Ongoing under-reporting of clinically relevant safety data in phase II studies of tyrosine kinase inhibitors

status: publishe

Real-world outcomes of nivolumab and cabozantinib in metastatic renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium

Objectives: In the present study, we explored the real-world efficacy of the immuno-oncology checkpoint inhibitor nivolumab and the tyrosine kinase inhibitor cabozantinib in the second-line setting. Methods: Using the International Metastatic Renal Cell Carcinoma Database Consortium (imdc) dataset, a retrospective analysis of patients with metastatic renal cell carcinoma (mrcc) treated with nivolumab or cabozantinib in the second line after prior therapy targeted to the vascular endothelial growth factor receptor (vegfr) was performed. Baseline characteristics and imdc risk factors were collected. Overall survival (os) and time to treatment failure (ttf) were calculated using Kaplan-Meier curves. Overall response rates (orrs) were determined for each therapy. Multivariable Cox regression analysis was performed to determine survival differences between cabozantinib and nivolumab treatment. Results: The analysis included 225 patients treated with nivolumab and 53 treated with cabozantinib. No significant difference in median os was observed: 22.10 months [95% confidence interval (ci): 17.18 months to not reached] with nivolumab and 23.70 months (95% ci: 15.52 months to not reached) with cabozantinib (p = 0.61). The ttf was also similar at 6.90 months (95% ci: 4.60 months to 9.20 months) with nivolumab and 7.39 months (95% ci: 5.52 months to 12.85 months) with cabozantinib (p = 0.20). The adjusted hazard ratio (hr) for nivolumab compared with cabozantinib was 1.30 (95% ci: 0.73 to 2.3), p = 0.38. When adjusted by imdc criteria and age, the hr was 1.32 (95% ci: 0.74 to 2.38), p = 0.35. Conclusions: Real-world imdc data indicate comparable os and ttf for nivolumab and cabozantinib. Both agents are reasonable therapeutic options for patients progressing after initial first-line vegfr-targeted therapy.status: publishe

Real-world outcomes of nivolumab and cabozantinib in metastatic renal cell carcinoma:Results from the international metastatic renal cell carcinoma database consortium

Objectives: In the present study, we explored the real-world efficacy of the immuno-oncology checkpoint inhibitor nivolumab and the tyrosine kinase inhibitor cabozantinib in the second-line setting. Methods: Using the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) dataset, a retrospective analysis of patients with metastatic renal cell carcinoma (MRCC) treated with nivolumab or cabozantinib in the second line after prior therapy targeted to the vascular endothelial growth factor receptor (VEGFR) was performed. Baseline characteristics and imdc risk factors were collected. Overall survival (OS) and time to treatment failure (TTF) were calculated using Kaplan–Meier curves. Overall response rates (ORRS) were determined for each therapy. Multivariable Cox regression analysis was performed to determine survival differences between cabozantinib and nivolumab treatment. Results: The analysis included 225 patients treated with nivolumab and 53 treated with cabozantinib. No significant difference in median OS was observed: 22.10 months [95% confidence interval (CI): 17.18 months to not reached] with nivolumab and 23.70 months (95% CI: 15.52 months to not reached) with cabozantinib (p = 0.61). The TTF was also similar at 6.90 months (95% CI: 4.60 months to 9.20 months) with nivolumab and 7.39 months (95% CI: 5.52 months to 12.85 months) with cabozantinib (p = 0.20). The adjusted hazard ratio (HR) for nivolumab compared with cabozantinib was 1.30 (95% CI: 0.73 to 2.3), p = 0.38. When adjusted by IMDC criteria and age, the HR was 1.32 (95% CI: 0.74 to 2.38), p = 0.35. Conclusions: Real-world IMDC data indicate comparable OS and TTF for nivolumab and cabozantinib. Both agents are reasonable therapeutic options for patients progressing after initial first-line VEGFR-targeted therapy

