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4513
Background: Patients (pts) with advanced renal cell carcinoma with sarcomatoid features (sRCC) have poor prognosis and suboptimal outcomes with anti-VEGF targeted therapy. ...Nivolumab plus ipilimumab (N+I) demonstrated superior objective response rate (ORR) and overall survival (OS) vs sunitinib (S) in previously untreated pts with International Metastatic RCC Database Consortium (IMDC) intermediate/poor (I/P)-risk, clear-cell, advanced RCC in the phase 3 CheckMate 214 trial. Methods: We performed a post-hoc exploratory analysis of N+I vs S in CheckMate 214 sRCC pts. The presence of sarcomatoid features was assessed by keyword search for “sarcomatoid” in pts with available local pathology reports accompanying pretreatment tumor samples. Results: 842 (77%) of 1096 intention-to-treat pts had local pathology reports available, including 112 randomized pts with I/P-risk sRCC (N+I, n = 60; S, n = 52). Baseline characteristics of sRCC pts were balanced between arms. Notably, 47% vs 53% of I/P-risk sRCC pts in the N+I and S arms had tumor PD-L1 expression ≥1% at baseline, which was higher than in all I/P-risk pts (N+I, 26% vs S, 29%). In descriptive analyses performed at a minimum follow-up of 30 months, confirmed ORR and complete response rate per investigator (RECIST v1.1), OS, and progression-free survival (PFS) per investigator were improved with N+I vs S in I/P-risk pts with sRCC (Table). No new safety signals were seen in sRCC pts. Conclusions: In this post-hoc descriptive subgroup analysis of CheckMate 214, N+I demonstrated promising efficacy and prolonged survival vs S, with consistent safety, in previously untreated, I/P-risk, advanced clear-cell RCC with sarcomatoid features. Prospective studies of N+I that include pts with sRCC are ongoing. Clinical trial information: NCT02231749. Table: see text
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4546
Background: Initial results of the phase 2 KEYNOTE-052 (NCT02335424) study led to approval of pembro for cisplatin-ineligible patients (pts) with advanced UC. Updated results ...representing follow-up of over 2 y since last pt enrolled are presented. Methods: Pts had confirmed advanced UC, were cisplatin-ineligible (ECOG PS 2, CrCl ≥30 to ˂60 mL/min, grade ≥2 neuropathy/hearing loss, NYHA Class III heart failure), and received no prior chemotherapy for metastatic disease. Pts received pembro 200 mg IV Q3W until progression, unacceptable toxicity, withdrawal, or 24 mo of therapy, whichever occurred first. Primary end point was confirmed ORR (RECIST v1.1, independent central review). Key secondary end points: duration of response (DOR), overall survival (OS), and safety. Data cutoff was September 26, 2018. Results: Among pts assessed (N = 370), median age was 74 y, 85% had visceral disease, and 30% were PD-L1 positive (combined positive score CPS ≥10). Median follow-up was 11.4 mo (range, 0.1-41.2) for all pts and 29.3 mo (range 7-41.2) for responders. Confirmed ORR was 29% (95% CI, 24-34): complete response, 9% (n = 33); partial response, 20% (n = 73). Median DOR was 30.1 mo (95% CI, 18.1-not reached NR); 67% and 52% of pts had DOR ≥12 and ≥24 mo, respectively. Median OS was 11.3 mo (range 9.7-13.1); 12- and 24-mo OS rates were 47% and 31%, respectively. In pts with CPS ˂10 (n = 251) and ≥10 (n = 110), respectively, confirmed ORR was 20% (95%CI, 16-26) and 47% (95% CI, 38-57). Median DOR for pts with CPS < 10 and ≥10 was 18.2 mo (95% CI, 9.7-NR) and NR (95% CI, 18.1-NR); DOR ≥24 mo was 45% and 57%, respectively. Median OS for pts with CPS < 10 and ≥10 was 9.7 mo (95% CI, 7.6-11.5) and 18.5 mo (95% CI, 12.2-28.5); 24-mo OS rates were 24% and 47% respectively. Treatment-related adverse events (AEs) occurred in 67% of pts. Most common were fatigue and pruritus (18% each); 21% were grade ≥3, including 1 death (myositis). Conclusions: With extended follow-up, pembro continued to elicit clinically meaningful, durable antitumor activity in cisplatin-ineligible pts with advanced UC and was more pronounced in those with PD-L1 expression CPS ≥10. Pembro safety profile was as expected. Clinical trial information: NCT02335424.
