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Highlighting Key Developments in Clinical and Strategic Thinking
From Web-Based Sources.
Updated April 2018.

GU ASCO 2018 Report and Highlights
New information on combination therapies dominated the agenda at this year’s GU ASCO Symposium as cliical trials further evaluatedwhether the use of these approaches have potential benefit in a frontline setting.

Axitinib + Pembrolizumab Is Tolerable, Exhibits Promising Antitumor
Activity in Treatment-Naïve Patients With Advanced RCC

SAN FRANCISCO—Axitinib with pembrolizumab has been shown to be tolerable and to exhibit promising antitumor activity in treatment-naïve patients with advanced renal cell carcinoma (RCC). This outcome of an ongoing open-label phase Ib study was reported at the 2018 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium. Michael B. Atkins, MD, of Georgetown University Lombardi Comprehensive Cancer Center, explained that prior studies of programmed death-1 (PD-1) checkpoint inhibitors + tyrosine kinase inhibitors of the vascular endothelial growth factor (VEGF) pathway have been characterized by excess toxicity, precluding further development. Dr Atkins and colleagues hypothesized that axitinib, a more selective VEGF-pathway inhibitor, + pembrolizumab (anti-PD-1) would be well tolerated and yield antitumor activity in treatment-naïve patients with advanced RCC.

The phase Ib trial was composed of a dose-finding phase to determine the maximum tolerated dose and dose expansion phase. Axitinib 5 mg was administered orally twice daily with pembrolizumab 2 mg per kg of body weight intravenously every 3 weeks. Tumors were assessed using Response Evaluation Criteria in Solid Tumors v1.1 at baseline, week 12, and every 6 weeks thereafter. The primary endpoint was dose-limiting toxicity during the first 2 cycles (6 weeks). Secondary endpoints evaluated safety, objective response rate, progression-free survival, and overall survival.

No unexpected toxicities were observed. A total of 3 dose-limiting toxicities were reported among the 11 patients treated in the dose-finding phase. A transient ischemic attack was reported in 1 patient and 2 patients received <75% of the planned axitinib dosage due to treatment-related toxicity. At the cut-off date in 2017, 25 patients were receiving study treatment. The most common (at least 10%) grade ≥3 all-causality adverse events included hypertension (23%), diarrhea (10%), and fatigue (10%). The most common (>10%) potentially immune-related adverse events included diarrhea (29%), increased alanine aminotransferase (17%), and aspartate amino-transferase (13%), hypothyroidism (13%), and fatigue (12%).

The objective response rate was 73.1% . Median progression-free survival was 20.9 months. Overall survival data were not mature after the minimum follow-up period of 17.6 months, and 6 treatment-unrelated deaths were reported. Dr Atkins concluded that the combination of axitinib + pembrolizumab was shown to be tolerable and to exhibit promising antitumor activity in treatment-naïve patients with advanced RCC. A randomized phase III comparison of axitinib + pembrolizumab vs sunitinib monotherapy is underway.

An Inflammation Scoring Tool Predicts Overall Survival
in Localized Clear Cell RCC

A high-risk clear cell RCC inflammatory score has been shown to be an independent and significant predictor of overall survival, with comparable accuracy to accepted prognostic tools.

This outcome of a retrospective validation study was reported at the 2018 ASCO Genitourinary Cancers Symposium.

Kevin Richard Melnick, DO, of Emory University School of Medicine, explained that a previously created and analyzed composite RCC inflammatory score composed of preoperative serum markers was found to be a significant and independent predictor of overall survival in RCC, with accuracy at least as good as other established prognostic tools. Dr Melnick and colleagues set out to validate the prognostic significance of this novel score in a new, independent cohort of patients with localized clear cell RCC. The new cohort was randomly selected from a group of patients with localized clear cell RCC, who underwent nephrectomy from 2007 to 2017. Data for the group was contained in the investigators’ nephrectomy database.

