Untreated aRCC Research Articles

PCN131 Cost-Effectiveness Models and Resource Use/Cost Inputs for Untreated Advanced/Metastatic Renal Cell Carcinoma- A Systematic Literature Review

To ascertain and evaluate the availability of health economic evidence (costs, resource use, and economic evaluations), in the global published literature, for patients with previously untreated, advanced or metastatic renal cell carcinoma (aRCC). A systematic literature review (SLR) with two independent reviewers was conducted in August 2019. MEDLINE, Embase, EconLit, health technology assessments’ (HTA) databases, and National Health Service Economic Evaluation Database (NHS EED) were searched without applying time limits. Additionally, ISPOR conference proceedings and HTA agencies’ websites were hand searched. Publications of interest were restricted to economic models and studies reporting cost-benefit evaluations, costs, or healthcare resource use (HCRU) data for aRCC. Clinical trials were excluded. Among 101 publications included in the review, the majority were on economic models (n=77), covering several countries and interventions. Most of the economic modeling studies were conducted in the United States (US) (n=12), Spain (n=6), the United Kingdom (n=5), Italy (n=5), and China (n=5). The top 5 most reported treatments amongst economic models were sunitinib (n=51), pazopanib (n=20), nivolumab+ipilimumab (n=13), bevacizumab+interferon-alpha-2a (n=13), and sorafenib (n=7). Other study designs included in the SLR were 16 claims database analyses, 6 reviews on patient medical records, and 2 registry studies. Among these, the majority were conducted in the US (n=16). These studies presented both cost and HCRU data, although most of the identified HCRU data were reported in these references (9 out of 14 total HCRU studies). These studies reported on fewer number and variety of treatments, with most being sunitinib (n=7), pazopanib (n=5), or unspecified targeted therapy (n=5). Treatment-specific cost-effectiveness data for previously untreated aRCC patients are available in the global literature. However, more granular and local-level evidence of HCRU data in this population is needed to cover interventions and countries more broadly.

First-line PD-1/PD-L1 inhibitor monotherapy for advanced renal cell carcinoma (aRCC): A multi-institutional cohort.

e17109 Background: Combination regimens containing a programmed cell death protein 1 (PD-1) or a programmed cell death ligand 1 (PD-L1) inhibitor improve the clinical outcomes of previously untreated aRCC. These regimens are clinically active but are associated with adverse events (AEs). One prospective study (KEYNOTE-427) has shown clinical activity of pembrolizumab monotherapy in aRCC. We aimed to describe the utilization and outcomes of single-agent PD-1/PD-L1 in previously untreated aRCC patients (pts). Methods: Consecutive pts treated with front-line PD-1/PD-L1 monotherapy for aRCC were included. Descriptive statistics were used to analyze outcomes including overall response rate (ORR), progression-free survival (PFS) and safety. Results: A total of 28 pts (median age 60; 32% ECOG 2/3; intermediate/poor risk 86%/14%; 35% non-clear cell aRCC) were identified. Common sites of metastases included lung (57%), lymph nodes (39%), bone (21%) and brain (21%). Pts received pembrolizumab (n = 9), avelumab (n = 1) or nivolumab (n = 18) due to pt/physician’s decision (46%), poor performance status (29%) or clinical trial (21%). In evaluable pts (n = 24), the ORR was 33% in ccRCC and 30% in nccRCC. With a median follow up of 13 months (mo), the median PFS was 6.3 mo (CI 95%, 1.5-11.1) and 16 pts progressed on therapy. Frequent AEs (57%) included fatigue (21%), myalgias/arthralgias (11%) and hypothyroidism (7%). No significant grade AEs (G3+) were noted. After progression on PD-1/PD-L1 (n = 16), 39% received a subsequent anti-VEGF (cabozantinib n = 6; sunitinib n = 4; pazopanib n = 1), 42% went to hospice or died and 21% were lost to follow up. Conclusions: First-line single-agent treatment with PD-1/PD-L1 inhibitors showed a favorable safety profile and clinical activity in patients with clear cell and non-clear cell aRCC who were not considered for a combination regimen. [Table: see text]

A phase III study (COSMIC-313) of cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced renal cell carcinoma of intermediate or poor-risk.