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TPS4592
Background: Management of MIBC includes both surgery and systemic therapy. Neoadjuvant, cisplatin-based combination chemotherapy has demonstrated improved pathologic complete ...response (pCR), event-free survival (EFS), and OS compared with radical cystectomy alone. Many patients still develop recurrence, including progression to metastasis. Novel strategies such as combining chemotherapy and immunotherapy in a neoadjuvant setting and consolidating response post cystectomy in the adjuvant setting may improve clinical outcomes. Durvalumab is a selective, high affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. PD-L1 inhibition with durvalumab, in combination with a standard neoadjuvant regimen (G+C), may improve immune-mediated antitumor response and increase the rates of pathologic responses and long-term survival. Methods: NIAGARA (NCT03732677) is a Phase 3, randomized, open-label, multicenter, global study that will enroll ~1050 patients randomized (1:1) to durvalumab and G+C combination (Arm 1) or G+C (Arm 2) as neoadjuvant chemotherapy prior to radical cystectomy. Following radical cystectomy and during adjuvant therapy, patients in Arm 1 will receive durvalumab monotherapy for 8 cycles (8 months); patients in Arm 2 will receive no adjuvant treatment. Patients with resectable MIBC (clinical stage T2N0M0-T4aN0M0) with transitional cell histology planning to undergo a radical cystectomy will be included. Primary endpoints are pCR rates at time of cystectomy following neoadjuvant treatment and EFS. Secondary and exploratory endpoints include proportion of patients who achieve pathologic response <P2 (stages Pa, P1, and carcinoma in situ) at time of cystectomy following neoadjuvant treatment, EFS at 24 months, metastasis-free survival, proportion of patients who undergo cystectomy, and OS at 5 years. Safety, patient-reported outcomes, pharmacokinetics, immunogenicity, and biomarkers will also be assessed. Enrollment opened in Dec 2018. Clinical trial information: NCT03732677.
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4553
Background: BISCAY is a biomarker-directed Ph1b multi-arm platform study exploring the combination of targeted therapies with anti-PD-L1, Durvalumab, in advanced urothelial cancer. ...Methods: Next generation sequencing (NGS) of tumour tissue samples from > 380 patients(pts) was performed using the FoundationOne assay alongside IHC for PD-L1. ct DNA from pts enrolled in trial modules at treatment initiation was profiled using the Guardant Health OMNI platform assessing a panel of 500 genes. For a subset of pts, serial plasma samples were also analysed to monitor early signs of response vs. resistance and changes in ct DNA dynamics using a bespoke NGS panel of 10 genes. Results: To date 149 pts have been actively enrolled across 7 different biomarker selected and unselected treatment modules. Across all screened pts the most prevalent genomic alterations in tumour tissue were TERT promoter (65%), TP53 (59%), KMT2D 21%, KDM6A 21%, with the most common CNV CDKN2A/ B loss (32 %). All enrolled pts tested had detectable ctDNA in plasma. Similar genomic alterations, both frequency and type, were detected in both plasma ctDNA and tumour tissue with high concordance for module specific biomarkers used for patient allocation (80% (8/10) for ATM, BRCA1 and 2). Alterations in putative biomarkers predictive of response to anti-PD-L1, such as HRR/MMR alterations and high bTMB levels ( > 20mut/Mb) were observed in22% and 40% patient plasma samples, respectively. Correlations between biomarkers across modules treatment efficacy have been explored. Conclusions: All pts with advanced bladder cancer enrolled on BISCAY who were plasma profiled had detectable ctDNA; frequencies of genomic alterations (in both tumour tissue and plasma) were comparable to prior published data sets. ctDNA may be an attractive alternative to tissue-based NGS, providing comprehensive dynamic snapshots of genomic landscapes at the start and during therapy, and warrants further prospective investigation in trials.
