Long-Term Survival in Patients With Relapsed/Refractory Advanced Renal Cell Carcinoma Treated With Tivozanib: Analysis of the Phase III TIVO-3 Trial.

BACKGROUND: Tivozanib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) with efficacy in advanced renal cell carcinoma (RCC). Long-term exploratory analyses from the TIVO-3 trial in relapsed/refractory (R/R) RCC including patients (26%) with prior immuno-oncology (IO) therapy are reported. METHODS: Patients with R/R advanced RCC that progressed with 2 or 3 prior systemic therapies (≥1 VEGFR TKI) were randomized to tivozanib 1.5 mg QD or sorafenib 400 mg BID, stratified by IMDC risk and previous therapy. Safety, investigator-assessed long-term progression-free survival (LT-PFS), and serial overall survival (OS) were assessed. RESULTS: Mean time on treatment was 11.0 months with tivozanib (n = 175) and 6.3 months with sorafenib (n = 175). Fewer grade ≥3 treatment-related adverse events occurred with tivozanib (46%) than sorafenib (55%). Dose modification rates were lower with tivozanib than sorafenib across age/prior IO subgroups; prior IO therapy did not impact dose reductions or discontinuations in either arm. Landmark LT-PFS rates were higher with tivozanib (3 years: 12.3% vs 2.4%; 4 years: 7.6% vs 0%). After 22.8 months mean follow-up, the OS HR was 0.89 (95% CI, 0.70-1.14); when conditioned on 12-month landmark PFS, tivozanib showed significant OS improvement over sorafenib (HR, 0.45; 95% CI, 0.22-0.91; 2-sided P = .0221). CONCLUSIONS: Tivozanib demonstrated a consistent safety profile and long-term survival benefit in patients with R/R advanced RCC who were alive and progression free at 12 months. These post hoc exploratory analyses of LT-PFS and conditional OS support a clinically meaningful improvement with tivozanib versus sorafenib in this advanced RCC population.

Activity of Tivozanib in Non-clear Cell Renal Cell Carcinoma: Subgroup Analysis From a Phase II Randomized Discontinuation Trial.

BACKGROUND: Non-clear cell renal cell carcinoma (nccRCC) is a blanket term for a collection of heterogeneous and biologically diverse RCC histologies, including but not limited to papillary, chromophobe, and unclassified subtypes. Tivozanib is a selective vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) that demonstrated activity in RCC with clear cell component. The objective of this analysis was to determine the efficacy of tivozanib in histologically unclassified/mixed RCC. METHODS: We identified patients with nccRCC enrolled in Study 201 (NCT00502307) between October 2007 and July 2008. This was a phase II randomized discontinuation trial of tivozanib in patients with RCC who had no prior VEGFR-targeted treatment. Clinical outcomes including investigator-assessed objective response rate (ORR), disease control rate (DCR, defined by complete response + partial response + stable disease), and progression-free survival (PFS) were examined. RESULTS: Of the 272 patients enrolled, 46 (16.9%) patients had nccRCC: 11 (4%) papillary, 2 (0.7%) chromophobe, 2 (0.7%) collecting duct, and 31 (11.4%) mixed/unclassified. Of the 46 patients with nccRCC, 38 were continuously treated with tivozanib and the best ORR was 21.1% (confirmed) and 31.6% (confirmed and unconfirmed). The DCR was 73.7% and median PFS was 6.7 months (95% confidence interval, 125-366 days). There were no new safety signals compared to the ITT population. Limitations include the small number of individual nccRCC subtypes and the randomized discontinuation design. CONCLUSION: Tivozanib demonstrated activity and a favorable safety profile in patients with nccRCC. These data add to the body of evidence supporting the use of VEGFR-TKI in advanced nccRCC.

Tivozanib in Patients with Advanced Renal Cell Carcinoma Previously Treated With Axitinib: Subgroup Analysis from TIVO-3.

BACKGROUND: In phase III TIVO-3 trial, tivozanib improved progression-free survival (PFS) compared to sorafenib for patients with metastatic renal cell carcinoma (mRCC). However, the effectiveness of this drug after exposure to other selective VEGFR agents has not yet been defined. Herein, we characterize the clinical efficacy of tivozanib in patients with mRCC previously treated with axitinib. METHODS: We identified patients from the intention to treat (ITT) population, in the TIVO-3 trial, who received treatment with axitinib before enrolment in the study and evaluated PFS, response rate (RR), and safety. RESULTS: Out of 350 patients, 172 (83:89, tivozanib:sorafenib) had received prior treatment with axitinib in TIVO-3. In this subgroup, PFS was 5.5 months with tivozanib and 3.7 months with sorafenib (HR 0.68). RR was 13% and 8% favoring tivozanib. CONCLUSIONS: Tivozanib is active in the treatment of patients with mRCC who have progressed on prior therapies, including axitinib.

