- Email: [email protected]
Refining the Toxicity Profile of Crizotinib
Editorial
Refining the Toxicity Profile of Crizotinib Benjamin Solomon, MBBS, PhD, FRACP
C
rizotinib (Xalkori) is an orally available, small molecule inhibitor of the ALK, ROS1 and c-MET tyrosine kinases. It is standard of care for the management of ALK-positive non-small cell lung cancer (NSCLC)1,2 and has activity in ROS1 rearranged NSCLC3 and c-MET amplified NSCLC.4 Accelerated approval of crizotinib by the U.S. Food and Drug Administration was granted in August 2011 for the treatment of advanced ALK-positive NSCLC on basis of a phase I and phase II trial, with initial data from 255 patients. Since then, crizotinib has been approved in approximately 78 countries and received by thousands of ALK-positive NSCLC patients worldwide. Data from the initial clinical trials with crizotinib indicated that it was effective, safe, and generally well tolerated. In the phases 1, 2, and 3 studies of crizotinib, the most often reported adverse events were visual changes, nausea, diarrhea, vomiting, edema, constipation, and elevated transaminases.1,2,5,6 The most serious toxicities were hepatotoxicity and pneumonitis.1,2,5,6 As one would expect, with increasing clinical experience with crizotinib over recent years other toxicities have been described including asymptomatic bradycardia7 and decreased total testosterone in males.6 In this issue of the Journal of Thoracic Oncology, information is provided on additional potential toxicity from crizotinib including renal impairment, renal cysts, and hypersensitivity. Impaired renal function associated with crizotinib treatment has previously been reported in recent case series.8–10 The largest of these by Brosnan et al8 describe a 23.9% mean reduction in estimated glomerular filtration rate (eGFR), calculated with Chronic Kidney Disease Epidemiology Collaboration method, in a series of 38 ALK-positive NSCLC patients treated with crizotinib. The majority of patients had complete recovery of eGFR to baseline upon cessation of crizotinib. The mechanism underlying the creatinine alteration and in particular if it was associated with a true nephrotoxicity or if it reflected a disproportional alteration in tubular creatinine secretion was unclear. In this issue of the Journal of Thoracic Oncology, Camidge et al.11 attempt to shed light on the apparent changes in renal function based on detailed evaluation of two crizotinib-treated individuals by serial calculation of eGFR using the Chronic Kidney Disease Epidemiology Collaboration equation in parallel with direct measurement of 24-hour creatinine clearance or iothalamate assessment. Somewhat conflicting results were observed. In one patient, treatment with crizotinib resulted in a rise in serum creatinine and decrease in measured GFR. Cessation of crizotinib resulted in a fall in his serum creatinine and a rise both in his estimated GFR and his measured GFR. In a second patient, interruption of crizotinib treatment resulted in an increase in estimated GFR, but a rechallenge with crizotinib was associated with a fall in eGFR but a rise in iothalamate-measured GFR. These results while observational and based on descriptions of only two patients, confirm that the rise in serum creatinine is reversible and that it may, or may not be, associated with a true alteration in renal function. So what are the practical implications of dosing crizotinib in patients with impaired renal function? Guidance is provided by the crizotinib product information which indicates that no starting dose adjustment is required for patients with mild or moderate renal impairment (creatinine clearance 30–89 ml/min) based on population pharmacokinetic analysis
Address for correspondence: Benjamin Solomon, MBBS, PhD, FRACP, Department of Medical Oncology, Peter MacCallum Cancer Centre, St. Andrew’s Place, East Melbourne, Victoria 3002, Australia. E-mail: [email protected] DOI: 10.1097/JTO.0000000000000375 Copyright © 2014 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/14/0911-1596
1596
Journal of Thoracic Oncology ® • Volume 9, Number 11, November 2014
Journal of Thoracic Oncology ® • Volume 9, Number 11, November 2014
