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4501
Background: Dysregulated metabolism is a hallmark of RCC, driven by overexpression of glutaminase (GLS), a key enzyme of glutamine metabolism. Telaglenastat (Tela) is an ...investigational, first-in-class, selective, oral GLS inhibitor that blocks glutamine utilization and critical downstream pathways. Preclinically, Tela synergized w/ cabozantinib (Cabo), a VEGFR2/MET/AXL inhibitor, against RCC tumors. In a Ph 1 study cohort, Tela+Cabo showed encouraging safety/efficacy as 2L+ therapy for mRCC. This trial compared Tela+Cabo vs Pbo+Cabo in previously treated pts w/ clear-cell mRCC (NCT03428217). Methods: Eligible pts had 1-2 prior lines of systemic therapy for mRCC, including ≥1 anti-angiogenic therapy or nivolumab + ipilimumab (nivo/ipi), KPS ≥70%, measurable disease (RECIST 1.1), no prior Cabo or other MET inhibitor. Pts were randomized 1:1 to receive Cabo (60 mg PO QD) with either Tela (800 mg PO BID) or Pbo, until disease progression/unacceptable toxicity, and were stratified by prior PD-(L)1 inhibitor therapy (Y/N) and IMDC prognostic risk group. Primary endpoint was progression-free survival (PFS; RECIST 1.1) by blinded independent radiology review. The study was designed to detect a PFS hazard ratio (HR) of 0.69 w/ alpha 0.05 and 85% power. Data cutoff date: August 31, 2020. Results: 444 pts were randomized (221 Tela+Cabo; 223 Pbo+Cabo). Baseline characteristics were balanced between arms. Median follow-up was 11.7 mo; 276 pts received prior ICI, including 128 w/ prior nivo/ipi. Median PFS (mPFS) was 9.2 mo for Tela+Cabo vs 9.3 mo for Pbo+Cabo (HR = 0.94; 95% CI: 0.74, 1.21; stratified log-rank P= 0.65) with overall response rates (ORR; confirmed) of 31% with Tela+Cabo vs 28% Pbo+Cabo, respectively. Overall survival was not mature at data cutoff. In a prespecified subgroup analysis in pts w/ prior ICI, mPFS was numerically longer w/ Tela+Cabo than Pbo+Cabo (11.1 vs 9.2 mo, respectively; unstratified HR = 0.77; 95% CI: 0.56, 1.06). In the Pbo+Cabo arm, mPFS was 9.2 mo for pts w/ prior ICI exposure and 9.5 mo for pts without, and ORR was 32% and 20%, respectively; if ICI included nivo/ipi, ORR was 37%. Rates of adverse events (AEs) were similar between arms.Grade 3-4 AEs occurred in 71% of Tela+Cabo pts and 79% of Pbo+Cabo pts and included hypertension (17% vs 18%) and diarrhea (15% vs 13%). Cabo was discontinued due to AEs in 10% of Tela+Cabo pts and 15% of Pbo+Cabo pts. Conclusions: The addition of Tela did not improve the efficacy of Cabo in mRCC in this study. Tela+Cabo was well tolerated with AEs consistent with known risks of both agents. The study provides valuable insight on efficacy outcomes of a contemporary population of pts w/ mRCC who receive Cabo in the 2/3L setting. Clinical trial information: NCT03428217.