A multicenter, phase Ib/II, open-label study of tivozanib with durvalumab in advanced hepatocellular carcinoma (DEDUCTIVE).

Durvalumab, a PD-L1 inhibitor, is part of an immunotherapeutic drug class shown to have prolonged survival benefit in patients with advanced stage hepatocellular carcinoma (HCC). Tivozanib is a potent and selective VEGFR 1, 2 and 3 tyrosine kinase inhibitor. While these medications have both demonstrated single-agent activity in HCC and have been combined safely with other therapies, there is no data on their concurrent therapeutic effects. In the phase Ib DEDUCTIVE trial, the combination of tivozanib plus durvalumab is evaluated for safety and tolerability. Here, the design of and rationale for this trial in both treatment naive patients and those who progress on atezolizumab and bevacizumab for advanced or metastatic HCC are described. Clinical Trial Registration: NCT03970616.

Real-world clinical outcomes with first-line avelumab in locally advanced/metastatic Merkel cell carcinoma in the USA: SPEAR-Merkel.

Aim: To assess clinical outcomes in patients with locally advanced (la) or metastatic (m) Merkel cell carcinoma (MCC) initiating first-line (1L) avelumab in a USA community oncology setting. Materials & methods: Adults with laMCC or mMCC initiating 1L avelumab were identified from The US Oncology Network electronic health record database and chart review. Results: Median overall survival and progression-free survival were not reached in laMCC (n = 9) vs 20.2 and 10.0 months in mMCC (n = 19); response rates were similar (66.7% vs 63.2%). Conclusion: This is the first study to show clinical benefit in patients with laMCC receiving 1L avelumab in a US real-world setting. Response rates in patients with mMCC were consistent with pivotal trials.

Lay abstract Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Because MCC progresses quickly, many patients have a poor prognosis. Avelumab is a type of drug that helps the patient's immune system to fight cancer. Avelumab was the first such drug approved by the US FDA for treating metastatic MCC based on the results of the JAVELIN Merkel 200 clinical trial. In SPEAR-Merkel, we studied how MCC patients with locally advanced as well as metastatic disease responded when they were treated with first-line avelumab in a real-world setting. These patients were from oncology practices in communities throughout the USA. Overall response rates in SPEAR-Merkel were comparable between patients with locally advanced and metastatic MCC. Importantly, we found that these patients experienced survival benefit similar to patients in the JAVELIN Merkel 200 (part B) study and other real-world studies.

Temporal Characteristics of Adverse Events of Tivozanib and Sorafenib in Previously Treated Kidney Cancer.

INTRODUCTION: Tivozanib, vascular endothelial growth factor receptor inhibitor, met the primary endpoint of improved progression free survival compared to sorafenib in the phase 3 TIVO-3 study in patients with previously treated metastatic renal cell carcinoma. In this study we sought to understand the temporal characteristics of treatment related adverse events (TRAEs) and frequency and timing of the dose modifications. MATERIALS AND METHODS: In this open label, randomized, phase 3 TIVO-3 study, previously treated patients with a diagnosis of metastatic renal cell carcinoma and with measurable disease were included. Patients were randomized to receive either tivozanib 1.5 mg orally once daily in 4-week cycles or sorafenib 400 mg orally twice daily continuously. Based on updated safety analysis data (cutoff date of August 15, 2019), time to onset of the most commonly reported TRAEs, duration of toxicity, rate of dose modifications was calculated for each treatment arm. RESULTS: Overall, 350 patients were randomly assigned to receive tivozanib or sorafenib;173 patients from the tivozanib arm and 170 patients from the sorafenib arm were included in this analysis. Patients received a median of 11.9 cycles (336 days) and 6.7 cycles (192 days) of tivozanib and sorafenib, respectively. Dose reductions, interruptions and treatment discontinuations were 25%, 50%, and 21%, and 39%, 50%, and 30% in the tivozanib and sorafenib arms, respectively, with a longer time to onset of TRAEs in the tivozanib arm. CONCLUSION: Tivozanib was associated with less TRAEs, fewer dose modifications, a longer time to onset and a shorter duration of TRAEs compared to sorafenib.

