Daniel C. Cho

The Efficacy of the Novel Dual PI3-Kinase/mTOR Inhibitor NVP-BEZ235 Compared with Rapamycin in Renal Cell Carcinoma

Purpose: Inhibitors of TORC1 have been shown to be active in patients with metastatic renal cell carcinoma (RCC). As the phosphatidylinositol 3-kinase (PI3K) pathway activates numerous other kinases, transcription factors, and proteins associated with cell growth and survival besides mammalian target of rapamycin (mTOR), disruption of this pathway upstream of mTOR may be more effective than inhibition of TORC1 alone. Experimental Design: To investigate this possibility, the dual PI3K/mTOR inhibitor NVP-BEZ235 was compared with rapamycin in RCC cell lines and xenografts generated from 786-O and A498 cells. Results: Treatment of RCC cell lines with NVP-BEZ235 in vitro resulted in the nuclear translocation of p27, greater reduction in tumor cell proliferation, and more complete suppression of Akt, Mnk-1, eIF4E, and 4EBP-1 phosphorylation and cyclin D1 and hypoxia-inducible factor 2α (HIF2α) expression than that achieved with rapamycin. The reduction of HIF2α levels correlated with reduced HIF activity as determined by luciferase assay. NVP-BEZ235 induced growth arrest in both the 786-O and A498 xenografts that was associated with inhibition of Akt and S6 phosphorylation as well as the induction of apoptosis and reduction in markers of tumor cell proliferation. In contrast, rapamycin induced only minimal growth retardation. Conclusion: Dual inhibition of PI3K/mTOR with NVP-BEZ235 induced growth arrest in RCC cell lines both in vitro and in vivo more effectively than inhibition of TORC1 alone. These results provide the rationale for the clinical assessment of agents such as NVP-BEZ235 in patients with advanced RCC. Clin Cancer Res; 16(14); 3628–38. ©2010 AACR.

Carbonic anhydrase IX and pathological features as predictors of outcome in patients with metastatic clear-cell renal cell carcinoma receiving vascular endothelial growth factor-targeted therapy.

Study Type – Prognosis (retrospective cohort)
Level of Evidence 2b

Pneumonitis associated with mTOR inhibitors therapy in patients with metastatic renal cell carcinoma: Incidence, radiographic findings and correlation with clinical outcome

BACKGROUND Mammalian target of rapamycin (mTOR) inhibitors are approved for use in patients with metastatic renal cell carcinoma (mRCC) and are under investigation in several other malignancies. We assessed the incidence, clinical presentation and computed tomography (CT) findings of pneumonitis associated with mTOR inhibitors in mRCC. Correlation between radiological findings of pneumonitis and clinical outcome was also determined. METHODS We retrospectively reviewed the clinical data and serial CT scans from patients with mRCC treated with either temsirolimus or everolimus. Serial chest CT scans were reviewed in consensus, read by two independent radiologists for the presence of pneumonitis, and corresponding clinical data were reviewed for symptoms and clinical outcome. The baseline and follow up CTs were reviewed to assess outcome to therapy. RESULTS The study population consisted of 46 pts, 21 treated with temsirolimus and 25 with everolimus (M:F 2.5:1; median 63 years, range 31-79 years). CT evidence of pneumonitis was seen in 14/46 pts (30%), at a median of 56days on mTOR inhibitor treatment (range 31-214 days). Respiratory symptoms at the time of radiographically detected pneumonitis, were observed in 7pts. Stable disease (SD) by Response Evaluation Criteria in Solid Tumours (RECIST) was achieved in 12/14 pts (86%) who developed radiographic pneumonitis compared to 14/32 (44%) without pneumonitis (p=0.01) The mean change of tumour long axis size for target lesions by RECIST, normalised for 30 days on therapy was -2.9% in the pneumonitis group and +4.3% in the non-pneumonitis group (p=.002). CONCLUSIONS Preliminary data suggest that pneumonitis may be a marker of stable disease by RECIST and therefore, of therapeutic benefit. Careful patient assessment should be undertaken before the drug is discontinued.

Retrospective Analysis of the Safety and Efficacy of Interleukin-2 After Prior Vegf-targeted Therapy in Patients With Advanced Renal Cell Carcinoma