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TPS42
Background: Cabozantinib (CABO) is an oral receptor tyrosine kinase inhibitor of MET, VEGFR, and TAM family receptors (TYRO3, AXL, and MER). It is approved for patients (pts) with ...RCC after prior therapy with antiangiogenic therapy, and has demonstrated clinical activity in UC. In clinical studies, CABO exposure increased circulating CD8+ T cells and reduced immune-suppressive monocytes and Tregs. In preclinical tumor models, CABO increased MHC class 1 expression on tumor cells and reduced myeloid-derived suppressor cells. CABO may facilitate an immune-permissive tumor environment and may enhance response to immune checkpoint inhibitors. Atezolizumab (ATEZO), an anti-PD-L1 mAb, is approved for: locally advanced/metastatic UC in pts who are cisplatin-ineligible or have disease progression during/following platinum-containing chemo; pts with metastatic NSCLC and disease progression during/following platinum-containing chemo. We present the study design of an ongoing phase 1b study combining CABO with ATEZO in pts with locally advanced/metastatic UC or RCC. Methods: This multicenter, phase 1b, open-label study aims to assess safety, tolerability, preliminary efficacy, and pharmacokinetics of CABO in combination with ATEZO (NCT03170960). The study will enroll pts with advanced UC (bladder, renal pelvis, ureter, urethra) or RCC. It consists of two stages: dose escalation and expansion. In the dose-escalation stage (3+3 design), a recommended CABO dose for the combination will be established. In the expansion stage, four tumor-specific cohorts will be enrolled: 1) pts with UC who have progressed on/after platinum-containing chemo; 2) chemo-naïve pts with UC who are cisplatin ineligible; 3) chemo-naïve pts with UC who are cisplatin eligible; and 4) untreated pts with RCC with clear cell histology; the primary objective is to determine the objective response rate in each cohort. Exploratory objectives include correlation of tumor and plasma biomarkers, and changes in immune cell profiles with clinical outcome. The study has been initiated and enrollment target is 120 pts across the 4 expansion cohorts. Clinical trial information: NCT03170960.
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62
Background: Standard early endpoints are often poor predictors of overall survival (OS) for immunotherapies. There is a need for new intermediate endpoints to support upcoming ...combination studies with immune checkpoint inhibitors. We investigated the predictive performance of on-treatment tumor growth rate (TGR) estimates to predict OS in atezolizumab clinical trials in patients (pts) with metastatic urinary carcinoma (mUC). Methods: Atezolizumab showed durable response, prolonged OS and good tolerability supporting its therapeutic use in mUC (Rosenberg, Lancet 2016; Balar, lancet 2017; Powles, EACR-AACR-SIC 2017). A multivariate model linking baseline patient characteristics and TGR (estimated using time profile of sum of longest diameters (SLD) of target lesions, RECIST 1.1) to OS was developed using phase 2 data (IMvigor210) and validated to predict phase 3 trial (IMvigor211). Results: To estimate TGR, patients needed to have at least one post-baseline measurement: n = 365/429 (85%) in IMvigor210 (102 in cohort 1, 1L cisplatin-ineligible and 263 in cohort 2, prior platinum-treated 2L+) and n = 745/902 treated (83%) in IMvigor211 (prior platinum-treated 2/3L). A lognormal model with independent baseline prognostic factors (alkaline phosphatase, ECOG performance status and number of metastatic sites) and estimated TGR was developed. The model predicted OS distributions in the two IMvigor210 cohorts in all comers as well as by PD-L1 expression on tumor-infiltrating immune cells (IC). In IMvigor211, SLD profiles in atezolizumab and chemotherapy arms crossed at about 40 weeks with more initial shrinkage in chemotherapy-treated pts but slower overall TGR in atezolizumab-treated pts. The IMvigor210 OS model predicted OS hazard ratio (HR) in IMvigor211 in all comers with post-baseline tumor scans (model-predicted HR prediction interval: 0.80 0.70-0.92 vs. 0.74 observed) as well as by IC status: 0.66 0.50-0.87 vs. 0.70 observed in IC23. Conclusions: Model-based TGR is a promising exploratory endpoint and is being investigated to support early decisions in signal-seeking atezolizumab combination trials in mUC.
