- Email: [email protected]
Combination therapy in kidney cancer: the next revolution?
Comment
Treatment of renal cell carcinoma seems to be at the dawn of a golden era. Through re-evaluation of the immunological paradigm, the focus has shifted to new immunomodulators as promising agents for future treatment of metastatic disease.1 Results of studies with PD-1 inhibitors have attracted the attention of experts worldwide. However, in The Lancet Oncology, Robert Motzer and colleagues report findings of a randomised phase 2 study2 that reopens the hypothesis—until now rejected by several negative studies—of a synergistic combination of VEGF receptor tyrosine kinase inhibitors and mTOR inhibitors for the treatment of metastatic renal cell carcinoma. The strategy investigated by Motzer and colleagues consists of double inhibition of two principal molecular targets of renal cancer: the VEGF and mTOR pathways. This option has been examined in previous studies, but almost all came to unfavourable conclusions in terms of efficacy and, in particular, toxicity.3–6 In this study, Motzer and co-workers tested a new VEGF receptor tyrosine kinase inhibitor, lenvatinib, alone and in combination with the mTOR inhibitor everolimus for second-line therapy in patients progressing on a first-line VEGF receptor-targeted tyrosine kinase inhibitor. The primary outcome was progression-free survival, which was significantly longer for patients allocated lenvatinib plus everolimus than for those allocated everolimus alone (hazard ratio 0·40, 95% CI 0·24–0·68; p=0·0005). Furthermore, those allocated lenvatinib alone had longer progressionfree survival than did those assigned everolimus alone (0·61, 0·38–0·98; p=0·048). The hazard ratio of 0·40 for progression-free survival is by far the most notable result obtained since the first tyrosine kinase inhibitor was introduced for treatment of metastatic renal cell carcinoma. The value of lenvatinib is reminiscent of the pivotal trial in which sunitinib outclassed interferon as first-line therapy for metastatic renal cell carcinoma.7 With respect to secondary endpoints, the proportion of patients achieving an objective response is noteworthy (43% with the combination, 27% with lenvatinib alone, and 6% with everolimus alone). Furthermore, overall survival was prolonged with
lenvatinib plus everolimus, albeit with less robustness than for progression-free survival or response. Moreover, analysis of the characteristics of the study population shows an unusually high proportion of poor-risk patients (20–39% in the combination arm, depending on the prognostic score used), suggesting the reproducibility of similar results in real-life populations. These findings reinforce the potential effect of this trial on future clinical practice. Nevertheless, despite the promising efficacy results, the two reported deaths in the lenvatinib groups from toxic effects are alarming and certainly not negligible. Moreover, the frequency of grade 3–4 diarrhoea with combination therapy (20%) and of grade 3–4 proteinuria with lenvatinib alone (19%) suggest that careful reflections are needed about appropriate dose reductions and management of toxic effects. A strategy of first-line followed by second-line tyrosine kinase inhibition to maintain suppression of the VEGF pathway (VEGF pressure) possibly represents an appropriate therapeutic approach, independent of mTOR inhibition. Indeed, lenvatinib alone showed improvements in outcomes compared with everolimus alone.2 In support of this idea, researchers on the AXIS trial8 and METEOR trial9 investigated second-line treatment with the VEGF receptor tyrosine kinase inhibitors axitinib, sorafenib, and cabozantinib and reported good results, showing that maintenance of VEGF pressure works. The added value of the study by Motzer and colleagues is the synergistic effect of the double block of VEGF and mTOR pathways, the power of which could entice a change to clinical practice even before reaching phase 3 evidence. These findings suggest that the potential of the well-known molecular mechanisms is far from exhausted and deserves further consideration. In conclusion, the atmosphere of enthusiasm for immunological treatments for metastatic renal cell carcinoma should not overshadow the validity of proven tumour-targeted strategies, combinations of which can achieve good results. Further research into the optimum sequencing of therapies targeting the tumour and also the immune system will be needed if we are to achieve our ideal goal of converting metastatic renal cell carcinoma into a chronic disease.
www.thelancet.com/oncology Published online October 16, 2015 http://dx.doi.org/10.1016/S1470-2045(15)00325-3
David Mccarthy/Science Photo Library
Combination therapy in kidney cancer: the next revolution?
