- Email: [email protected]
Nilotinib, imatinib, and GIST therapy
Comment
provide insights into mechanisms of treatment resistance to inform new therapeutic approaches. Further studies to investigate whether monitoring of circulating tumour DNA can be used to improve outcomes for patients with diffuse large B-cell lymphoma are clearly warranted. The clinical adoption of minimal residual disease monitoring with BCR-ABL RT-PCR in patients with chronic myeloid leukaemia has required the undertaking of many well-designed clinical trials to establish the best way to implement this approach in the clinic. Similar efforts will be needed for approaches based on circulating tumour DNA, focused on optimisation and standardisation of next-generationsequencing technologies for analysis, to establish the optimum testing schedule and identify specific at-risk populations and those highly likely to be cured through appropriately designed prospective clinical trials.
We declare no competing interests. 1
2
3
4
5
6
7
8
Sarah-Jane Dawson, *John F Seymour Molecular Biomarkers and Translational Genomics Laboratory and Department of Medical Oncology (S-JD) and Department of Haematology (JFS), Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia; and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia (S-JD, JFS) [email protected]
9
10
Hughes T, Deininger M, Hochhaus A, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006; 108: 28–37. Anker P, Mulcahy H, Chen XQ, Stroun M. Detection of circulating tumour DNA in the blood (plasma/serum) of cancer patients. Cancer Metastasis Rev 1999; 18: 65–73. Dawson SJ, Tsui DW, Murtaza M, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med 2013; 368: 1199–209. Murtaza M, Dawson SJ, Tsui DW, et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 2013; 497: 108–12. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 2014; 32: 3059–68. Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 2010; 28: 4184–90. Cheah CY, Hofman MS, Dickinson M, et al. Limited role for surveillance PETCT scanning in patients with diffuse large B-cell lymphoma in complete metabolic remission following primary therapy. Brit J Cancer 2013; 109: 312–7. Roschewski M, Dunleavy K, Pittaluga S, et al. Circulating tumour DNA and CT monitoring in patients with untreated diffuse large B-cell lymphoma: a correlative biomarker study. Lancet Oncol 2015; published online April 2. http://dx.doi.org/10/1016/S14702045(15)70106-3. Arnold A, Cossman J, Bakhshi A, Jaffe ES, Waldmann TA, Korsmeyer SJ. Immunoglobulin-gene rearrangements as unique clonal markers in human lymphoid neoplasms. N Engl J Med 1983; 309: 1593–99. El Messaoudi S, Rolet F, Mouliere F, Thierry AR. Circulating cell free DNA: Preanalytical considerations. Clin Chim Acta 2013; 424: 222–30.
The discovery of driver mutations in gastrointestinal stromal tumours (GISTs) in the KIT or in PDGFRA oncogenes, and the subsequent incorporation of the tyrosine kinase inhibitor imatinib to the therapy of advanced disease, has resulted in remarkable therapeutic progress. Median overall survival of patients with metastatic tumours has risen from a few months to around 60 months in the last decade.1 Unfortunately, however, most patients will eventually develop resistance to imatinib after a median of 2 years,1,2 mainly due to the acquisition of secondary KIT and PDGFRA mutations. In these patients, two multi-targeted tyrosine kinase inhibitors, sunitinib and regorafenib, have shown activity—sunitinib in second-line therapy3 and regorafenib in third-line treatment.4 However, their effects are limited, with sunitinib resulting in a progression-free survival of around 6·5 months and regorafenib in a progression-free survival of about 5 months. Therefore, great room for improvement www.thelancet.com/oncology Vol 16 May 2015
remains, and a crucial step forward would be to enhance the efficacy of first-line therapy. Nilotinib, a potent second-generation tyrosine kinase inhibitor against BCR-ABL, KIT, and PDGFRα, has shown superior activity to imatinib in the treatment of Philadelphia chromosome-positive chronic myeloid leukaemia.5 In studies in GIST cell lines, nilotinib had similar potency to imatinib in inhibiting KIT, but nilotinib was able to accumulate at higher intracellular concentrations than imatinib.6 This finding suggests that nilotinib might be less susceptible than imatinib is to cellular transport-driven resistance. In The Lancet Oncology, Jean-Yves Blay and colleagues7 describe the results of a large randomised phase 3 study of nilotinib versus imatinib as first-line therapy of advanced GIST. The study approach was bold, in view of the high activity and favourable safety of imatinib and the scarcity of available data about nilotinib in this setting. In fact, it constitutes the first head-to-head clinical trial comparing
Nephron (CC BY-SA) via Wikimedia Common
Nilotinib, imatinib, and GIST therapy
Published Online April 14, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70179-8 See Articles page 550
483
Comment