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4520
Background: In the phase 3 JAVELIN Bladder 100 trial, avelumab 1L maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) vs BSC alone in patients ...(pts) with advanced UC that had not progressed on 1L platinum-based chemotherapy (HR, 0.69 95% CI: 0.56, 0.86; 1-sided P= 0.0005). We report post hoc analyses in previously unreported clinical and genomic subgroups. Methods: In JAVELIN Bladder 100 (NCT02603432), eligible pts had unresectable locally advanced or metastatic UC without progression after 4-6 cycles of 1L gemcitabine + cisplatin or carboplatin, and were randomized to receive avelumab + BSC (n = 350) or BSC alone (n = 350). The primary endpoint was OS, in all randomized pts and pts with PD-L1+ tumors (Ventana SP263 assay). In this exploratory analysis, we analyzed OS in disease stage and site subgroups, in pts with PD-L1+ tumors who received 1L gemcitabine + carboplatin, and in genomic subtypes (RNAseq whole-transcriptome profiling of tumor tissue) defined using data from The Cancer Genome Atlas (TCGA 2017). Interaction tests were not performed. Results: Prolonged OS was observed in the avelumab + BSC arm vs the BSC alone arm in pts with upper or lower tract tumors, metastatic or locally advanced (LA) and unresectable disease (prior to chemotherapy), and lymph node-only disease post-chemotherapy (Table). OS was also prolonged with avelumab + BSC in pts in PD-L1+ tumors who had received 1L gemcitabine + carboplatin, consistent with findings in the overall population. In genomic subtypes, the OS benefit for avelumab + BSC was apparent across TCGA subtypes except luminal. Conclusions: An OS benefit was seen for avelumab 1L maintenance + BSC vs BSC alone across subgroups of interest. Results are consistent with previously reported findings, further supporting avelumab 1L maintenance as a standard of care for pts with advanced UC that has not progressed with 1L platinum-containing chemotherapy. Clinical trial information: NCT02603432. Table: see text
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4556
Background: Simlukafusp α (SIM, FAP-IL2v) is a novel IL-2v immunocytokine engineered to preferentially activate effector CD8 T and NK cells, but not regulatory T cells (Tregs), due ...to abolished binding to Interleukin-2 receptor α (IL-2Rα) and retained affinity to IL-2Rβγ. High affinity binding of SIM to fibroblast activation protein (FAP), expressed on cancer-associated fibroblasts, mediates its accumulation in malignant lesions. Methods: The Dose-Escalation (DE) consisted of: Arm A: SIM 5-25 mg weekly for 4 weeks, and every 2 weeks (Q2W) thereafter in combination with atezolizumab ATZ 840mg Q2W; and Arm B: same as Arm A + bevacizumab BEV 10 mg/kg Q2W. Patients (pts) not previously treated were evaluated in the Extension Part: Arm C (n=3): SIM + ATZ every 3 weeks (Q3W); or Arm D (n=25): SIM + ATZ + BEV (“triplet”) Q3W. Primary objectives were: finding the recommended dose of SIM and assessment of objective response rate (ORR) by RECIST v1.1. Results: We enrolled 69 pts with unresectable advanced/ metastatic clear-cell and/or sarcomatoid RCC. Median age of patients was 57 years (range: 35-78). The recommended dose for extension of SIM was 10 mg. Median treatment duration in days in each arm were: A: 106 (range: 1-877); B: 324 (8-940); C: 659 (71-768); D: 437 (1-682). Twenty-five pts are evaluable for therapeutic activity in Arm A ORR: 24% (6 PR; 90% CI 12.95, 40.12); 15 in Arm B 46.7% (1 CR, 6PR; 90% CI 27.67, 66.68); 3 in Arm C 33.3% (1PR; 90% CI 7.83, 74.65); and 23 in Arm D 47.8% (2 CR, 9 PR; 90% CI 35.74, 68.15). Twelve patients are ongoing on study treatment. Treatment related grade 3 and 4 adverse events (AE) occurred respectively in 69.7% and 9.1% patients. The most common serious AEs were pyrexia (10.6 %) and infusion-related reactions (9.1%). 65.2% Of the patients reported at least one AE of elevations in liver transaminases/GGT/ alkaline phosphatase/bilirubin. Drug-related AEs led to dose modification/interruption in 37.9 % of the pts, and treatment discontinuation in 3% of the patients. SIM led to preferential expansion and activation of NK and CD8 T cells (but not Tregs) in peripheral blood and augmented tumor infiltration and tumor inflammation. Intriguingly responses were observed not only in pts with PD-L1 positive or inflamed tumors, but also in pts with PD-L1 negative tumors (n=13) or poorly infiltrated tumors classified as immune deserts (n=2). Conclusions: The combination of SIM with ATZ ± BEV was feasible with an acceptable safety profile. Clinical activity was more favorable for the triplet among the study Arms, but comparable to the ATZ + BEV combination in the IMmotion151 (Rini B, et al 2019). Observed pharmacodynamic findings were consistent with the expected effects. Clinical trial information: NCT03063762.