TPS5102 Background: Cabozantinib (C) inhibits tyrosine kinases involved in tumor growth, angiogenesis, and immune regulation, including MET, VEGFR, and TAM kinases (Tyro3, AXL, MER), and may promote an immune-permissive tumor environment, resulting in enhanced response to immune checkpoint inhibitors. C has shown preliminary clinical activity and tolerability in combination with the PD-1 inhibitor nivolumab (N) and as part of a triplet combination with N and the CTLA-4 inhibitor ipilimumab (I) in patients (pts) with advanced renal cell carcinoma (aRCC) (Nadal et al. ASCO 2018). C is approved for pts with aRCC, and N+I is approved as a combination therapy in pts with previously untreated aRCC of intermediate or poor risk. We present the study design of a phase 3 trial of C+N+I vs N+I in previously untreated pts with aRCC of IMDC intermediate or poor risk (NCT03937219). Methods: This randomized, double-blind, controlled phase 3 study evaluates the efficacy and safety of C+N+I vs N+I in previously untreated pts with IMDC intermediate or poor risk aRCC. Eligible pts are randomized 1:1 to receive C+N+I or N+I in combination with placebo, stratified by IMDC prognostic score and geographic region. Pts receive C (40 mg oral QD) + N (3 mg/kg IV Q3W) x 4 doses + I (1 mg/kg IV Q3W) x 4 doses, followed by C (40 mg oral QD) + N (480 mg IV flat dose Q4W). Control pts receive C-matched placebo and the same treatment regimen for N+I as the experimental arm. N will be administered for a maximum of 2 years. Eligibility criteria include histologically confirmed metastatic or aRCC with a clear cell component, intermediate or poor risk RCC per IMDC criteria, measurable disease per RECIST 1.1, KPS ≥70%, adequate organ and marrow function and age ≥18 years. Exclusion criteria include prior systemic therapy for aRCC and uncontrolled significant illnesses. The primary endpoint is PFS per RECIST 1.1 by BICR; the secondary endpoint is OS. Additional endpoints include ORR, safety, correlation of biomarkers with outcomes, and pharmacokinetics of C in combination with N+I. The first patient was enrolled in June 2019 and enrollment is ongoing. Clinical trial information: NCT03937219 .

Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma

Background:The phase 3 JAVELIN Renal 101 trial (NCT02684006) demonstrated significantly improved progression-free survival (PFS) with first-line avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma (aRCC). We report updated efficacy data from the second interim analysis.Patients and methods:Treatment-naive patients with aRCC were randomized (1 : 1) to receive avelumab (10 mg/kg) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were PFS and overall survival (OS) among patients with programmed death ligand 1–positive (PD-L1+) tumors. Key secondary end points were OS and PFS in the overall population.Results:Of 886 patients, 442 were randomized to the avelumab plus axitinib arm and 444 to the sunitinib arm; 270 and 290 had PD-L1+ tumors, respectively. After a minimum follow-up of 13 months (data cut-off 28 January 2019), PFS was significantly longer in the avelumab plus axitinib arm than in the sunitinib arm {PD-L1+ population: hazard ratio (HR) 0.62 [95% confidence interval (CI) 0.490–0.777]}; one-sided P < 0.0001; median 13.8 (95% CI 10.1–20.7) versus 7.0 months (95% CI 5.7–9.6); overall population: HR 0.69 (95% CI 0.574–0.825); one-sided P < 0.0001; median 13.3 (95% CI 11.1–15.3) versus 8.0 months (95% CI 6.7–9.8)]. OS data were immature [PD-L1+ population: HR 0.828 (95% CI 0.596–1.151); one-sided P = 0.1301; overall population: HR 0.796 (95% CI 0.616–1.027); one-sided P = 0.0392].Conclusion:Among patients with previously untreated aRCC, treatment with avelumab plus axitinib continued to result in a statistically significant improvement in PFS versus sunitinib; OS data were still immature.Clinical Trial number:NCT02684006.