a new agent against imatinib in GIST. However, since use of imatinib is moving towards adjuvant therapy in most high-risk patients, it is prudent to investigate new alternatives for the first-line therapy of advanced disease. In this carefully designed phase 3 study, interim analyses for futility and superiority were planned. The accrual of patients was stopped prematurely because the futility boundary was crossed at the first analysis. The results showed significantly better progression-free survival—the primary endpoint of the trial—with imatinib treatment (hazard ratio [HR] 1·47, 95% CI 1·10–1·95). Even more relevant, overall survival was better with imatinib (HR 1·85, 95% CI 1·20–2·86). An interesting exploratory analysis of correlation with genotype showed better overall survival associated with imatinib in KIT exon 9 and 11 mutations and wild-type GIST subgroups. In terms of progression-free survival, imatinib was superior in KIT exon 9 mutation and wild-type GIST subgroups, whereas the results for the KIT exon 11 mutation subgroup were similar for both agents. As the authors suggest, informative censoring following the interim analysis might have changed this latter effect. When we look at the results, the conclusion leaves no doubt: at present, imatinib should be the first-line treatment for patients with advanced GIST, irrespective of the genotype they harbour. Consequently, the only option available today to enhance first-line therapeutic results in everyday medical practice is to optimise imatinib treatment. Notably, the overall survival reported in the imatinib group of the study compares favourably with that reported in previous clinical trials,2 which could suggest that management of these patients has improved over time. Methods to optimise imatinib treatment include monitoring of imatinib plasma levels in patients with poor response or unusual side-effects, improving patient adherence, examination of mutational analysis systematically, administration of high doses of imatinib to patients with KIT exon 9 mutations, and combined surgery in selected responding patients. However, the negative results recorded in the trial raise a question about its rationale. Is it not prudent to have solid preclinical and early clinical data supporting the experimental approach before embarking on a large-scale trial? In a recent phase 3 trial of patients with advanced GIST who had been previously treated with imatinib and sunitinib, nilotinib showed no advantages in progression-free or overall survival compared with 484
resumption of treatment with the previous tyrosine kinase inhibitor.8 Nevertheless, in a post-hoc analysis, nilotinib was associated with improved overall survival in the subset of patients treated with only two previous lines of therapy. However, despite the negative results in the firstline and third-line phase 3 trials, I do not believe that nilotinib should be discarded from the treatment of GIST. There is still a great need and scope for progress in the treatment of this disease. At present, the best results in clinics are reached with the sequential use of different available agents, combined with judicious personalisation of therapy according to the mutational status. The potential of nilotinib in specific populations should be explored in greater depth.9,10 GIST constitutes a heterogeneous disease in which intensified study of the correlation between primary and acquired mutations and response to different agents could contribute to their more efficient use. Xavier Garcia del Muro Sarcoma Multidisciplinary Unit and Medical Oncology Department, Institut Català d’Oncologia, IDIBELL, Barcelona 08908, Spain [email protected] I have received personal fees for consultancy and lectures from Pfizer and Bayer. 1
2
3
4
5 6
7
8
9
10
Blanke CD, Demetri GD, von Mehren M, et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol 2008; 26: 620–25. Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 2004; 364: 1127–34. Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006; 368: 1329–38. Demetri GD, Reichardt P, Kang Y-K, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebocontrolled, phase 3 trial. Lancet 2013; 381: 295–302. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 2010; 362: 2251–59. Prenen H, Guetens G, de Boeck G, et al. Cellular uptake of the tyrosine kinase inhibitors imatinib and AMN107 in gastrointestinal stromal tumor cell lines. Pharmacology 2006; 77: 11–16. Blay J-Y, Shen L, Kang Y-K, et al. Nilotinib versus imatinib as first-line therapy for patients with unresectable or metastatic gastrointestinal stromal tumours (ENESTg1): a randomised phase 3 trial. Lancet Oncol 2015; published online April 14. http://dx.doi.org/10.1016/S1470-2045(15)70105-1. Reichardt P, Blay JY, Gelderblom H, et al. Phase III study of nilotinib versus best supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib. Ann Oncol 2012; 23: 1680–87. Sako H, Fukuda K, Saikawa Y, et al. Antitumor effect of the tyrosine kinase inhibitor nilotinib on gastrointestinal stromal tumor (GIST) and imatinibresistant GIST cells. PLoS One 2014; 9: e107613. Hsueh YS, Lin CL, Chiang NJ, et al. Selecting tyrosine kinase inhibitors for gastrointestinal stromal tumor with secondary KIT activation-loop domain mutations. PLoS One 2013; 8: e65762.