Sunitinib is widely used as first-line treatment for metastatic clear cell renal cancer (MCRC). No reports are known of treatment after sunitinib failure. As irinotecan, cisplatin, and mitomycin-C ...(IPM) chemotherapy has been reported to influence MCRC after progression on cytokine therapy, we report on the outcome of 11 patients treated with IPM after sunitinib failure.
Eleven patients with progression of disease on sunitinib therapy were treated with 4, monthly cycles of monthly IPM.
Nine out of 11 patients progressed during IPM therapy. The median time to progression was 1.4 months (95% CI: 0.7-2.1 months), while the overall survival was 4.2 months (95% CI: 0.9-2.3). Overall 10 patients have died of progressive renal cancer. One patient had a radiological response to therapy and remains progression free 11 months after treatment. Four of the 10 patients required a dose reduction for grade 3 or 4 toxicities.
IPM alone does not appear to benefit patients with MCRC who previously progressed during sunitinib therapy. The median progression-free survival and overall survival for these patients is short.
Sunitinib and pazopanib are antiangiogenic tyrosine kinase inhibitors (TKI) used to treat metastatic renal cell carcinoma (RCC). However, the ability of these drugs to extend progression-free and ...overall survival in this patient population is limited by drug resistance. It is possible that treatment outcomes in RCC patients could be improved by rationally combining TKIs with other agents. Here, we address whether inhibition of the Ras-Raf-MEK-ERK1/2 pathway is a rational means to improve the response to TKIs in RCC. Using a xenograft model of RCC, we found that tumors that are resistant to sunitinib have a significantly increased angiogenic response compared with tumors that are sensitive to sunitinib in vivo. We also observed significantly increased levels of phosphorylated ERK1/2 in the vasculature of resistant tumors, when compared with sensitive tumors. These data suggested that the Ras-Raf-MEK-ERK1/2 pathway, an important driver of angiogenesis in endothelial cells, remains active in the vasculature of TKI-resistant tumors. Using an in vitro angiogenesis assay, we identified that the MEK inhibitor (MEKI) trametinib has potent antiangiogenic activity. We then show that, when trametinib is combined with a TKI in vivo, more effective suppression of tumor growth and tumor angiogenesis is achieved than when either drug is utilized alone. In conclusion, we provide preclinical evidence that combining a TKI, such as sunitinib or pazopanib, with a MEKI, such as trametinib, is a rational and efficacious treatment regimen for RCC.
Aims
Patients with advanced urothelial carcinoma (UC) who progress after platinum‐based chemotherapy have a poor prognosis, and there is a medical need to improve current treatment options. ...Ramucirumab plus docetaxel significantly improved progression‐free survival but not overall survival (OS) in platinum‐refractory advanced UC (RANGE trial; NCT02426125). Here, we report the exposure‐response (ER) of ramucirumab plus docetaxel using data from the RANGE trial.
Methods
Pharmacokinetic (PK) samples were collected (cycle 1‐3, 5, 9 day 1 and 30 days from treatment discontinuation), and PK data were analysed using population PK (popPK) analysis. The minimum ramucirumab concentration after first dose administration (Cmin,1, or trough concentration immediately prior to the second dose) was derived by popPK analysis and used as the exposure parameter for ER analysis. Cox proportional hazards regression models and matched case‐control analyses were used to evaluate the relationship between Cmin,1 and OS. The Cmin,1 relationship with safety was assessed descriptively.
Results
Several poor prognostic factors (ECOG 1, haemoglobin concentration <100 g/L, presence of liver metastases) appeared more frequently in the lower exposure quartiles, suggesting a possible disease‐PK interaction. A significant association was identified between Cmin,1 and OS (P = .0108). Higher exposure quartiles were associated with longer survival and smaller hazard ratios compared to placebo. No new exposure‐safety trends were observed within the exposure range (ramucirumab 10 mg/kg once every 3 weeks).
Conclusions
This prespecified ER analyses suggests a positive relationship between efficacy and ramucirumab exposure, with an imbalance associated with disease prognostic factors. Further investigation may elucidate a possible disease‐PK relationship.
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