that crizotinib exposure did not alter with this level of renal dysfunction.5 In patients with more significant renal impairment (creatinine clearance <30 ml/min) increased exposure to crizotinib has been observed and the recommended starting dose is 250 mg once daily.5 In patients with documented renal impairment, or in patients noted to have rising creatinine on crizotinib treatment, avoidance of factors that may exacerbate renal impairment, e.g., concomitant use of nephrotoxic drugs seems appropriate. The data regarding the potential reversibility of creatinine alterations are reassuring and caution should be taken in ceasing crizotinib solely on basis of elevated creatinine without additional measures of renal function. Information about an additional renal toxicity of crizotinib, namely the development of renal cysts, is provided by the report of Lin et al.12 While the development of renal cysts has been previously reported in the context of crizotinib treatment,5 Lin et al provide a retrospective review to indicate that the frequency of cysts may be higher than previously suspected. In this study, 32 patients treated with crizotinib underwent radiological review of serial contrast-enhanced computed tomography scans done before and after initiation of crizotinib treatment. Curiously, a higher than expected 23 of 32 (72%) had simple cysts on baseline scans (Bozniak category 1).13 Eight of 32 patients (7/32 with baseline cysts and 1/9 without) had an increase in number or size of cysts within the kidney with 4 of 32 developing complex renal cysts (Bozniak category II–IV).13 Importantly, cysts in three of five patients regressed on withholding crizotinib. This report suggests that the renal cysts appear likely to be more frequent than the 4% described in the U.S. package insert5 and should enter the differential diagnosis for a patient on crizotinib treatment who develops simple or complex cysts on crizotinib treatment. The mechanism of cyst formation is uncertain and no biopsy information is provided to help elucidate this. Further questions remain unanswered: What for example are the effects of age, sex, ethnicity or crizotinib concentration on frequency of cysts? It is reassuring, however, that the cysts are reversible after discontinuation of crizotinib. A separate report from Klempner et al14 describes a complex renal cyst on crizotinib that regressed despite continued therapy with crizotinib. Finally, Awad and collegues15 describe two cases of hypersensitivity to crizotinib. Hypersensitivity reactions to anticancer treatments commonly occur with cytotoxic drugs such as carboplatin or taxanes and monoclonal antibodies such as rituximab or cetuximab but hypersensitivity reactions to small molecules have been reported less frequently. In this report, two cases of hypersensitivity to crizotinib characterized by the eruption of a pruritic rash in the absence of other symptoms such as fever, hypotension, bronchospasm, or angioedema are described. While no skin testing results are provided, and the specific immunologic mechanisms responsible for the hypersensitivity are not clear, in both patients it was possible to continue treatment with crizotinib after use of a 12-step desensitization protocol.16 Importantly, however, continued exposure to drug is required to maintain the state of tolerance induced by the desensitization, and once treatment is interrupted, rechallenge with drug may result in further
Editorial
hypersensitivity. While use of alternative ALK inhibitors may be an option for some patients, as the authors point out, the incidence of cross reactivity is unknown and the desensitization protocol appears to be a reasonable and effective strategy to manage this apparently rare side effect allowing continued treatment with crizotinib. An essential requirement of postmarketing pharmacovigilance is reporting of adverse events by clinicians. It is through these mechanisms as well as by systematic collection of data by the drug sponsor and regulatory authorities that previously unrecognized adverse events or harmful drug interactions be identified. The observational data provided in these reports in this issue of the Journal of Thoracic Oncology add to the clinical experience with crizotinib and help define the toxicity profile of crizotinib, albeit with small patient numbers. It appears, though, that the significant efficacy and safety profile that led to the initial accelerated approval of crizotinib has been maintained over time. References 1. Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol 2012;13:1011–1019. 2. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368:2385–2394. 