Lancet Oncol 2015 Published Online October 16, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)00325-3 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(15)00290-9
1
Comment
*Sebastiano Buti, Melissa Bersanelli
5
Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy [email protected] 6
We declare no competing interests. 1
2
3
4
2
Motzer RJ, Escudier B, McDermott DF, et al, for the CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015; published online Sept 25. DOI:10.1056/ NEJMoa1510665. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol 2015; published online Oct 16. http://dx.doi.org/S1470-2045(15)00290-9. Molina AM, Feldman DR, Voss MH, et al. Phase 1 trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma. Cancer 2012; 118: 1868–76. Patel PH, Senico PL, Curiel RE, Motzer RJ. Phase I study combining treatment with temsirolimus and sunitinib malate in patients with advanced renal cell carcinoma. Clin Genitourin Cancer 2009; 7: 24–27.
7 8
9
Patnaik A, Ricart A, Cooper JS, et al. A phase I, pharmacokinetic and pharmacodynamic study of sorafenib (S), a multi-targeted kinase inhibitor in combination with temsirolimus (T), an mTOR inhibitor in patients with advanced solid malignancies. Proc Am Soc Clin Oncol 2007; 25 (suppl 18): abstr 3512. Rosenberg JE, Weinberg VK, Claros C, et al. Phase I study of sorafenib and RAD001 for metastatic clear cell renal cell carcinoma. Proc Am Soc Clin Oncol 2008; 26 (suppl 15): abstr 5109. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356: 115–24. Motzer RJ, Escudier B, Tomczak P, et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol 2013; 14: 552–62. Choueiri TK, Escudier B, Powles T, et al, for the METEOR investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015; published online Sept 25. DOI:10.1056/ NEJMoa1510016.
www.thelancet.com/oncology Published online October 16, 2015 http://dx.doi.org/10.1016/S1470-2045(15)00325-3
Treatment of renal cell carcinoma seems to be at the dawn of a golden era. Through re-evaluation of the immunological paradigm, the focus has shifted to new immunomodulators as promising agents for future treatment of metastatic disease.1 Results of studies with PD-1 inhibitors have attracted the attention of experts worldwide. However, in The Lancet Oncology, Robert Motzer and colleagues report findings of a randomised phase 2 study2 that reopens the hypothesis—until now rejected by several negative studies—of a synergistic combination of VEGF receptor tyrosine kinase inhibitors and mTOR inhibitors for the treatment of metastatic renal cell carcinoma. The strategy investigated by Motzer and colleagues consists of double inhibition of two principal molecular targets of renal cancer: the VEGF and mTOR pathways. This option has been examined in previous studies, but almost all came to unfavourable conclusions in terms of efficacy and, in particular, toxicity.3–6 In this study, Motzer and co-workers tested a new VEGF receptor tyrosine kinase inhibitor, lenvatinib, alone and in combination with the mTOR inhibitor everolimus for second-line therapy in patients progressing on a first-line VEGF receptor-targeted tyrosine kinase inhibitor. The primary outcome was progression-free survival, which was significantly longer for patients allocated lenvatinib plus everolimus than for those allocated everolimus alone (hazard ratio 0·40, 95% CI 0·24–0·68; p=0·0005). Furthermore, those allocated lenvatinib alone had longer progressionfree survival than did those assigned everolimus alone (0·61, 0·38–0·98; p=0·048). The hazard ratio of 0·40 for progression-free survival is by far the most notable result obtained since the first tyrosine kinase inhibitor was introduced for treatment of metastatic renal cell carcinoma. The value of lenvatinib is reminiscent of the pivotal trial in which sunitinib outclassed interferon as first-line therapy for metastatic renal cell carcinoma.7 With respect to secondary endpoints, the proportion of patients achieving an objective response is noteworthy (43% with the combination, 27% with lenvatinib alone, and 6% with everolimus alone). Furthermore, overall survival was prolonged with