A phase III study (COSMIC-313) of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in patients (pts) with previously untreated advanced renal cell carcinoma (aRCC) of intermediate or poor risk.

TPS767 Background: C inhibits tyrosine kinases involved in tumor growth, angiogenesis, and immune regulation, including MET, VEGFR, and TAM kinases (Tyro3, AXL, MER), and may promote an immune-permissive tumor environment, resulting in enhanced response to immune checkpoint inhibitors. C has shown preliminary clinical activity and tolerability in combination with the PD-1 inhibitor N and as part of a triplet combination with N and the CTLA-4 inhibitor I in pts with aRCC (Nadal et al. ASCO 2018). C is approved for pts with aRCC, and N+I is approved as a combination therapy in pts with previously untreated aRCC of intermediate or poor risk. We present the study design of a phase 3 trial of C+N+I vs N+I in previously untreated pts with aRCC of IMDC intermediate or poor risk (NCT03937219). Methods: This randomized, double-blind, controlled phase 3 study evaluates the efficacy and safety of C+N+I vs N+I in previously untreated pts with IMDC intermediate or poor risk aRCC. Eligible pts are randomized 1:1 to receive C+N+I or N+I in combination with placebo, stratified by IMDC prognostic score and geographic region. Pts receive C (40 mg oral QD) + N (3 mg/kg IV Q3W) x 4 doses + I (1 mg/kg IV Q3W) x 4 doses, followed by C (40 mg oral QD) + N (480 mg IV flat dose Q4W). Control pts receive C-matched placebo and the same treatment regimen for N+I as the experimental arm. N will be administered for a maximum of 2 years. Eligibility criteria include histologically confirmed metastatic or aRCC with a clear cell component, intermediate or poor risk RCC per IMDC criteria, measurable disease per RECIST 1.1, KPS ≥70%, adequate organ and marrow function and age ≥18 years. Exclusion criteria include prior systemic therapy for aRCC and uncontrolled significant illnesses. The primary endpoint is PFS per RECIST 1.1 by BICR; the secondary endpoint is OS. Additional endpoints include ORR, safety, correlation of biomarkers with outcomes, and pharmacokinetics of C in combination with N+I. The first patient was enrolled in June 2019 and enrollment is ongoing. Clinical trial information: NCT03937219.

Phase II trial of cytoreductive stereotactic hypofractionated radiotherapy with combination ipilimumab/nivolumab for metastatic kidney cancer (CYTOSHRINK).

TPS761 Background: Randomized data from the interferon era demonstrated modest survival benefits of cytoreductive nephrectomy (CN) in patients with advanced renal cell carcinoma (aRCC). Results from SURTIME and CARMENA, conducted in the VEGF-targeted therapy era, have challenged the routine use of upfront CN especially in IMDC intermediate and poor risk patients. Furthermore, the treatment landscape in aRCC now includes first-line combination immunotherapy. Data from the Checkmate-214 trial showed that intermediate/poor risk patients have improved overall survival and objective response rate with ipilimumab and nivolumab (I/N) compared to sunitinib. Stereotactic body radiation therapy (SBRT) provides a convenient method for cytoreduction of the primary kidney lesion and may induce an ‘abscopal effect’, leading to enhanced systemic anti-tumour immune response. We hypothesize that SBRT to the primary kidney mass in aRCC patients will enhance the efficacy of I/N compared to standard of care I/N alone. Methods: This phase II trial randomizes untreated aRCC patients in a 2:1 fashion to I/N plus SBRT (30-40 Gy in 5 fractions) to the primary kidney mass between cycles 1 and 2 (experimental arm, E), versus standard of care I/N alone (standard arm, S). Eligible patients have biopsy-proven aRCC (any histology), IMDC intermediate/poor risk disease, and who decline or are unsuitable for CN. Patients with a primary kidney lesion ≥ 20cm, previous abdominal radiation precluding SBRT, or who have a contraindication to I/N are excluded. The primary objective is to compare the efficacy of I/N plus SBRT versus I/N alone, as determined by the hazard ratio for progression free survival (PFS). Secondary objectives include evaluation of safety, overall survival, objective response rate, and health-related quality of life. Exploratory analyses include blood immune signatures and stool microbiome. Up to 78 patients will be enrolled under the assumption of an improved 12-month PFS from 50% (S) to 75% (E), using a two-sided α=0.1, power=80%, and accounting for loss-to-follow-up and stratification using IMDC criteria 1-2 vs 3-6. Clinical trial information: NCT04090710.