Real-World Outcomes Among US Veterans Health Administration Patients Newly Diagnosed with Metastatic Renal Cell Carcinoma and Treated with First-Line Monotherapy.

INTRODUCTION: Substantial unmet needs exist among patients with metastatic renal cell carcinoma (mRCC). This retrospective study evaluated treatment patterns as well as clinical and economic outcomes associated with first-line monotherapy among patients with mRCC in the USA. METHODS: Newly diagnosed patients with mRCC initiating at least one first-line therapy (1L) from 1 October 2013 to 31 March 2018 (index date = 1L start date) were identified from the US Veterans Health Administration database. Treatment patterns, clinical outcomes (time to next treatment [TNT] defined by earliest of switch to non-index therapy or re-initiation of index therapy after a more than 90-day gap, time to treatment discontinuation [TTD], overall survival [OS]), and costs were evaluated among patients treated with tyrosine kinase inhibitors (TKI), mammalian target of rapamycin inhibitors (mTOR), immune checkpoint inhibitors (ICI), and other monotherapies. Standard descriptive statistics were presented. The Kaplan-Meier method was used to evaluate clinical outcomes. RESULTS: Of 759 patients (median age 68.0 years), 85.0%, 8.0%, 4.3%, and 2.6% were treated with TKI, mTOR, ICI, or other therapy in 1L, respectively. Advancement rates (to second-line [2L] therapy) ranged from 10.0 (ICI) to 45.1 per 100 person years (TKI). The 12-month OS rates ranged from 47.4% (TKI) to 67.7% (mTOR). The median TNT ranged from 3.8 (mTOR) to 9.6 months (ICI), and median TTD ranged from 2.3 (mTOR) to 4.7 months (TKI). Total all-cause mean costs per patient per month ranged from $12,466 (mTOR) to $19,812 (ICI). CONCLUSION: These results indicate high unmet medical needs among patients with mRCC treated with 1L monotherapies. Novel combination therapies (e.g., ICI + ICI, ICI + TKI) may improve front-line outcomes for patients with poor prognoses.

Effects of early vs delayed progression on clinical and economic outcomes in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors as first-line therapy: results from the IMPACT RCC claims data analysis.

BACKGROUND: A key therapeutic goal of metastatic renal cell carcinoma (mRCC) treatment is delayed disease progression. The degree to which early therapeutic success affects downstream outcomes is not well established. OBJECTIVE: To assess the clinical and economic impact of early vs delayed disease progression in patients with mRCC treated with first-line (1L) tyrosine kinase inhibitors (TKIs) followed by second-line (2L) therapy in the US Veterans Health Administration (VHA) database. METHODS: Adult patients newly diagnosed with mRCC who were treated with a TKI as 1L therapy and who progressed to 2L therapy from October 1, 2013, through March 31, 2018, were identified from the US VHA database. Patients were stratified by median time from initiation of 1L therapy to initiation of 2L therapy into early (median time or sooner)and delayed (longer than the median) progression cohorts. Clinical outcomes (time to 2L therapy discontinuation, time to third-line [3L] treatment initiation, and overall survival) were assessed descriptively, and health care resource utilization and costs were compared between patients in the early and those in the delayed progression cohorts. Survival analyses (Kaplan-Meier curves) were used to estimate descriptively the median time to discontinuation, time to next line of treatment, and time to death for each cohort. Multivariate analysis was performed to adjust for the influence of differences in cohort characteristics, and Cox proportional hazards models were used to descriptively assess the impact of predictive factors on clinical outcomes. RESULTS: 289 patients were included in the analysis: 145 in the early progression cohort and 144 in the delayed progression cohort. Baseline characteristics were similar between the early and delayed progression cohorts. Median time from 1L therapy initiation to 2L therapy discontinuation was 7.9 months in the early progression cohort and 18.0 months in the delayed progression cohort, whereas time from 1L therapy initiation to 3L therapy initiation was 9.4 and 21.8 months, respectively; overall survival was 19.7 and 36.4 months, respectively. Descriptive analysis revealed generally lower risks for 2L therapy discontinuation (HR = 0.40, 95% CI = 0.31-0.52), 3L therapy initiation (HR = 0.42, 95% CI = 0.32-0.55), and death (HR = 0.46, 95% CI = 0.33-0.64) for those with delayed progression. After adjustment for possible confounding factors, comparative analysis during the follow-up period showed that delayed progression was associated with a shorter median all-cause hospital length of stay (0.4 days vs 0.8 days for early progression; P = 0.0004), fewer pharmacy visits (3.57 vs 4.08 visits; P = 0.0266), and lower total health care costs ($10,342 vs $13,388; P = 0.0347) per patient per month. CONCLUSIONS: In patients with mRCC, early progression after 1L therapy initiation is associated with generally worse clinical outcomes and statistically significantly greater health care resource utilization and costs than delayed progression. This finding highlights the importance of initiating therapy with an optimal 1L treatment regimen that has been proven to delay disease progression. DISCLOSURES This study was sponsored by EMD Serono Inc., an affiliate of Merck KGaA, and Pfizer Inc. EMD Serono Inc. and Pfizer Inc. were involved in the study design; the collection, analysis, and interpretation of the data; the writing of the report; and the decision to submit the report for publication. Liu and Bhanegaonkar are employed by EMD Serono Inc., an affiliate of Merck KGaA. Kasturi was employed by EMD Serono Inc., an affiliate of Merck KGaA, at the time of this study. Kim and Krulewicz are employed by Pfizer Inc. Dieyi is an employee of STATinMED Research, which received consulting fees from EMD Serono Inc. and Pfizer Inc. Hutson has received grants from Pfizer Inc., Astellas Pharma Inc., Janssen Pharmaceuticals, Exelixis, Inc., and Eisai Co., Ltd., outside of this work. Data from this analysis were presented at the Virtual International Society for Pharmacoeconomics and Outcomes Research 2020 conference, May 18-20, 2020; the virtual American Society of Clinical Oncology Annual Meeting, May 29-31, 2020; and AMCP Nexus 2020 Virtual, October 20-23, 2020.