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4500
Background: In the first interim analysis of the randomized, multicenter, open-label, phase 3 KEYNOTE-426 study (NCT02853331), treatment with pembro + axi significantly improved ...OS, PFS, and ORR vs sunitinib monotherapy in treatment-naive advanced ccRCC. Extended follow-up (median, 30.6 mo) continued to demonstrate the superior efficacy of pembro + axi vs sunitinib monotherapy in this patient population. Here, we present the results of the prespecified final analysis with 42.8-mo median follow-up. Methods: Treatment-naive patients (pts) with advanced ccRCC, KPS ≥70%, and measurable disease (RECIST v1.1) were randomly assigned 1:1 to receive pembro 200 mg IV Q3W for up to 35 doses + axi 5 mg orally BID or sunitinib 50 mg orally QD on a 4-wk on/2-wk off schedule until progression, intolerable toxicity, or withdrawal. Randomization was stratified by IMDC risk (favorable vs intermediate vs poor) and geographic region (North America vs Western Europe vs Rest of World). Dual primary endpoints were OS and PFS. Secondary endpoints were ORR, DOR, and safety. The protocol-specified final analysis was based on a target of 404 OS events. No formal hypothesis testing was performed because all efficacy endpoints were met previously at the first interim analysis; nominal P values are reported. Results: Overall, 861 pts were randomly assigned to receive pembro + axi (n=432) or sunitinib (n=429). Median duration of follow-up, defined as time from randomization to the database cutoff date, was 42.8 mo (range, 35.6-50.6). At data cutoff, 418 pts had died: 193 (44.7%) of 432 pts in the pembro + axi arm vs 225 (52.4%) of 429 pts in the sunitinib arm. Compared with sunitinib, pembro + axi improved OS (median: 45.7 vs 40.1 mo; HR, 0.73 95% CI, 0.60-0.88; P<0.001) and PFS (median: 15.7 vs 11.1 mo; HR, 0.68 95% CI, 0.58-0.80; P<0.0001). The 42-mo OS rate was 57.5% with pembro + axi vs 48.5% with sunitinib; the 42-mo PFS rate was 25.1% with pembro + axi vs 10.6% with sunitinib. For pembro + axi vs sunitinib, ORR was 60.4% vs 39.6% ( P<0.0001); CR rate was 10.0% vs 3.5%; median DOR was 23.6 mo (range 1.4+ to 43.4+) vs 15.3 mo (range, 2.3-42.8+). Subsequent anticancer therapy was administered to 47.2% of pts in pembro + axi arm vs 65.5% of pts in sunitinib arm. Although a similar proportion of pts in each arm received VEGF/VEGFR inhibitors, only 10.2% of pts in the pembro + axi arm received subsequent treatment with a PD-1/L1 inhibitor compared to 48.7% of pts in the sunitinib arm. No new safety signals were observed. Conclusions: With a median follow-up of 42.8 mo, this is the longest follow-up of an anti-PD–1/L1 immunotherapy combined with a VEGF/VEGFR inhibitor for first-line RCC. These results show that pembro + axi continues to demonstrate superior efficacy over sunitinib with respect to OS, PFS, and ORR, with no new safety signals. Clinical trial information: NCT02853331.
