Thomas Hutson D.O.

Powles, T., Atkins, M.B., Escudier, B., Motzer, R.J., Rini, B.I., Fong, L., Joseph, R.W., Pal, S.K., Sznol, M., Hainsworth, J., Stadler, W.M., Hutson, T.E., Ravaud, A., Bracarda, S., Suarez, C., Choueiri, T.K., Reeves, J., Cohn, A., Ding, B., Leng, N., Hashimoto, K., Huseni, M., Schiff, C. and McDermott, D.F. (2021). “Efficacy and Safety of Atezolizumab Plus Bevacizumab Following Disease Progression on Atezolizumab or Sunitinib Monotherapy in Patients with Metastatic Renal Cell Carcinoma in IMmotion150: A Randomized Phase 2 Clinical Trial.” Eur Urol Mar 4;S0302-2838(21)00003-8. [Epub ahead of print].

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BACKGROUND: The use of immune checkpoint inhibitors combined with vascular endothelial growth factor (VEGF)-targeted therapy as second-line treatment for metastatic clear cell renal cancer (mRCC) has not been evaluated prospectively. OBJECTIVE: To evaluate the efficacy and safety of atezolizumab + bevacizumab following disease progression on atezolizumab or sunitinib monotherapy in patients with mRCC. DESIGN, SETTING, AND PARTICIPANTS: IMmotion150 was a multicenter, randomized, open-label, phase 2 study of patients with untreated mRCC. Patients randomized to the atezolizumab or sunitinib arm who had investigator-assessed progression as per RECIST 1.1 could be treated with second-line atezolizumab + bevacizumab. INTERVENTION: Patients received atezolizumab 1200 mg intravenously (IV) plus bevacizumab 15 mg/kg IV every 3 wk following disease progression on either atezolizumab or sunitinib monotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The secondary endpoints analyzed during the second-line part of IMmotion150 included objective response rate (ORR), progression-free survival (PFS), and safety. PFS was examined using Kaplan-Meier methods. RESULTS AND LIMITATIONS: Fifty-nine patients in the atezolizumab arm and 78 in the sunitinib arm were eligible, and 103 initiated second-line atezolizumab + bevacizumab (atezolizumab arm, n = 44; sunitinib arm, n = 59). ORR (95% confidence interval [CI]) was 27% (19-37%). The median PFS (95% CI) from the start of second line was 8.7 (5.6-13.7) mo. The median event follow-up duration was 19.4 (12.9-21.9) mo among the 25 patients without a PFS event. Eighty-six (83%) patients had treatment-related adverse events; 31 of 103 (30%) had grade 3/4 events. Limitations were the small sample size and selection for progressors. CONCLUSIONS: The atezolizumab + bevacizumab combination had activity and was tolerable in patients with progression on atezolizumab or sunitinib. Further studies are needed to investigate sequencing strategies in mRCC. PATIENT SUMMARY: Patients with advanced kidney cancer whose disease had worsened during treatment with atezolizumab or sunitinib began second-line treatment with atezolizumab + bevacizumab. Tumors shrank in more than one-quarter of patients treated with this combination, and side effects were manageable.

Jacob, A., Shook, J. and Hutson, T. (2021). “The implementation of lenvatinib/everolimus or lenvatinib/pembrolizumab combinations in the treatment of metastatic renal cell carcinoma.” Expert Rev Anticancer Ther Jan 6;1-8. [Epub ahead of print]. 1-8.

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Introduction: There are 400,000 new cases of Renal Cell Carcinoma (RCC) and 175,000 deaths worldwide every year. Currently available frontline therapies to treat RCC have less toxicity than previously employed therapeutic agents, but drug resistance is still a clinically significant problem. Drug resistance occurs through angiogenic escape by the activation of pathways that are independent of the VEGF targets of most first-line therapies. The lenvatinib/everolimus and lenvatinib/pembrolizumab are part of a new generation of combinations that can combat this method of resistance to extend both progression-free survival and overall survival in patients with metastatic RCC. Areas covered: This article discusses the evolution of current data on the efficacy and safety of these two combinations and future directions for their implementation in the treatment of advanced renal cell carcinoma. Expert opinion: Future research will focus on these combinations in contrast with other currently approved regimens. Once specific biomarkers that predict response to treatment are identified, the future of treatment of mRCC will involve specifically tailored therapies for a patient’s genotype. Therapies unique only to the patient undergoing treatment will increase both efficacy and safety of new treatments, and that is the truly exciting future that awaits this field.