Efficacy and immune-related adverse event associations in avelumab-treated patients.

BACKGROUND: Adverse events (AEs) of special interest that arise during treatment with immune checkpoint inhibitors, including immune-related AEs (irAEs), have been reported to be associated with improved clinical outcomes. We analyzed patients treated with avelumab from the JAVELIN Solid Tumor and Merkel 200 trials, examining the association between AEs and efficacy while adjusting for confounding factors such as treatment duration and event order. METHODS: We analyzed efficacy and safety data from 1783 patients treated with the programmed death ligand 1 inhibitor avelumab who were enrolled in expansion cohorts of the JAVELIN Solid Tumor and Merkel 200 trials. To analyze the association between irAEs and efficacy with regard to survival, we used a time-dependent Cox model with time-varying indicators for irAEs, as well as multistate models that accounted for competing risks and time inhomogeneity. RESULTS: 295 patients (16.5%) experienced irAEs and 454 patients (25.5%) experienced infusion-related reactions. There was a reduced risk of death in patients who experienced irAEs compared with those who did not (HR 0.71, 95% CI 0.59 to 0.85) using the time-dependent Cox model. The multistate model did not suggest that the occurrence of irAEs could predict response; however, it predicted a higher chance of irAEs occurring after a response. No association was observed between response and infusion-related reactions. CONCLUSIONS: Patients who experience irAEs showed improved survival. Although irAEs are not predictors for response to immune checkpoint inhibitors, increased vigilance for irAEs is needed after treatment with avelumab. TRIAL REGISTRATION NUMBERS: NCT01772004 and NCT02155647.

Efficacy and safety of avelumab treatment in patients with metastatic Merkel cell carcinoma: experience from a global expanded access program.

BACKGROUND: Avelumab, a human anti-programmed death-ligand 1 immunoglobulin G1 monoclonal antibody, showed favorable efficacy and safety in patients with metastatic Merkel cell carcinoma (mMCC) in the phase II JAVELIN Merkel 200 trial, leading to approval in multiple countries. We describe real-world experience with avelumab in patients with mMCC from an expanded access program. METHODS: Eligible patients had mMCC and progressive disease during or after chemotherapy or were ineligible for chemotherapy or clinical trial participation. Patients received an initial 3-month supply of avelumab (administered as 10 mg/kg intravenously every 2 weeks until progressive disease or unacceptable toxicity); resupply was allowed following complete response, partial response, stable disease, or clinical benefit per physician assessment. RESULTS: Between December 15, 2015, and March 4, 2019, 558 of 620 requests from 38 countries were medically approved, and 494 patients received avelumab. Among 240 evaluable patients, the objective response rate was 46.7% (complete response in 22.9%, including 3 of 16 potentially immunocompromised patients), and the disease control rate was 71.2%. The median duration of treatment in evaluable patients with response was 7.9 months (range, 1.0-41.7) overall and 5.2 months (range, 3.0-13.9) in immunocompromised patients. No new safety signals were identified. The expanded access program closed for new requests on December 31, 2018, as required after regulatory approval; benefitting patients continued to receive avelumab. CONCLUSIONS: The avelumab expanded access program for patients with mMCC demonstrated efficacy and safety in a real-world setting, consistent with the results from JAVELIN Merkel 200, and provided a treatment for patients with limited options.