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4553
Background: First-line N+C significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) vs S in aRCC patients (pts) in the phase ...3 CheckMate 9ER trial, leading to FDA approval of N+C in this setting. A deeper understanding of how baseline disease characteristics may impact clinical outcomes with N+C vs S may inform clinical decision making. Methods: Pts with clear cell aRCC were randomized to N 240 mg IV Q2W + C 40 mg PO QD vs S 50 mg PO QD (4 weeks of 6-week cycles). In this post hoc exploratory analysis, PFS, OS, and ORR were evaluated across pt subgroups defined by baseline IMDC risk status, organ sites of metastases (mets), number of organs with any lesions, or target lesion size. Consistent with primary/secondary efficacy endpoints in ITT pts, PFS and ORR were evaluated per RECIST v1.1 by blinded independent central review in subgroups. Results: Median follow-up in ITT pts was 23.5 months. PFS, OS, and ORR (including complete response CR) outcomes are summarized in the table across subgroups: IMDC risk (favorable FAV, intermediate I, poor P); number of organs with ≥ 1 target/nontarget lesion (T/NT; 1 and ≥ 2); sum of diameters of target lesions (sDTL; < and ≥ median 72.1 mm), and in pts with liver, bone, or lung mets. The PFS HR favored N+C vs S and median (m) PFS was longer with N+C vs S across all subgroups. The OS HR also favored N+C vs S across most subgroups. ORR ranged from 38%–66% (N+C) vs 10%–44% (S) across subgroups, and CR benefits were seen with N+C in most subgroups. Additional outcomes including landmark OS and response details in subgroups will be reported. Conclusions: Consistent with outcomes in ITT pts, efficacy benefits with N+C vs S were observed regardless of IMDC risk status, organ site of mets, or extent of tumor burden at baseline. These results support N+C as a new first-line treatment option for pts with aRCC. Clinical trial information: NCT03141177. Table: see text
Kidney cancer is a major urological disease globally, with more than 400 000 new cases diagnosed every year.
To investigate incidence and mortality trends for kidney cancer and their associations ...with modifiable risk factors for kidney cancer.
The most up-to-date figures on kidney cancer incidence and mortality were collected from the GLOBOCAN database and the Cancer Incidence in Five Continents (CI5). Data on total alcohol consumption and the prevalence of smoking, overweight, diabetes, and hypertension were extracted from the World Health Organization Global Health Observatory data repository.
Age-standardized rates (ASRs) for incidence and mortality and their correlations with potential risk factors for kidney cancer were investigated. Multivariable linear regression analysis was also conducted. The 10-yr temporal patterns for incidence are presented as the average annual percent change with 95% confidence interval using joinpoint regression analysis.
Globally, there is wide variation in kidney cancer incidence and mortality. There were positive correlations between rates of smoking, alcohol consumption, and overweight and ASRs of kidney cancer incidence and mortality. Multivariable regression analysis revealed that alcohol consumption and overweight were significant risk factors for kidney cancer incidence, while smoking and alcohol consumption were significant risk factors for kidney cancer mortality. There was an increasing trend for the incidence of kidney cancer globally, with a particularly prominent trend for European countries. Of note, increasing incidence of kidney cancer is evident even for younger individuals aged <50 yr. However, cancer registries vary by country and period and there is a lack of data regarding the severity of risk factors and disease characteristics such as the distribution of histological groups, tumor grading, and staging.
There is an increasing trend for kidney cancer incidence globally, particularly in European countries and the younger population. Modifiable risk factors for kidney cancer incidence and mortality have been identified. The increasing incidence of kidney cancer among younger individuals is worrying and warrants early action on possible preventive measures.
The incidence of kidney cancer has been increasing globally, particularly in European countries and the younger population. Risk factors include smoking, alcohol consumption, overweight, and hypertension, and these factors are all modifiable.
The incidence of kidney cancer has been increasing globally, particularly in European countries and the younger population. Risk factors include smoking, alcohol consumption, overweight, and hypertension, and these factors are all modifiable.