Agents targeting vascular endothelial growth factor (VEGF) signaling have been advocated as frontline therapy for advanced renal cancer. The role of interleukin 2 (IL-2) therapy after resistance to VEGF-targeted therapy remains unexplored. We conducted a retrospective analysis of the tolerability and efficacy of IL-2 therapy in patients who had previously received VEGF-targeted therapy. Twenty-three consecutive patients who received salvage IL-2 therapy were analyzed. Fifteen patients had received prior tyrosine kinase inhibitors (TKIs) (sorafenib or sunitinib), whereas 8 patients had received bevacizumab alone. Six of 23 patients did not receive week 2 of cycle 1 of treatment. All 6 of these patients had received prior TKIs. The incidence of severe cardiac toxicities, including 1 sudden cardiac death, in patients receiving prior TKI was 40% (95% confidence interval, 16.3-67.7%), significantly higher than what is expected from historical experience. Only 1 of 23 patients proceeded to receive a second cycle of IL-2. No patients achieved a partial or complete response to therapy. This retrospective analysis highlights unexpected and severe cardiac toxicities in patients receiving IL-2 after VEGF-targeted TKI therapy. The assumption that IL-2 therapy can be safely administered after TKI therapy may not be valid. Further examination of the safety of this sequential approach is necessary and more cautious patient selection seems warranted.

GSK-3β Inhibition Enhances Sorafenib-induced Apoptosis in Melanoma Cell Lines

Glycogen synthase kinase-3β (GSK-3β) can participate in the induction of apoptosis or, alternatively, provide a survival signal that minimizes cellular injury. We previously demonstrated that the multikinase inhibitor sorafenib induces apoptosis in melanoma cell lines. In this report, we show that sorafenib activates GSK-3β in multiple subcellular compartments and that this activation undermines the lethality of the drug. Pharmacologic inhibition and/or down-modulation of the kinase enhances sorafenib-induced apoptosis as determined by propidium iodide staining and by assessing the mitochondrial release of apoptosis-inducing factor and Smac/DIABLO. Conversely, the forced expression of a constitutively active form of the enzyme (GSK-3βS9A) protects the cells from the apoptotic effects of the drug. This protective effect is associated with a marked increase in basal levels of Bcl-2, Bcl-xL, and survivin and a diminution in the degree to which these anti-apoptotic proteins are down-modulated by sorafenib exposure. Sorafenib down-modulates the pro-apoptotic Bcl-2 family member Noxa in cells with high constitutive GSK-3β activity. Pharmacologic inhibition of GSK-3β prevents the disappearance of Noxa induced by sorafenib and enhances the down-modulation of Mcl-1. Down-modulation of Noxa largely eliminates the enhancing effect of GSK-3 inhibition on sorafenib-induced apoptosis. These data provide a strong rationale for the use of GSK-3β inhibitors as adjuncts to sorafenib treatment and suggest that preservation of Noxa may contribute to their efficacy.

Two phase 2 trials of the novel Akt inhibitor perifosine in patients with advanced renal cell carcinoma after progression on vascular endothelial growth factor-targeted therapy.

The clinical activity of allosteric inhibitors of mammalian target of rapamycin (mTOR) inhibitors in renal cell carcinoma (RCC) may be limited by upstream activation of phosphatidylinositol 3 (PI3)‐kinase/Akt resulting from mTOR1 inhibition. On the basis of this rationale, 2 independent phase 2 trials (Perifosine 228 and 231) were conducted to assess the efficacy and safety of the novel Akt inhibitor perifosine in patients with advanced RCC who had failed on previous vascular endothelial growth factor (VEGF)‐targeted therapy.

Future directions in renal cell carcinoma: 2011 and beyond.

Emerging from a largely cytokine-based era, the last several years have witnessed a dramatic change in the therapeutic landscape of renal cancer. Molecularly targeted and antiangiogenic agents now form the backbone of most therapeutic strategies for patients with advanced renal cell carcinoma (RCC). Although the next few years may not see such broad paradigm shifts, there remains significant room for improvement in the care of patients with RCC. This review discusses challenges that face physicians and researchers as well as innovations that may contribute to improving the therapeutic outcomes for patients with RCC.

Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial

BACKGROUND Previous studies combining PD-1 checkpoint inhibitors with tyrosine kinase inhibitors of the VEGF pathway have been characterised by excess toxicity, precluding further development. We hypothesised that axitinib, a more selective VEGF inhibitor than others previously tested, could be combined safely with pembrolizumab (anti-PD-1) and yield antitumour activity in patients with treatment-naive advanced renal cell carcinoma. METHODS In this ongoing, open-label, phase 1b study, which was done at ten centres in the USA, we enrolled patients aged 18 years or older who had advanced renal cell carcinoma (predominantly clear cell subtype) with their primary tumour resected, and at least one measureable lesion, Eastern Cooperative Oncology Group performance status 0-1, controlled hypertension, and no previous systemic therapy for renal cell carcinoma. Eligible patients received axitinib plus pembrolizumab in a dose-finding phase to estimate the maximum tolerated dose, and additional patients were enrolled into a dose-expansion phase to further establish safety and determine preliminary efficacy. Axitinib 5 mg was administered orally twice per day with pembrolizumab 2 mg/kg given intravenously every 3 weeks. We assessed safety in all patients who received at least one dose of axitinib or pembrolizumab; antitumour activity was assessed in all patients who received study treatment and had an adequate baseline tumour assessment. The primary endpoint was investigator-assessed dose-limiting toxicity during the first two cycles (6 weeks) to estimate the maximum tolerated dose and recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02133742. FINDINGS Between Sept 23, 2014, and March 25, 2015, we enrolled 11 patients with previously untreated advanced renal cell carcinoma to the dose-finding phase and between June 3, 2015, and Oct 13, 2015, we enrolled 41 patients to the dose-expansion phase. All 52 patients were analysed together. No unexpected toxicities were observed. Three dose-limiting toxicities were reported in the 11 patients treated during the 6-week observation period (dose-finding phase): one patient had a transient ischaemic attack and two patients were only able to complete less than 75% of the planned axitinib dose because of treatment-related toxicity. At the data cutoff date (March 31, 2017), 25 (48%) patients were still receiving study treatment. Grade 3 or worse treatment-related adverse events occurred in 34 (65%) patients; the most common included hypertension (n=12 [23%]), diarrhoea (n=5 [10%]), fatigue (n=5 [10%]), and increased alanine aminotransferase concentration (n=4 [8%]). The most common potentially immune-related adverse events (probably related to pembrolizumab) included diarrhoea (n=15 [29%]), increased alanine aminotransferase concentration (n=9 [17%]) or aspartate aminotransferase concentration (n=7 [13%]), hypothyroidism (n=7 [13%]), and fatigue (n=6 [12%]). 28 (54%) patients had treatment-related serious adverse events. At data cutoff, 38 (73%; 95% CI 59·0-84·4) patients achieved an objective response (complete or partial response). INTERPRETATION The treatment combination of axitinib plus pembrolizumab is tolerable and shows promising antitumour activity in patients with treatment-naive advanced renal cell carcinoma. Whether or not the combination works better than a sequence of VEGF pathway inhibition followed by an anti-PD-1 therapy awaits the completion of a phase 3 trial comparing axitinib plus pembrolizumab with sunitinib monotherapy (NCT02853331). FUNDING Pfizer Inc.

PI3K inhibition potentiates Bcl‐2‐dependent apoptosis in renal carcinoma cells

Inhibitors of PI3‐K/Akt are currently being assessed clinically in patients with advanced RCC. Identification of therapeutic strategies that might enhance the efficacy of PI3‐K/Akt inhibitors is therefore of great interest. As PI3‐K inhibition would be expected to have many pro‐apoptotic effects, we hypothesized that there may be unique synergy between PI3‐K inhibitors and BH3‐mimetics. Towards this end, we assessed the combination of the PI3K inhibitor LY 294002 and the Bcl‐2 family inhibitor ABT‐737 in RCC cell lines. We found that the combinatorial treatment with these agents led to a significant increase in PARP cleavage and cell death in all RCC cell lines. The synergized cell death was correlated with decreased levels of Mcl‐1 and XIAP, and increased levels in Bim, and appears critically dependent upon the activation of caspase 3 and 8. The enhanced lethality observed with the combination also appears dependent upon the regulation of XIAP, Mcl‐1 and Bim levels. Our results suggest that the combination of PI3‐K inhibitors with BH3‐mimetics may be a viable therapeutic strategy in RCC.

Predictors of response to sequential sunitinib and the impact of prior VEGF-targeted drug washout in patients with metastatic clear-cell renal cell carcinoma

OBJECTIVE To identify factors that can be used to identify metastatic clear cell RCC patients more likely to benefit from sequential sunitinib. PATIENTS AND METHODS We identified patients who failed sorafenib or bevacizumab and subsequently received sunitinib. We looked at objective response rates (ORR), progression-free survival (PFS), and overall survival (OS) to sunitinib in relation to baseline clinical variables. RESULTS Seventy-one patients received sunitinib sequential therapy. Median duration of follow-up after starting sunitinib was 9.3 months. Median PFS was 5.8 months; median OS was not reached. Significantly higher ORR was seen in patients with normal hemoglobin (25.6%) [defined as >12 gm/dl for female; >13 gm/dl for male]. In addition, a shorter PFS for patients with low hemoglobin, and patients with time from diagnosis to first treatment ≤ 1 year was found. There was a shorter OS for patients ≥ 60 years old, with brain metastasis, low hemoglobin, and time from diagnosis to treatment ≤ 1 year. There was no difference in ORR, PFS, or OS in patients who started sunitinib after or within a 30-day period. CONCLUSIONS Metastatic clear-cell RCC patients with anemia have less clinical benefit from sequential sunitinib after failure of bevacizumab or sorafenib. Other factors associated with poor outcome include brain metastases, older age, and <1 year between diagnosis and first treatment. Importantly, no difference in outcomes was observed if sequential therapy was initiated within or after 30 days. External validation and prospective evaluation are needed to confirm these findings.