lenvatinib plus everolimus, albeit with less robustness than for progression-free survival or response. Moreover, analysis of the characteristics of the study population shows an unusually high proportion of poor-risk patients (20–39% in the combination arm, depending on the prognostic score used), suggesting the reproducibility of similar results in real-life populations. These findings reinforce the potential effect of this trial on future clinical practice. Nevertheless, despite the promising efficacy results, the two reported deaths in the lenvatinib groups from toxic effects are alarming and certainly not negligible. Moreover, the frequency of grade 3–4 diarrhoea with combination therapy (20%) and of grade 3–4 proteinuria with lenvatinib alone (19%) suggest that careful reflections are needed about appropriate dose reductions and management of toxic effects. A strategy of first-line followed by second-line tyrosine kinase inhibition to maintain suppression of the VEGF pathway (VEGF pressure) possibly represents an appropriate therapeutic approach, independent of mTOR inhibition. Indeed, lenvatinib alone showed improvements in outcomes compared with everolimus alone.2 In support of this idea, researchers on the AXIS trial8 and METEOR trial9 investigated second-line treatment with the VEGF receptor tyrosine kinase inhibitors axitinib, sorafenib, and cabozantinib and reported good results, showing that maintenance of VEGF pressure works. The added value of the study by Motzer and colleagues is the synergistic effect of the double block of VEGF and mTOR pathways, the power of which could entice a change to clinical practice even before reaching phase 3 evidence. These findings suggest that the potential of the well-known molecular mechanisms is far from exhausted and deserves further consideration. In conclusion, the atmosphere of enthusiasm for immunological treatments for metastatic renal cell carcinoma should not overshadow the validity of proven tumour-targeted strategies, combinations of which can achieve good results. Further research into the optimum sequencing of therapies targeting the tumour and also the immune system will be needed if we are to achieve our ideal goal of converting metastatic renal cell carcinoma into a chronic disease.
www.thelancet.com/oncology Published online October 16, 2015 http://dx.doi.org/10.1016/S1470-2045(15)00325-3
David Mccarthy/Science Photo Library
Combination therapy in kidney cancer: the next revolution?
Lancet Oncol 2015 Published Online October 16, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)00325-3 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(15)00290-9
1
Comment
*Sebastiano Buti, Melissa Bersanelli
5
Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy [email protected] 6
We declare no competing interests. 1
2
3
4
2
Motzer RJ, Escudier B, McDermott DF, et al, for the CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015; published online Sept 25. DOI:10.1056/ NEJMoa1510665. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol 2015; published online Oct 16. http://dx.doi.org/S1470-2045(15)00290-9. Molina AM, Feldman DR, Voss MH, et al. Phase 1 trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma. Cancer 2012; 118: 1868–76. Patel PH, Senico PL, Curiel RE, Motzer RJ. Phase I study combining treatment with temsirolimus and sunitinib malate in patients with advanced renal cell carcinoma. Clin Genitourin Cancer 2009; 7: 24–27.
7 8
9
Patnaik A, Ricart A, Cooper JS, et al. A phase I, pharmacokinetic and pharmacodynamic study of sorafenib (S), a multi-targeted kinase inhibitor in combination with temsirolimus (T), an mTOR inhibitor in patients with advanced solid malignancies. Proc Am Soc Clin Oncol 2007; 25 (suppl 18): abstr 3512. Rosenberg JE, Weinberg VK, Claros C, et al. Phase I study of sorafenib and RAD001 for metastatic clear cell renal cell carcinoma. Proc Am Soc Clin Oncol 2008; 26 (suppl 15): abstr 5109. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356: 115–24. Motzer RJ, Escudier B, Tomczak P, et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol 2013; 14: 552–62. Choueiri TK, Escudier B, Powles T, et al, for the METEOR investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015; published online Sept 25. DOI:10.1056/ NEJMoa1510016.
www.thelancet.com/oncology Published online October 16, 2015 http://dx.doi.org/10.1016/S1470-2045(15)00325-3