A multiphase model for three-dimensional tumor growth

Several mathematical formulations have analyzed the time-dependent behaviour of a tumor mass. However, most of these propose simplifications that compromise the physical soundness of the model. Here, multiphase porous media mechanics is extended to model tumor evolution, using governing equations obtained via the Thermodynamically Constrained Averaging Theory (TCAT). A tumor mass is treated as a multiphase medium composed of an extracellular matrix (ECM); tumor cells (TC), which may become necrotic depending on the nutrient concentration and tumor phase pressure; healthy cells (HC); and an interstitial fluid (IF) for the transport of nutrients. The equations are solved by a Finite Element method to predict the growth rate of the tumor mass as a function of the initial tumor-to-healthy cell density ratio, nutrient concentration, mechanical strain, cell adhesion and geometry. Results are shown for three cases of practical biological interest such as multicellular tumor spheroids (MTS) and tumor cords. First, the model is validated by experimental data for time-dependent growth of an MTS in a culture medium. The tumor growth pattern follows a biphasic behaviour: initially, the rapidly growing tumor cells tend to saturate the volume available without any significant increase in overall tumor size; then, a classical Gompertzian pattern is observed for the MTS radius variation with time. A core with necrotic cells appears for tumor sizes larger than 150 μm, surrounded by a shell of viable tumor cells whose thickness stays almost constant with time. A formula to estimate the size of the necrotic core is proposed. In the second case, the MTS is confined within a healthy tissue. The growth rate is reduced, as compared to the first case – mostly due to the relative adhesion of the tumor and healthy cells to the ECM, and the less favourable transport of nutrients. In particular, for tumor cells adhering less avidly to the ECM, the healthy tissue is progressively displaced as the malignant mass grows, whereas tumor cell infiltration is predicted for the opposite condition. Interestingly, the infiltration potential of the tumor mass is mostly driven by the relative cell adhesion to the ECM. In the third case, a tumor cord model is analyzed where the malignant cells grow around microvessels in a 3D geometry. It is shown that tumor cells tend to migrate among adjacent vessels seeking new oxygen and nutrient. This model can predict and optimize the efficacy of anticancer therapeutic strategies. It can be further developed to answer questions on tumor biophysics, related to the effects of ECM stiffness and cell adhesion on tumor cell proliferation

Phase I evaluation of the effects of ketoconazole and rifampicin on cediranib pharmacokinetics in patients with solid tumours

<p>Purpose: To investigate any effect of a CYP3A4 inhibitor (ketoconazole) or inducer (rifampicin) on cediranib steady-state pharmacokinetics in patients with advanced solid tumours.</p> <p>Methods: In two Phase I, open-label trials, patients received once-daily oral doses of cediranib alone [20 mg (ketoconazole study); 45 mg (rifampicin study)] for 7 days followed by cediranib at the same dose with ketoconazole 400 mg/day for 3 days or once-daily rifampicin 600 mg/day for 7 days, respectively. Patients then continued to receive once-daily cediranib.</p> <p>Results: In the ketoconazole study, 46 patients were dosed; 38 were evaluable for C ss,max, 36 for AUCss. gMean AUCss and C ss,max for cediranib 20 mg increased by 21 % (94 % CI 9–35 %) and 26 % (94 % CI 10–43 %), respectively, in the presence of ketoconazole. In the rifampicin study, 64 patients were dosed; 44 were evaluable for C ss,max and 41 for AUCss. gMean AUCss and C ss,max for cediranib 45 mg decreased by 39 % (90 % CI 34–43 %) and 23 % (90 % CI 16–30 %), respectively, in the presence of rifampicin. gMean ratios for AUCss and C ss,max were >1 for ketoconazole and >1 for rifampicin and CIs were outside the pre-specified equivalence boundaries, indicating a statistically significant effect. Significant inter-patient variability in cediranib AUCss and C ss,max was observed. The safety profile of cediranib was similar to that reported previously.</p> <p>Conclusions: Co-administration of ketoconazole or rifampicin had statistically significant effects on steady-state pharmacokinetics of cediranib in patients with advanced solid tumours. Therefore, caution is advised when administering cediranib with potent enzyme inhibitors or inducers.</p&gt