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e16004
Background: The effect of prior immune checkpoint inhibition therapy (CI) on the efficacy of subsequent chemotherapy is largely unknown in MUC. The identification of the optimal ...sequence of chemotherapy and IO is yet to be determined, but may influence outcomes. Methods: A retrospective audit and comparison of patients who progressed after first and second line CI and received subsequent standard chemotherapy was performed. Date was collected across a broad spectrum of CI. We report on patient’s characteristics and response rates of 28 sequential patients collected from two institutions who received chemotherapy after CI. Patients were separated into 2 cohorts. Cohort A had not previously received chemotherapy (n = 14), cohort B had previously received at least 1 chemotherapy regimen (n = 14). Central radiology review was performed. We assessed objective response rate by RECIST v 1.1. Kaplan Meier method was used. Results: Median age for the whole cohort was 64 yrs (45-80). ECOG was 0/1 in 89,3% and 2 in 10,7% at the time of starting chemotherapy. The commonest chemotherapy regimen in cohort A and B were carboplatin-gemcitabine (71%) and carboplatin paclitaxel (50%) respectively. 75% of the patients were intermediate risk group. In Cohort A 63% responded to chemotherapy whereas in cohort B only 3 patients showed response. The median change in target lesions in the front line immunotherapy cohort was -60% (-81 to +1%). Both patients who responded to 2
nd
line chemotherapy after CI had a long interval between first and 2
nd
line chemotherapy (9-24 months). Conclusions: Chemotherapy maintains its efficacy after front line CI with deep responses. Although numbers are modest, results strongly suggest patients should be offered chemotherapy in this setting.
First-line (1L) maintenance avelumab prolonged overall survival (OS) in patients with advanced urothelial carcinoma (aUC) in JAVELIN Bladder 100. OS was measured from maintenance initiation in ...patients with disease control following 1L platinum-based therapy (PBT). The OS impact of maintenance for the 1L PBT-treated population is unknown since it was not measured from 1L initiation, nor can it be benchmarked with other 1L therapies. To characterize the OS impact of maintenance avelumab, we used an oncology simulation model to estimate the OS of maintenance-eligible and -ineligible patients with aUC from 1L PBT initiation.
We developed a simulated cohort of 1L PBT-treated patients with aUC, including those who did and did not receive maintenance avelumab. Eligibility was assessed at 5.6 months post 1L PBT initiation based on the JAVELIN trial design. Among the 1L-treated population, 58% (95% credible interval CrI 49-67%) were projected to be eligible (calculated from contemporary phase 3 trials); of those, 85% were assumed to receive maintenance. The model estimated median OS (mOS) among a maintenance-ineligible simulated cohort which when combined with the maintenance-eligible cohort yielded an estimated OS in the overall maintenance- intended population from 1L PBT initiation.
Approximately half of the modeled 1L PBT-treated population received maintenance. Estimated mOS was 10.1 months (95% CrI 7.5-13.5) for the maintenance-ineligible cohort, 29.3 months (95% CrI 24.8-33.9) for the maintenance-eligible, received maintenance cohort, and 15.9 months (95% CrI 13.2-19.1) in the overall maintenance-intended, 1L PBT-treated population, including those eligible and ineligible for maintenance.
The model shows that maintenance avelumab has a modest impact on OS in the overall 1L PBT-treated population of patients with aUC. While maintenance avelumab improves OS for eligible patients, a large proportion of the maintenance-intended population may not receive maintenance due to ineligibility or physician/patient choice.
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429
