T h e N E W E N G L A N D J O U R N A L of M E D I C I N E
3. Ba§ M. Clinical efficacy o f icatibant in the treatm ent o f acute hereditary angioedema during the FAST-3 trial. Expert Rev Clin Immunol 2012;8:707-17. 4. Nosbaum A, Bouillet L, Floccard B, et al. M anagem ent o f
angiotensin-converting enzyme inhibitor-related angioedema: recom m endations from the French N ational Center for Angioedema. Rev Med Interne 2013;34:209-13. (In French.) DOI: 10.1056/NEJMcl503671
Lenvatinib in Radioiodine-Refractory Thyroid Cancer Schlumberger et al. (Feb. 12 is sue)1 report that lenvatinib, as compared with placebo, showed significant improvements in progression-free survival and response rate among patients with radioiodine-refractory thy roid cancer. However, 76% o f the patients had grade 3 or higher treatment-related toxic events, and there were an increased number o f deaths during lenvatinib treatment. Furthermore, 6 of the 20 deaths in the lenvatinib group appeared to be treatment-related. Therefore, it is crucial to identify predictive biomarkers to identify pa tients who will benefit most from lenvatinib treatment. These markers might be found at the genetic level,23although the presence of BRAF or HAS mutations did not predict a benefit for lenva tinib in this study.1 Alternatively, the occurrence of adverse events might act as a surrogate bio marker of drug activity because the occurrence of treatment-related toxic effects is associated with pharmacodynamic effects of the drug.2'4 Recent ly, it has been suggested that such factors as tumor shrinkage and a severe grade o f hyper tension, proteinuria, and fatigue induced by len vatinib were significantly correlated with the area under the curve for the dosing interval.5 Therefore, it would be interesting to know whether the authors found a correlation between adverse events and treatment outcome.
t o t h e e d it o r :
H y o jin Lee, M.D. Hwan-Jung Yun, M.D. Samyong Kim, M.D. Chungnam National University College o f Medicine Daejeon, South Korea [email protected]
No potential conflict o f interest relevant to this letter was re ported.
proteinuria as biomarkers o f response to anti-angiogenic ther apy. Expert Opin Drug Metab Toxicol 2012;8:283-93. 5. Koyama N, Saito K, Nishioka Y, et al. Pharmacodynamic change in plasma angiogenic proteins: a dose-escalation phase 1 study of the multi-kinase inhibitor lenvatinib. BMC Cancer 2014;14:530. DOI: 10.1056/NEJMcl503150
Lee and colleagues correct ly describe the profile of adverse events associ ated with lenvatinib, but these side effects should be considered in light of the relatively long treat ment duration for lenvatinib versus placebo (298.8 vs. 67.1 person-years) and exposure (269.5 vs. 65.4 person-years). Furthermore, grade 4 ad verse events were infrequent, with similar rates in the two study groups (lenvatinib, 11.9%; pla cebo, 7.6%). When rates of serious adverse events were adjusted for treatment duration, the differ ence between lenvatinib and placebo was mar ginal for nonfatal serious adverse events (0.93 and 0.78 episodes per person-year, respectively) and absent for fatal events (0.07 and 0.10 episodes per person-year, respectively). Of the six treatmentrelated deaths in the lenvatinib group, four were nonspecific in their cause (sudden death, general deterioration, and two unspecified). Thus, it is challenging to directly attribute these deaths to lenvatinib treatment. Therefore, we believe that the lenvatinib safety profile should not detract from the remarkable efficacy results that were observed. We agree that the identification of sur rogate biomarkers for efficacy would be useful; analysis o f biomarkers on the basis of data from our trial is under way. t h e a u t h o r s reply :
Martin Schlumberger, M.D. Institut Gustave Roussy Villejuif, France [email protected]
Makoto Tahara, M.D., Ph.D. 1. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib ver sus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 2015;372:621-30. 2. Ravaud A, Schmidinger M. Clinical biomarkers o f response in advanced renal cell carcinoma. Ann Oncol 2013;24:2935-42. 3. Dienstmann R, Brana 1, Rodon J, Tabernero J. Toxicity as a bio marker o f efficacy of molecular targeted therapies: focus on EGFR and VEGF inhibiting anticancer drugs. Oncologist 2011;16:1729-40. 4. Horsley L, Marti K, Jayson GC. Is the toxicity o f anti-angio genic drugs predictive o f outcome? A review o f hypertension and 1 8 6 8
N E N G L J M E D 3 7 2 ;1 9
National Cancer Center Hospital East Kashiwa Japan
LoriJ. W irth, M.D. Massachusetts General Hospital Boston, MA
Since publication o f their article, the authors report no fur ther potential conflict o f interest. DOI: 10.1056/NEJMcl503150
N E J M .O R G
MAY 7, 2015
Copyright © Massachusetts Medical Society 2015.