www.thelancet.com/oncology Vol 16 May 2015
provide insights into mechanisms of treatment resistance to inform new therapeutic approaches. Further studies to investigate whether monitoring of circulating tumour DNA can be used to improve outcomes for patients with diffuse large B-cell lymphoma are clearly warranted. The clinical adoption of minimal residual disease monitoring with BCR-ABL RT-PCR in patients with chronic myeloid leukaemia has required the undertaking of many well-designed clinical trials to establish the best way to implement this approach in the clinic. Similar efforts will be needed for approaches based on circulating tumour DNA, focused on optimisation and standardisation of next-generationsequencing technologies for analysis, to establish the optimum testing schedule and identify specific at-risk populations and those highly likely to be cured through appropriately designed prospective clinical trials.
We declare no competing interests. 1
2
3
4
5
6
7
8
Sarah-Jane Dawson, *John F Seymour Molecular Biomarkers and Translational Genomics Laboratory and Department of Medical Oncology (S-JD) and Department of Haematology (JFS), Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia; and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia (S-JD, JFS) [email protected]
9
10
Hughes T, Deininger M, Hochhaus A, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006; 108: 28–37. Anker P, Mulcahy H, Chen XQ, Stroun M. Detection of circulating tumour DNA in the blood (plasma/serum) of cancer patients. Cancer Metastasis Rev 1999; 18: 65–73. Dawson SJ, Tsui DW, Murtaza M, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med 2013; 368: 1199–209. Murtaza M, Dawson SJ, Tsui DW, et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 2013; 497: 108–12. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 2014; 32: 3059–68. Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 2010; 28: 4184–90. Cheah CY, Hofman MS, Dickinson M, et al. Limited role for surveillance PETCT scanning in patients with diffuse large B-cell lymphoma in complete metabolic remission following primary therapy. Brit J Cancer 2013; 109: 312–7. Roschewski M, Dunleavy K, Pittaluga S, et al. Circulating tumour DNA and CT monitoring in patients with untreated diffuse large B-cell lymphoma: a correlative biomarker study. Lancet Oncol 2015; published online April 2. http://dx.doi.org/10/1016/S14702045(15)70106-3. Arnold A, Cossman J, Bakhshi A, Jaffe ES, Waldmann TA, Korsmeyer SJ. Immunoglobulin-gene rearrangements as unique clonal markers in human lymphoid neoplasms. N Engl J Med 1983; 309: 1593–99. El Messaoudi S, Rolet F, Mouliere F, Thierry AR. Circulating cell free DNA: Preanalytical considerations. Clin Chim Acta 2013; 424: 222–30.
The discovery of driver mutations in gastrointestinal stromal tumours (GISTs) in the KIT or in PDGFRA oncogenes, and the subsequent incorporation of the tyrosine kinase inhibitor imatinib to the therapy of advanced disease, has resulted in remarkable therapeutic progress. Median overall survival of patients with metastatic tumours has risen from a few months to around 60 months in the last decade.1 Unfortunately, however, most patients will eventually develop resistance to imatinib after a median of 2 years,1,2 mainly due to the acquisition of secondary KIT and PDGFRA mutations. In these patients, two multi-targeted tyrosine kinase inhibitors, sunitinib and regorafenib, have shown activity—sunitinib in second-line therapy3 and regorafenib in third-line treatment.4 However, their effects are limited, with sunitinib resulting in a progression-free survival of around 6·5 months and regorafenib in a progression-free survival of about 5 months. Therefore, great room for improvement www.thelancet.com/oncology Vol 16 May 2015
remains, and a crucial step forward would be to enhance the efficacy of first-line therapy. Nilotinib, a potent second-generation tyrosine kinase inhibitor against BCR-ABL, KIT, and PDGFRα, has shown superior activity to imatinib in the treatment of Philadelphia chromosome-positive chronic myeloid leukaemia.5 In studies in GIST cell lines, nilotinib had similar potency to imatinib in inhibiting KIT, but nilotinib was able to accumulate at higher intracellular concentrations than imatinib.6 This finding suggests that nilotinib might be less susceptible than imatinib is to cellular transport-driven resistance. In The Lancet Oncology, Jean-Yves Blay and colleagues7 describe the results of a large randomised phase 3 study of nilotinib versus imatinib as first-line therapy of advanced GIST. The study approach was bold, in view of the high activity and favourable safety of imatinib and the scarcity of available data about nilotinib in this setting. In fact, it constitutes the first head-to-head clinical trial comparing
Nephron (CC BY-SA) via Wikimedia Common
Nilotinib, imatinib, and GIST therapy
Published Online April 14, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70179-8 See Articles page 550
483
Comment