3. Ou Sh, Bang TJ, Camidge DR, et al. Efficacy and safety of crizotinib in patients with advanced ROS1-rearranged non-small cell lung cancer (NSCLC). J Clin Oncol 2013; 31(Suppl; abstr 8032. 4. Camidge DR, Ou SHI, Shapiro GI, et al. in J Clin Oncol 2014; 32(suppl; abstr 8001):5s. 5. United States Xalkori Package insert. Available at: www.fda.gov/drugs. Accessed September 8, 2014. 6. Kim Dk, Shn MJ, Yang P, et al. Updated results of a global phase II study with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC) Ann Oncol 2012; 23. 7. Ou SH, Tong WP, Azada M, Siwak-Tapp C, Dy J, Stiber JA. Heart rate decrease during crizotinib treatment and potential correlation to clinical response. Cancer 2013;119:1969–1975. 8. Brosnan EM, Weickhardt AJ, Lu X, et al. Drug-induced reduction in estimated glomerular filtration rate in patients with ALK-positive nonsmall cell lung cancer treated with the ALK inhibitor crizotinib. Cancer 2014;120:664–674. 9. Gastaud L, Ambrosetti D, Otto J, et al. Acute kidney injury following crizotinib administration for non-small-cell lung carcinoma. Lung Cancer 2013;82:362–364. 10. Martín Martorell P, Huerta Alvaro M, Solís Salguero MA, Insa Molla A. Crizotinib and renal insufficiency: a case report and review of the literature. Lung Cancer 2014;84:310–313. 11. Camidge DR, Brosnan EM, DeSilva C, Koo PJ, Chonchol M. Crizotinib effects on creatinine and non-creatinine–based measures of glomerular filtration rate. J Thorac Oncol 2014;9:1634–1637. 12. Lin Y-T, Wang Y-F, Yang JC-H, et al. Development of renal cysts after crizotinib treatment in advanced ALK-positive non–small-cell lung cancer. J Thorac Oncol 2014;9:1720–1725. 13. Warren KS, McFarlane J. The Bosniak classification of renal cystic masses. BJU Int 2005;95:939–942. 14. Klempner SJ, Aubin G, Dash A, Ou SH. Spontaneous regression of crizotinib-associated complex renal cysts during continuous crizotinib treatment. Oncologist 2014;19:1008–1010. 15. Awad MM, Lax TP, Slawski BR, Shaw AT. Successful desensitization of two patients with ALK-positive lung cancer and hypersensitivity to crizotinib. J Thorac Oncol 2014;9:1726–1728. 16. Castells MC, Tennant NM, Sloane DE, et al. Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases. J Allergy Clin Immunol 2008;122:574–580.
Copyright © 2014 by the International Association for the Study of Lung Cancer
1597
Refining the Toxicity Profile of Crizotinib Benjamin Solomon, MBBS, PhD, FRACP
C
rizotinib (Xalkori) is an orally available, small molecule inhibitor of the ALK, ROS1 and c-MET tyrosine kinases. It is standard of care for the management of ALK-positive non-small cell lung cancer (NSCLC)1,2 and has activity in ROS1 rearranged NSCLC3 and c-MET amplified NSCLC.4 Accelerated approval of crizotinib by the U.S. Food and Drug Administration was granted in August 2011 for the treatment of advanced ALK-positive NSCLC on basis of a phase I and phase II trial, with initial data from 255 patients. Since then, crizotinib has been approved in approximately 78 countries and received by thousands of ALK-positive NSCLC patients worldwide. Data from the initial clinical trials with crizotinib indicated that it was effective, safe, and generally well tolerated. In the phases 1, 2, and 3 studies of crizotinib, the most often reported adverse events were visual changes, nausea, diarrhea, vomiting, edema, constipation, and elevated transaminases.1,2,5,6 The most serious toxicities were hepatotoxicity and pneumonitis.1,2,5,6 As one would expect, with increasing clinical experience with crizotinib over recent years other toxicities have been described including asymptomatic bradycardia7 and decreased total testosterone in males.6 In this issue of the Journal of Thoracic Oncology, information is provided on additional potential toxicity from crizotinib including renal impairment, renal cysts, and hypersensitivity. Impaired renal function associated with crizotinib treatment has previously been reported in recent case series.8–10 The largest of these by Brosnan et al8 describe a 23.9% mean reduction in estimated glomerular filtration rate (eGFR), calculated with Chronic Kidney Disease Epidemiology Collaboration method, in a series of 38 ALK-positive NSCLC patients treated with crizotinib. The majority of patients had complete recovery of eGFR to baseline upon cessation of crizotinib. The mechanism underlying the creatinine alteration and in particular if it was associated with a true nephrotoxicity or if it reflected a disproportional alteration in tubular creatinine secretion was unclear. In