Biomarker composition, cut-offs, and calculations of the RCC inflammatory score were recreated accurately from the previous publication. The final score was the sum of points accrued for each biomarker, ranging from 0 – 10, followed by stratification into baseline (0), low (1 – 3), intermediate (4 – 6), and high-risk (7 – 10) groups. Receiver-operating characteristics and chi-square analysis were performed to compare the prognostic ability of this novel score vs the Stage, SIze, Grade, and Necrosis (SSIGN), UCLA Integrated  Scoring System (UISS), modified Glasgow Prognostic Score (mGPS, and Leibovich scores. The impact on overall survival was analyzed using multivariate logistic regression analysis.

IMotion 150: Atezolizumab Plus Bevacizumab Shows Potential
Results from the phase II IMmotion150 study that compared atezolizumab (Tecentriq) plus bevacizumab (Avastin) and atezolizumab monotherapy to sunitinib (Sutent) alone in patients with previously untreated, locally advanced or metastatic RCC were also presented the GU ASCO meeting. IMmotion150 is the first randomized clinical trial to evaluate the combination of atezolizumab and bevacizumab in advanced RCC. The study was designed to inform further clinical development of this combination, and these study results reinforce the potential of the combination in this setting.

Patients whose disease expressed programmed cell death ligand 1 (PD-L1) and were treated with atezolizumab plus bevacizumab had a 36% reduction in the risk of the disease worsening or death compared to people treated with sunitinib alone (median progression-free survival = 14.7 vs 7.8 months; hazard ratio [HR] = 0.64; 95% confidence interval [CI] = 0.38–1.08). No progression-free survival advantage was observed compared to sunitinib in the intention-to-treat population (median = 11.7 vs 8.4 months; HR = 1.00; 95% CI = 0.69–1.45).

Median duration of response has not yet been reached after 20.7 months of follow-up across treatment arms. Adverse events in the atezolizumab-plus-bevacizumab arm were consistent with those observed in previous studies of each drug.

First-line Pazopanib May Improve Outcomes in Advanced RCC
PFS among patients with intermediate-risk advanced clear-cell renal cell carcinoma (aCCRCC) is significantly longer with pazopanib than temsirolimus as first-line therapy, according to the findings of a randomized phase II clinical trial presented at the 2018 Genitourinary Cancers Symposium. Pazopanib therapy also appeared to elicit a better objective response rate (ORR). Median PFS, the study’s primary end point, was 5.2 months (95% CI 3.6–7.4) for pazopanib compared with 2.6 months (95% CI 1.9–4.2) for temsirolimus, Nizar M. Tannir, MD, and colleagues at the University of Texas Health Science Center at Houston reported. Among patients with intermediate-risk disease as defined by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria, pazopanib was associated with a significant 62% decreased risk of progression compared with temsirolimus  The median overall survival was 12 months (95% CI 8.3–20.1) for the pazopanib group and 7.4 months (95% CI 5.3–17.4) for the temsirolimus group. The study found no significant difference between the drugs among patients in the IMDC poor-risk group.

Phase 3 Trial Design Outlined for Lenvatinib in Combination
with Everolimus or Pembrolizumab vs Sunitinib

Investigators reviewed the design of a multicenter, open-label, phase 3 trial of lenvatinib plus everolimus or pembrolizumab vs sunitinib as first-line treatment for advanced RCC. Patients will be randomized 1:1:1 to receive LEN 18 mg/d + EVE 5 mg/d, LEN 20 mg/d + PEM 200 mg every 3 weeks, or SUN 50 mg/d (on a schedule of 4 weeks on treatment followed by 2 weeks off) until disease progression, unacceptable toxicity, withdrawal of consent, or study end. Enrollment of 735 patients is planned.

The primary endpoint is to assess superiority of LEN+EVE or LEN+PEM over single-agent SUN as first-line treatment for advanced RCC in improving progression-free survival (PFS) The secondary endpoints: comparison of objective response rate (ORR), overall survival, PFS on next-line therapy, health-related quality of life, and safety and tolerability in pts receiving LEN+EVE or LEN+PEM vs SUN.

Exploratory endpoints: PFS in the LEN+PEM arm using immune-related RECIST, comparison of duration of response, disease control rate, and clinical benefit rate in pts treated with LEN+EVE or LEN+PEM vs SUN, and analysis of the relationship between blood biomarkers and outcome. KCJ