a new agent against imatinib in GIST. However, since use of imatinib is moving towards adjuvant therapy in most high-risk patients, it is prudent to investigate new alternatives for the first-line therapy of advanced disease. In this carefully designed phase 3 study, interim analyses for futility and superiority were planned. The accrual of patients was stopped prematurely because the futility boundary was crossed at the first analysis. The results showed significantly better progression-free survival—the primary endpoint of the trial—with imatinib treatment (hazard ratio [HR] 1·47, 95% CI 1·10–1·95). Even more relevant, overall survival was better with imatinib (HR 1·85, 95% CI 1·20–2·86). An interesting exploratory analysis of correlation with genotype showed better overall survival associated with imatinib in KIT exon 9 and 11 mutations and wild-type GIST subgroups. In terms of progression-free survival, imatinib was superior in KIT exon 9 mutation and wild-type GIST subgroups, whereas the results for the KIT exon 11 mutation subgroup were similar for both agents. As the authors suggest, informative censoring following the interim analysis might have changed this latter effect. When we look at the results, the conclusion leaves no doubt: at present, imatinib should be the first-line treatment for patients with advanced GIST, irrespective of the genotype they harbour. Consequently, the only option available today to enhance first-line therapeutic results in everyday medical practice is to optimise imatinib treatment. Notably, the overall survival reported in the imatinib group of the study compares favourably with that reported in previous clinical trials,2 which could suggest that management of these patients has improved over time. Methods to optimise imatinib treatment include monitoring of imatinib plasma levels in patients with poor response or unusual side-effects, improving patient adherence, examination of mutational analysis systematically, administration of high doses of imatinib to patients with KIT exon 9 mutations, and combined surgery in selected responding patients. However, the negative results recorded in the trial raise a question about its rationale. Is it not prudent to have solid preclinical and early clinical data supporting the experimental approach before embarking on a large-scale trial? In a recent phase 3 trial of patients with advanced GIST who had been previously treated with imatinib and sunitinib, nilotinib showed no advantages in progression-free or overall survival compared with 484
resumption of treatment with the previous tyrosine kinase inhibitor.8 Nevertheless, in a post-hoc analysis, nilotinib was associated with improved overall survival in the subset of patients treated with only two previous lines of therapy. However, despite the negative results in the firstline and third-line phase 3 trials, I do not believe that nilotinib should be discarded from the treatment of GIST. There is still a great need and scope for progress in the treatment of this disease. At present, the best results in clinics are reached with the sequential use of different available agents, combined with judicious personalisation of therapy according to the mutational status. The potential of nilotinib in specific populations should be explored in greater depth.9,10 GIST constitutes a heterogeneous disease in which intensified study of the correlation between primary and acquired mutations and response to different agents could contribute to their more efficient use. Xavier Garcia del Muro Sarcoma Multidisciplinary Unit and Medical Oncology Department, Institut Català d’Oncologia, IDIBELL, Barcelona 08908, Spain [email protected] I have received personal fees for consultancy and lectures from Pfizer and Bayer. 1
2
3
4
5 6
7
8
9
10
Blanke CD, Demetri GD, von Mehren M, et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol 2008; 26: 620–25. Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 2004; 364: 1127–34. Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006; 368: 1329–38. Demetri GD, Reichardt P, Kang Y-K, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebocontrolled, phase 3 trial. Lancet 2013; 381: 295–302. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 2010; 362: 2251–59. Prenen H, Guetens G, de Boeck G, et al. Cellular uptake of the tyrosine kinase inhibitors imatinib and AMN107 in gastrointestinal stromal tumor cell lines. Pharmacology 2006; 77: 11–16. Blay J-Y, Shen L, Kang Y-K, et al. Nilotinib versus imatinib as first-line therapy for patients with unresectable or metastatic gastrointestinal stromal tumours (ENESTg1): a randomised phase 3 trial. Lancet Oncol 2015; published online April 14. http://dx.doi.org/10.1016/S1470-2045(15)70105-1. Reichardt P, Blay JY, Gelderblom H, et al. Phase III study of nilotinib versus best supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib. Ann Oncol 2012; 23: 1680–87. Sako H, Fukuda K, Saikawa Y, et al. Antitumor effect of the tyrosine kinase inhibitor nilotinib on gastrointestinal stromal tumor (GIST) and imatinibresistant GIST cells. PLoS One 2014; 9: e107613. Hsueh YS, Lin CL, Chiang NJ, et al. Selecting tyrosine kinase inhibitors for gastrointestinal stromal tumor with secondary KIT activation-loop domain mutations. PLoS One 2013; 8: e65762.
www.thelancet.com/oncology Vol 16 May 2015