this issue of the Journal of Thoracic Oncology, Camidge et al.11 attempt to shed light on the apparent changes in renal function based on detailed evaluation of two crizotinib-treated individuals by serial calculation of eGFR using the Chronic Kidney Disease Epidemiology Collaboration equation in parallel with direct measurement of 24-hour creatinine clearance or iothalamate assessment. Somewhat conflicting results were observed. In one patient, treatment with crizotinib resulted in a rise in serum creatinine and decrease in measured GFR. Cessation of crizotinib resulted in a fall in his serum creatinine and a rise both in his estimated GFR and his measured GFR. In a second patient, interruption of crizotinib treatment resulted in an increase in estimated GFR, but a rechallenge with crizotinib was associated with a fall in eGFR but a rise in iothalamate-measured GFR. These results while observational and based on descriptions of only two patients, confirm that the rise in serum creatinine is reversible and that it may, or may not be, associated with a true alteration in renal function. So what are the practical implications of dosing crizotinib in patients with impaired renal function? Guidance is provided by the crizotinib product information which indicates that no starting dose adjustment is required for patients with mild or moderate renal impairment (creatinine clearance 30–89 ml/min) based on population pharmacokinetic analysis
Address for correspondence: Benjamin Solomon, MBBS, PhD, FRACP, Department of Medical Oncology, Peter MacCallum Cancer Centre, St. Andrew’s Place, East Melbourne, Victoria 3002, Australia. E-mail: [email protected] DOI: 10.1097/JTO.0000000000000375 Copyright © 2014 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/14/0911-1596
1596
Journal of Thoracic Oncology ® • Volume 9, Number 11, November 2014
Journal of Thoracic Oncology ® • Volume 9, Number 11, November 2014
that crizotinib exposure did not alter with this level of renal dysfunction.5 In patients with more significant renal impairment (creatinine clearance <30 ml/min) increased exposure to crizotinib has been observed and the recommended starting dose is 250 mg once daily.5 In patients with documented renal impairment, or in patients noted to have rising creatinine on crizotinib treatment, avoidance of factors that may exacerbate renal impairment, e.g., concomitant use of nephrotoxic drugs seems appropriate. The data regarding the potential reversibility of creatinine alterations are reassuring and caution should be taken in ceasing crizotinib solely on basis of elevated creatinine without additional measures of renal function. Information about an additional renal toxicity of crizotinib, namely the development of renal cysts, is provided by the report of Lin et al.12 While the development of renal cysts has been previously reported in the context of crizotinib treatment,5 Lin et al provide a retrospective review to indicate that the frequency of cysts may be higher than previously suspected. In this study, 32 patients treated with crizotinib underwent radiological review of serial contrast-enhanced computed tomography scans done before and after initiation of crizotinib treatment. Curiously, a higher than expected 23 of 32 (72%) had simple cysts on baseline scans (Bozniak category 1).13 Eight of 32 patients (7/32 with baseline cysts and 1/9 without) had an increase in number or size of cysts within the kidney with 4 of 32 developing complex renal cysts (Bozniak category II–IV).13 Importantly, cysts in three of five patients regressed on withholding crizotinib. This report suggests that the renal cysts appear likely to be more frequent than the 4% described in the U.S. package insert5 and should enter the differential diagnosis for a patient on crizotinib treatment who develops simple or complex cysts on crizotinib treatment. The mechanism of cyst formation is uncertain and no biopsy information is provided to help elucidate this. Further questions remain unanswered: What for example are the effects of age, sex, ethnicity or crizotinib concentration on frequency of cysts? It is reassuring, however, that the cysts are reversible after discontinuation of crizotinib. A separate report from Klempner et al14 describes a complex renal cyst on crizotinib that regressed despite continued therapy with crizotinib. Finally, Awad and collegues15 describe two cases of hypersensitivity to crizotinib. Hypersensitivity reactions