Jacob, A., Shook, J. and Hutson, T. (2021). “The implementation of lenvatinib/everolimus or lenvatinib/pembrolizumab combinations in the treatment of metastatic renal cell carcinoma.” Expert Rev Anticancer Ther Jan 4. [ Epub ahead of print].

Full text of this article.

Introduction: There are 400,000 new cases of Renal Cell Carcinoma (RCC) and 175,000 deaths worldwide every year. Currently available frontline therapies to treat RCC have less toxicity than previously employed therapeutic agents, but drug resistance is still a clinically significant problem. Drug resistance occurs through angiogenic escape by the activation of pathways that are independent of the VEGF targets of most first-line therapies. The lenvatinib/everolimus and lenvatinib/pembrolizumab are part of a new generation of combinations that can combat this method of resistance to extend both progression-free survival and overall survival in patients with metastatic RCC. Areas covered: This article discusses the evolution of current data on the efficacy and safety of these two combinations and future directions for their implementation in the treatment of advanced renal cell carcinoma. Expert opinion: Future research will focus on these combinations in contrast with other currently approved regimens. Once specific biomarkers that predict response to treatment are identified, the future of treatment of RCC will involve specifically tailored therapies for a patient’s genotype. Therapies unique only to the patient undergoing treatment will increase both efficacy and safety of new treatments, and that is the truly exciting future that awaits this field.

Pal, S.K., Escudier, B.J., Atkins, M.B., Hutson, T.E., Porta, C., Verzoni, E., Needle, M.N., Powers, D., McDermott, D.F. and Rini, B.I. (2020). “Final Overall Survival Results from a Phase 3 Study to Compare Tivozanib to Sorafenib as Third- or Fourth-line Therapy in Subjects with Metastatic Renal Cell Carcinoma.” Eur Urol Sep 13;S0302-2838(20)30624-2. [Epub ahead of print.].

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Tivozanib is a potent and selective inhibitor of the VEGF receptor. In an open-label, randomized phase 3 trial, we compared tivozanib to sorafenib in patients with metastatic renal cell carcinoma (mRCC) who had received two or three prior therapies. We have previously reported that the study met its primary endpoint, demonstrating an improvement in progression-free survival with tivozanib versus sorafenib (5.6 mo vs 3.9 mo; hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.56-0.94; p=0.016). The current report reflects the final assessment of overall survival, showing no difference between treatment with tivozanib and sorafenib (HR 0.97, 95% CI 0.75-1.24). Given its activity and distinct tolerability profile, tivozanib represents a treatment option for patients with previously treated mRCC. PATIENT SUMMARY: We show that tivozanib, a targeted therapy, can delay tumor growth relative to an already approved targeted therapy (sorafenib) in patients with kidney cancer who have received two or three prior treatments. No difference in survival was observed.

Jacob, A., J. Shook and T. E. Hutson (2020). “Tivozanib, a highly potent and selective inhibitor of VEGF receptor tyrosine kinases, for the treatment of metastatic renal cell carcinoma.” Future Oncol 2020 Jul 21. [Epub ahead of print.].

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The VHL mutation-HIF upregulation-VEGF transcription sequence is the principal pathway in the development of renal cell carcinoma. Tyrosine kinase inhibitors target the VEGF receptors to inhibit further growth of renal cell carcinoma tumors. Tivozanib, originally named AV-951 and KRN-951, is a novel, orally bioavailable VEGF tyrosine kinase inhibitor that is selective for VEGF receptors 1, 2 and 3. Further, only picomolar concentrations of tivozanib are required to target these VEGF receptors and prevent phosphorylation; this potency prevents the debilitating side effects that occur with treatments whose mechanisms of action involve broad-spectrum tyrosine kinase inhibition. This review summarizes the growing body of evidence supporting tivozanib’s efficacy and safety in the treatment of advanced renal cell carcinoma.