Waldenstrom's macroglobulinemia and myelin-associated glycoprotein (MAG) immunoglobulin M (IgM) antibody-associated neuropathy was being treated with maintenance rituximab and intravenous immunoglobulin when he was started on pembrolizumab (2.26 mg/kg) for metastatic urothelial cancer 31 months after surgery and adjuvant chemotherapy. After his third dose of pembrolizumab, he developed a painful blistering papular rash of the distal extremities. He received two more doses of pembrolizumab before he also developed diarrhea, and it was held; he was initiated on 1 mg/kg prednisone for presumed ICI-induced dermatitis and colitis. Skin biopsy 10 weeks after cessation of pembrolizumab and taper of steroids to 20  mg daily revealed a unique bullous erythema multiforme. He was then admitted with dyspnea and imaging concerning for necrotizing pneumonia, but did not respond to antibiotic therapy. Bronchoscopy and biopsy revealed acute fibrinous organizing pneumonia. His symptoms failed to fully respond to multiple courses of high-dose systemic corticosteroids and a trial of azathioprine, but pneumonia, diarrhea, and skin rash all improved markedly with tacrolimus. The patient has since completed his therapy for tacrolimus, continues off of ICI, and has not experienced a recurrence of any irAEs, though has more recently experienced progression of his cancer. CONCLUSION: Despite immunosuppression with rituximab and intravenous immunoglobulin, two immunomodulators targeting B cells, ICI cessation, and systemic corticosteroid therapy, our patient developed two high-grade unusual irAEs, bullous erythema multiforme and acute fibrinous organizing pneumonia. Our patient's improvement with tacrolimus can offer critical insight into the pathophysiology of steroid-refractory irAEs.