3. Ba§ M. Clinical efficacy o f icatibant in the treatm ent o f acute hereditary angioedema during the FAST-3 trial. Expert Rev Clin Immunol 2012;8:707-17. 4. Nosbaum A, Bouillet L, Floccard B, et al. M anagem ent o f
angiotensin-converting enzyme inhibitor-related angioedema: recom m endations from the French N ational Center for Angioedema. Rev Med Interne 2013;34:209-13. (In French.) DOI: 10.1056/NEJMcl503671
Lenvatinib in Radioiodine-Refractory Thyroid Cancer Schlumberger et al. (Feb. 12 is sue)1 report that lenvatinib, as compared with placebo, showed significant improvements in progression-free survival and response rate among patients with radioiodine-refractory thy roid cancer. However, 76% o f the patients had grade 3 or higher treatment-related toxic events, and there were an increased number o f deaths during lenvatinib treatment. Furthermore, 6 of the 20 deaths in the lenvatinib group appeared to be treatment-related. Therefore, it is crucial to identify predictive biomarkers to identify pa tients who will benefit most from lenvatinib treatment. These markers might be found at the genetic level,23although the presence of BRAF or HAS mutations did not predict a benefit for lenva tinib in this study.1 Alternatively, the occurrence of adverse events might act as a surrogate bio marker of drug activity because the occurrence of treatment-related toxic effects is associated with pharmacodynamic effects of the drug.2'4 Recent ly, it has been suggested that such factors as tumor shrinkage and a severe grade o f hyper tension, proteinuria, and fatigue induced by len vatinib were significantly correlated with the area under the curve for the dosing interval.5 Therefore, it would be interesting to know whether the authors found a correlation between adverse events and treatment outcome.
t o t h e e d it o r :
H y o jin Lee, M.D. Hwan-Jung Yun, M.D. Samyong Kim, M.D. Chungnam National University College o f Medicine Daejeon, South Korea [email protected]
No potential conflict o f interest relevant to this letter was re ported.
proteinuria as biomarkers o f response to anti-angiogenic ther apy. Expert Opin Drug Metab Toxicol 2012;8:283-93. 5. Koyama N, Saito K, Nishioka Y, et al. Pharmacodynamic change in plasma angiogenic proteins: a dose-escalation phase 1 study of the multi-kinase inhibitor lenvatinib. BMC Cancer 2014;14:530. DOI: 10.1056/NEJMcl503150
Lee and colleagues correct ly describe the profile of adverse events associ ated with lenvatinib, but these side effects should be considered in light of the relatively long treat ment duration for lenvatinib versus placebo (298.8 vs. 67.1 person-years) and exposure (269.5 vs. 65.4 person-years). Furthermore, grade 4 ad verse events were infrequent, with similar rates in the two study groups (lenvatinib, 11.9%; pla cebo, 7.6%). When rates of serious adverse events were adjusted for treatment duration, the differ ence between lenvatinib and placebo was mar ginal for nonfatal serious adverse events (0.93 and 0.78 episodes per person-year, respectively) and absent for fatal events (0.07 and 0.10 episodes per person-year, respectively). Of the six treatmentrelated deaths in the lenvatinib group, four were nonspecific in their cause (sudden death, general deterioration, and two unspecified). Thus, it is challenging to directly attribute these deaths to lenvatinib treatment. Therefore, we believe that the lenvatinib safety profile should not detract from the remarkable efficacy results that were observed. We agree that the identification of sur rogate biomarkers for efficacy would be useful; analysis o f biomarkers on the basis of data from our trial is under way. t h e a u t h o r s reply :
Martin Schlumberger, M.D. Institut Gustave Roussy Villejuif, France [email protected]
Makoto Tahara, M.D., Ph.D. 1. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib ver sus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 2015;372:621-30. 2. Ravaud A, Schmidinger M. Clinical biomarkers o f response in advanced renal cell carcinoma. Ann Oncol 2013;24:2935-42. 3. Dienstmann R, Brana 1, Rodon J, Tabernero J. Toxicity as a bio marker o f efficacy of molecular targeted therapies: focus on EGFR and VEGF inhibiting anticancer drugs. Oncologist 2011;16:1729-40. 4. Horsley L, Marti K, Jayson GC. Is the toxicity o f anti-angio genic drugs predictive o f outcome? A review o f hypertension and 1 8 6 8
N E N G L J M E D 3 7 2 ;1 9
National Cancer Center Hospital East Kashiwa Japan
LoriJ. W irth, M.D. Massachusetts General Hospital Boston, MA
Since publication o f their article, the authors report no fur ther potential conflict o f interest. DOI: 10.1056/NEJMcl503150
N E J M .O R G
MAY 7, 2015
Copyright © Massachusetts Medical Society 2015.