Avelumab in patients with previously treated metastatic melanoma: phase 1b results from the JAVELIN Solid Tumor trial.

BACKGROUND: We report phase 1b data from patients enrolled in the JAVELIN Solid Tumor clinical trial (NCT01772004) with unresectable stage IIIC or IV melanoma that had progressed after ≥1 line of therapy for metastatic disease. PATIENTS AND METHODS: Patients received avelumab (10 mg/kg)-a human anti-PD-L1 antibody. Assessments included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: As of December 31, 2016, 51 patients were treated and followed for a median of 24.2 months (range, 16.1-31.5). Most patients had cutaneous (n = 28 [54.9%]) or ocular (n = 16 [31.4%]) melanoma and had received a median of 2 prior lines of therapy (range, 0-4), including ipilimumab (n = 26 [51.0%]). The confirmed ORR was 21.6% (95% CI, 11.3-35.3; complete response, 7.8%; partial response, 13.7%). The median duration of response was not estimable (95% CI, 2.6 months-not estimable). Median PFS and OS were 3.1 months (95% CI, 1.4-6.3) and 17.2 months (95% CI, 6.6-not estimable), respectively. Subgroup analyses suggested meaningful clinical activity (ORR [95% CI]) in patients with non-ocular melanoma (31.4% [16.9-49.3]), PD-L1-positive tumors (42.1% [20.3-66.5]), or prior ipilimumab therapy (30.8% [14.3-51.8]). Thirty-nine patients (76.5%) had a treatment-related adverse event (TRAE), most commonly infusion-related reaction (29.4%), fatigue (17.6%), and chills (11.8%); 4 patients (7.8%) had a grade 3 TRAE. Five patients (9.8%) had an immune-related TRAE (all were grade 1/2). No grade 4 TRAEs or treatment-related deaths were reported. CONCLUSION: Avelumab showed durable responses, promising survival outcomes, and an acceptable safety profile in patients with previously treated metastatic melanoma. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01772004 .

Avelumab in patients with previously treated metastatic adrenocortical carcinoma: phase 1b results from the JAVELIN solid tumor trial.

BACKGROUND: We assessed the efficacy and safety of avelumab, an anti-programmed death ligand 1 (PD-L1) antibody, in patients with previously treated metastatic adrenocortical carcinoma (mACC). METHODS: In this phase 1b expansion cohort, patients with mACC and prior platinum-based therapy received avelumab at 10 mg/kg intravenously every 2 weeks. Continuation of mitotane was permitted; however, mitotane levels during the study were not recorded. Tumor response was assessed by Response Evaluation Criteria In Solid Tumors v1.1. RESULTS: Fifty patients received avelumab and were followed for a median of 16.5 months. Prior treatment included ≥2 lines in 74.0%; mitotane was continued in 50.0%. The objective response rate (ORR) was 6.0% (95% CI, 1.3% to 16.5%; partial response in 3 patients). Twenty-one patients (42.0%) had stable disease as best response (disease control rate, 48.0%). Median progression-free survival was 2.6 months (95% CI, 1.4 to 4.0), median overall survival (OS) was 10.6 months (95% CI, 7.4 to 15.0), and the 1-year OS rate was 43.4% (95% CI, 27.9% to 57.9%). In evaluable patients with PD-L1+ (n = 12) or PD-L1- (n = 30) tumors (≥5% tumor cell cutoff), ORR was 16.7% vs 3.3% (P = .192). Treatment-related adverse events (TRAEs) occurred in 82.0%; the most common were nausea (20.0%), fatigue (18.0%), hypothyroidism (14.0%), and pyrexia (14.0%). Grade 3 TRAEs occurred in 16.0%; no grade 4 to 5 TRAEs occurred. Twelve patients (24.0%) had an immune-related TRAE of any grade, which were grade 3 in 2 patients (4.0%): adrenal insufficiency (n = 1), and pneumonitis (n = 1). CONCLUSIONS: Avelumab showed clinical activity and a manageable safety profile in patients with platinum-treated mACC. TRIAL REGISTRATION: Clinicaltrials.gov NCT01772004 ; registered January 21, 2013.