to anticancer treatments commonly occur with cytotoxic drugs such as carboplatin or taxanes and monoclonal antibodies such as rituximab or cetuximab but hypersensitivity reactions to small molecules have been reported less frequently. In this report, two cases of hypersensitivity to crizotinib characterized by the eruption of a pruritic rash in the absence of other symptoms such as fever, hypotension, bronchospasm, or angioedema are described. While no skin testing results are provided, and the specific immunologic mechanisms responsible for the hypersensitivity are not clear, in both patients it was possible to continue treatment with crizotinib after use of a 12-step desensitization protocol.16 Importantly, however, continued exposure to drug is required to maintain the state of tolerance induced by the desensitization, and once treatment is interrupted, rechallenge with drug may result in further
Editorial
hypersensitivity. While use of alternative ALK inhibitors may be an option for some patients, as the authors point out, the incidence of cross reactivity is unknown and the desensitization protocol appears to be a reasonable and effective strategy to manage this apparently rare side effect allowing continued treatment with crizotinib. An essential requirement of postmarketing pharmacovigilance is reporting of adverse events by clinicians. It is through these mechanisms as well as by systematic collection of data by the drug sponsor and regulatory authorities that previously unrecognized adverse events or harmful drug interactions be identified. The observational data provided in these reports in this issue of the Journal of Thoracic Oncology add to the clinical experience with crizotinib and help define the toxicity profile of crizotinib, albeit with small patient numbers. It appears, though, that the significant efficacy and safety profile that led to the initial accelerated approval of crizotinib has been maintained over time. References 1. Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol 2012;13:1011–1019. 2. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368:2385–2394. 3. Ou Sh, Bang TJ, Camidge DR, et al. Efficacy and safety of crizotinib in patients with advanced ROS1-rearranged non-small cell lung cancer (NSCLC). J Clin Oncol 2013; 31(Suppl; abstr 8032. 4. Camidge DR, Ou SHI, Shapiro GI, et al. in J Clin Oncol 2014; 32(suppl; abstr 8001):5s. 5. United States Xalkori Package insert. Available at: www.fda.gov/drugs. Accessed September 8, 2014. 6. Kim Dk, Shn MJ, Yang P, et al. Updated results of a global phase II study with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC) Ann Oncol 2012; 23. 7. Ou SH, Tong WP, Azada M, Siwak-Tapp C, Dy J, Stiber JA. Heart rate decrease during crizotinib treatment and potential correlation to clinical response. Cancer 2013;119:1969–1975. 8. Brosnan EM, Weickhardt AJ, Lu X, et al. Drug-induced reduction in estimated glomerular filtration rate in patients with ALK-positive nonsmall cell lung cancer treated with the ALK inhibitor crizotinib. Cancer 2014;120:664–674. 9. Gastaud L, Ambrosetti D, Otto J, et al. Acute kidney injury following crizotinib administration for non-small-cell lung carcinoma. Lung Cancer 2013;82:362–364. 10. Martín Martorell P, Huerta Alvaro M, Solís Salguero MA, Insa Molla A. Crizotinib and renal insufficiency: a case report and review of the literature. Lung Cancer 2014;84:310–313. 11. Camidge DR, Brosnan EM, DeSilva C, Koo PJ, Chonchol M. Crizotinib effects on creatinine and non-creatinine–based measures of glomerular filtration rate. J Thorac Oncol 2014;9:1634–1637. 12. Lin Y-T, Wang Y-F, Yang JC-H, et al. Development of renal cysts after crizotinib treatment in advanced ALK-positive non–small-cell lung cancer. J Thorac Oncol 2014;9:1720–1725. 13. Warren KS, McFarlane J. The Bosniak classification of renal cystic masses. BJU Int 2005;95:939–942. 14. Klempner SJ, Aubin G, Dash A, Ou SH. Spontaneous regression of crizotinib-associated complex renal cysts during continuous crizotinib treatment. Oncologist 2014;19:1008–1010. 15. Awad MM, Lax TP, Slawski BR, Shaw AT. Successful desensitization of two patients with ALK-positive lung cancer and hypersensitivity to crizotinib. J Thorac Oncol 2014;9:1726–1728. 16. Castells MC, Tennant NM, Sloane DE, et al. Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases. J Allergy Clin Immunol 2008;122:574–580.
Copyright © 2014 by the International Association for the Study of Lung Cancer
1597