950P - Association between depth of response and overall survival: Exploratory analysis in patients with previously untreated advanced renal cell carcinoma (aRCC) in CheckMate 214

950P - Association between depth of response and overall survival: Exploratory analysis in patients with previously untreated advanced renal cell carcinoma (aRCC) in CheckMate 214

Safety and efficacy of nivolumab plus ipilimumab (NIVO+IPI) in patients with advanced renal cell carcinoma (aRCC) with brain metastases: Interim analysis of CheckMate 920.

4517 Background: Previous clinical trials of patients (pts) with aRCC, including CheckMate 214, have mostly excluded pts with brain metastases. However, antitumor activity in pts with brain metastases has been observed in pts with melanoma treated with NIVO 1 mg/kg + IPI 3mg/kg and pts with non-small cell lung cancer treated with NIVO 240 mg + IPI 1mg/kg. CheckMate 920 is an ongoing, phase 3b/4 clinical trial of NIVO + IPI treatment in pts with aRCC with a high unmet medical need. Here, we present the safety and efficacy interim results for the cohort of pts with brain metastases. Methods: Pts with previously untreated aRCC of any histology, with asymptomatic brain metastases (not on corticosteroids or receiving radiation), and Karnofsky performance status ≥70% were assigned to treatment with NIVO 3 mg/kg + IPI 1 mg/kg every 3 weeks for 4 doses, followed by NIVO 480 mg every 4 weeks. Pts were treated until disease progression, unacceptable toxicity, or for a maximum of 2 years. The primary endpoint was the incidence of high-grade immune-mediated adverse events (IMAEs). Key secondary endpoints included progression-free survival (PFS) and objective response rate (ORR) by RECIST v1.1 per investigator. Exploratory endpoints included additional safety analyses and overall survival (OS). Results: Overall, 28 patients were enrolled in the brain metastases cohort. With a minimum follow-up of 6.47 months, grade 3-4 IMAEs within 100 days of last dose were reported in 6 cases. The grade 3-4 IMAEs observed in ≥ 1 patient were diarrhea, colitis, diabetic ketoacidosis, immune-mediated hepatitis, hypophysitis, and rash of any type (n = 1 each). No treatment-related grade 5 IMAEs were reported. ORR by RECIST v1.1 per investigator in all treated subjects was 28.6% (95% CI 13.2–48.7). Median PFS in all treated subjects was 9.0 months (95% CI 2.9–not estimable [NE]). Median OS has not been reached (95% CI 13.1–NE). Conclusions: In pts with aRCC and brain metastases who are often excluded from clinical trials, NIVO + IPI treatment showed a safety profile consistent with previous reports of this dosing regimen, with encouraging antitumor activity. Clinical trial information: NCT02982954.

Clinical and economic outcomes associated with sequential treatment in patients with advanced renal cell carcinoma (aRCC).