Background: Patients (pts) with advanced UTC who fail first-line therapy have poor prognoses. Durvalumab (D; anti-PD-L1) 10 mg/kg every 2 weeks is approved for treatment of ...metastatic urothelial carcinoma (mUC) after progression on platinum-based chemotherapy (CT). Further understanding of long-term safety and efficacy of D in platinum and non-platinum pretreated pts, using a fixed dose every 4 weeks (Q4W), is of value. Methods: Module A of the phase IIIb STRONG study (NCT03084471) investigated the safety of fixed-dose D (1500 mg, Q4W) in pts with urothelial and nonurothelial UTC who progressed on or after platinum/non-platinum CT. The primary endpoint was the number of pts with adverse events of special interest (AESIs) – events with an inflammatory or immune-mediated mechanism that may require interventions (eg, steroids/immunosuppressants), including immune-mediated adverse events (imAE). AEs with onset date on or after the date of first dose and up to 90 days after study discontinuation were included. Secondary endpoints included serious AEs and overall survival (OS). Exploratory endpoints included objective response rate (ORR) and disease control rate (DCR) (investigator assessed per RECIST 1.1). Results: A total of 867 pts received D monotherapy. Median age was 68.1 yr and 80.0% were male; 87.1% had an ECOG PS 0-1 and 12.7% had ECOG PS 2. Most (96.3%) had urothelial UTC, including urothelial variants. Tumor PD-L1 expression was high (≥25%) in 239/577 (41.4%) pts with available data. Median treatment and follow-up duration were 12.1 wk (range 1-128) and 13.8 mo (range 0.0-28.8), respectively. Safety data are reported in the table. Deaths related to study treatment occurred in 9 pts (1.0%). At data cutoff (March 31, 2020), 30.8% of pts were in survival follow-up. Median OS was 7.0 mo (95% CI: 6.4-8.2); OS rate at 1 and 2 yr was 35.8% (95% CI: 32.5-39.2) and 20.2% (95% CI: 16.5-24.1), respectively. ORR was 17.7% with complete responses in 5.1% of pts. DCR at 6 mo was 33.0%. Median OS of subgroups: PD-L1 high or low: 9.3 mo (95% CI: 6.7-12.7) and 6.5 mo (95% CI: 5.8-8.1); ECOG PS 0-1 or 2: 8.4 mo (95% CI: 7.2–9.8) and 3 mo (95% CI: 2.0-4.1); urothelial and nonurothelial UTC: 7.0 mo (95% CI: 6.4-8.2) and 7.0 mo (95% CI: 2.7-10.2), respectively. Conclusions: Fixed-dose D monotherapy Q4W is convenient with an acceptable safety profile in previously treated pts for UTC. Long-term safety and efficacy data reported are consistent with published studies of D and other IO agents in this setting. Clinical trial information: NCT03084471 . Table: see text
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313
Background: First-line NIVO+IPI demonstrates superior survival and response benefits in intent-to-treat (ITT) patients (pts) with aRCC after long-term follow-up in the phase 3 ...CheckMate 214 trial. Data are scarce on tumor relapse and patterns of disease progression with immuno-oncology agents in this setting. This exploratory analysis of CheckMate 214 characterizes patterns of progression with NIVO+IPI vs SUN with 4 years minimum follow-up. Methods: Pts with clear cell aRCC were randomized to NIVO+IPI Q3W×4 followed by NIVO monotherapy Q2W, or SUN QD×4 weeks (6-week cycle). Patterns of progression were characterized in ITT pts and analyzed post hoc using descriptive statistics. Progression patterns were defined by ≥ 20% target lesion growth (T), unequivocal progression of nontarget lesions (NT), and new lesion(s) (NL). Response and progression were assessed per independent radiology review committee via RECIST v1.1. Results: Radiographic progression (RP) was documented in 299/550 (54.4%) ITT pts with NIVO+IPI vs 289/546 (52.9%) with SUN. Among ITT pts with a confirmed response (objective response = 215/550 39.1%, NIVO+IPI vs 177/546 32.4%, SUN), 71/215 (33.0%) vs 84/177 (47.5%) pts experienced post-response RP with NIVO+IPI vs SUN; 8/59 (13.6%) vs 3/14 (21.4%) progressed after complete response, and 63/156 (40.4%) vs 81/163 (49.7%) progressed after partial response, respectively. The pattern of RP differed between arms (Table). With NIVO+IPI, 106/299 (35.5%) RPs resulted from NL only vs 74/289 (25.6%) with SUN, and this differential was more pronounced in pts with an initial confirmed response (36/71 50.7% vs 23/84 27.4%). Most NL-only RPs in initial responders occurred in a single organ (34/36 94.4% for NIVO+IPI; 20/23 87.0% for SUN) with the most common being lymph nodes (11/34 32.4%), brain (8/34 23.5%), and lung (5/34 14.7%) with NIVO+IPI, and lymph nodes (7/20 35.0%), brain (4/20 20.0%) and adrenal gland (3/20 15.0%) with SUN. Additional progression details, baseline characteristics, and key efficacy outcomes in progressors will be reported. Conclusions: Differential patterns of tumor relapse and disease progression were observed after long-term follow up of patients treated with NIVO+IPI vs SUN in CheckMate 214. NL-only progression occurred more often with NIVO+IPI vs SUN, in particular in the subset of pts who progressed post-response. These patterns may have therapeutic implications. Clinical trial information: NCT02231749 . Table: see text