4566 Background: Immuno-oncology therapies (IOs) and tyrosine kinase inhibitors (TKIs) are recommended for the treatment of aRCC. As new drugs and combination regimens emerge, there is interest in gaining a deeper understanding of optimal treatment sequencing. We aimed to assess clinical and economic outcomes associated with treatment sequences for untreated aRCC patients with IMDC intermediate/poor risk. Methods: A discrete event simulation model was developed to estimate the total costs and survival (in life-years; LYs) over patients’ lifetimes when receiving sequential treatment with nivolumab + ipilimumab (N+I), sunitinib (SUN), pazopanib (PAZ), or cabozantinib (CAB) as first-line (1L) treatment, and nivolumab (NIVO), axitinib (AXI), PAZ, CAB, or lenvatinib + everolimus (LEN+EVE) as second line (2L). Efficacy inputs were derived from the CheckMate 214 trial and a network meta-analysis based on available literature. Safety and cost data were obtained from literature and publicly available sources. Results: N+I initiating sequences were estimated to provide longer survival in mean LYs and lower mean costs/LY versus sequences with 1L TKIs (table). The estimates of incremental cost-effectiveness ratio (ICER) for N+I initiating sequences with 2L TKI monotherapy were well below the willingness-to-pay threshold of $50,000. Using 2L LEN+EVE, compared with 2L monotherapies, provided an incremental survival gain but at costs/LY close to $100,000. Conclusions: Use of 1L N+I followed by TKI monotherapy is estimated to provide longer survival while being more cost-effective versus TKIs followed by IOs or sequences cycling TKIs, mainly driven by a longer time to 2L treatment and longer treatment-free survival with N+I. Clinical trials with head-to-head comparisons of treatment sequences would be necessary to validate the findings of the study. [Table: see text]

Subgroup analysis from JAVELIN Renal 101: Outcomes for avelumab plus axitinib (A + Ax) versus sunitinib (S) in advanced renal cell carcinoma (aRCC).

544 Background: In the ongoing phase 3 JAVELIN Renal 101 trial, progression-free survival (PFS) was longer (median, 13.8 vs 8.4 mo; hazard ratio, 0.69; p=0.0001) and the objective response rate (ORR) was higher (51% vs 26%) with A + Ax vs S in patients with previously untreated aRCC. Here we report outcomes from an analysis of several prespecified subgroups. Methods: Patients were randomized 1:1 to receive A (10 mg/kg) IV every 2 weeks + Ax (5 mg) PO twice daily or S (50 mg) PO once daily for 4 wk (6-wk cycle). Primary and key secondary endpoints were PFS per independent review committee (IRC; RECIST v1.1) and OS in patients with PD-L1+ tumors (≥1% of immune cells) and in patients irrespective of PD-L1 expression; other secondary endpoints included OR per IRC (RECIST v1.1). Results: A total of 886 patients were randomized; 560 (63%) had PD-L1+ tumors. At data cut-off (Jun 2018), median follow-up was 12.0 vs 11.5 mo for A + Ax vs S groups. The table shows PFS and ORR by MSKCC and IMDC risk groups (F, favorable; I, intermediate; P, poor) and PD-L1 subgroup. Similar results for prognostic risk were seen in patients with PD-L1+ tumors. Outcome data (including PFS2) for additional clinical subgroups by baseline demographics and features will be presented. Clinical trial information: NCT02684006. Conclusions: A + Ax demonstrated PFS and OR benefit across all prognostic risk groups and PD-L1 subgroups vs S in aRCC.[Table: see text]

Treatment-free survival (TFS) after discontinuation of first-line nivolumab (NIVO) plus ipilimumab (IPI) or sunitinib (SUN) in intention-to-treat (ITT) and IMDC favorable-risk patients (pts) with advanced renal cell carcinoma (aRCC) from CheckMate 214.

564 Background: TFS characterizes the antitumor activity of immuno-oncology agents after treatment discontinuation. In CheckMate 214, pts with IMDC intermediate/poor-risk aRCC who discontinued first-line NIVO+IPI experienced significantly longer TFS than those who discontinued SUN (McDermott et al, ESMO 2018). Here, we continue the analysis of TFS from CheckMate 214 in ITT and IMDC favorable-risk pts. Methods: Pts with previously untreated, predominantly clear cell aRCC were randomized 1:1 to intravenous NIVO 3 mg/kg + IPI 1 mg/kg every 3 weeks for 4 doses followed by NIVO 3 mg/kg every 2 weeks, or oral SUN 50 mg daily for 4 weeks on, 2 weeks off (6-week cycles). TFS was defined as the time from protocol therapy cessation to the start of subsequent systemic anticancer therapy or death, whichever occurred first. TFS in pts who discontinued NIVO+IPI or SUN was compared using Kaplan–Meier methods and log-rank tests. This analysis was conducted for all ITT (NIVO+IPI, 550; SUN, 546) and IMDC favorable-risk (NIVO+IPI, 125; SUN, 124) pts in CheckMate 214. Results: Among 463 NIVO+IPI and 477 SUN ITT pts who discontinued protocol therapy, the median TFS was 3.0 months with NIVO+IPI vs 1.3 months with SUN (HR [95% CI]; 0.54 [0.46–0.62]; P&lt;0.0001); the TFS rates 2 years post-discontinuation were 21% vs 7%, respectively. In IMDC favorable-risk pts, 111 and 94 pts discontinued from NIVO+IPI and SUN, respectively. TFS in IMDC favorable-risk pts was also significantly longer with NIVO+IPI vs SUN (median, 6.3 vs 1.1 months; HR [95% CI]; 0.47 [0.34–0.65]; P&lt;0.0001). The TFS rates 2 years post-discontinuation in favorable-risk pts were 29% for NIVO+IPI vs 13% for SUN. Conclusions: Similar to the TFS benefit seen in intermediate/poor-risk pts with aRCC, first-line therapy with NIVO+IPI resulted in reduced need for second-line therapy in ITT and IMDC favorable-risk pts compared with SUN. The durable TFS benefit across risk groups despite discontinuation of therapy provides further evidence of the encouraging benefit-risk profile of NIVO+IPI over SUN in pts with previously untreated aRCC. Clinical trial information: NCT02231749.

The Evolving Landscape of Immunotherapy-Based Combinations for Frontline Treatment of Advanced Renal Cell Carcinoma.

Insights into the biology of advanced renal cell carcinoma (aRCC) and the development of agents targeting the vascular endothelial growth factor (VEGF) pathway have positively impacted the outcomes for patients with aRCC. With the recent approval of the dual immune checkpoint inhibitors (ICIs), nivolumab and ipilimumab, by the U.S. Food and Drug Administration (USFDA), and the European Medicines Agency (EMA), the era of VEGF monotherapy for untreated aRCC appears to be coming to an end for patients with access to the combination therapy. The frontline treatment options for renal cell carcinoma are evolving rapidly and will lead to the approval of other combination immunotherapies—especially those with VEGF inhibitors. Here we review the clinical data for dual immune checkpoint inhibition with nivolumab plus ipilimumab as well as the emerging data for ICI plus VEGF inhibitor combinations and discuss the challenges these will pose for the clinical practitioner.

Nivolumab in Renal Cell Carcinoma: Current Trends and Future Perspectives.

Targeted agents form the backbone of most therapeutic strategies in advanced renal cell carcinoma (aRCC) but ultimately resistance develops and toxicity often leads to discontinuation of treatment, limiting the clinical benefits of these treatments. Nivolumab, a fully human IgG4 anti-PD-1 antibody, selectively blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2 and provides a novel therapy option for patients with aRCC. In 2015, the pivotal phase III study CheckMate 025 led to the Food and Drug Administration approval of nivolumab in patients with aRCC who had received prior anti-angiogenic therapy, and in 2017, the phase III study CheckMate 214 showed that combined immunotherapy with nivolumab plus ipilimumab resulted in greater objective response rate and prolonged progression-free survival when compared with sunitinib in intermediate- and poor-risk patients with previously untreated aRCC. Early studies of nivolumab in association with anti-angiogenic therapy have generated enthusiasm and multiple combination trials are ongoing.