- Email: [email protected]
A selective ALK inhibitor in ALK-rearranged patients
Comment
Eye of Science/Science Photo Library
A selective ALK inhibitor in ALK-rearranged patients
Published Online April 30, 2013 http://dx.doi.org/10.1016/ S1470-2045(13)70170-0 See Articles page 590
564
ALK was first identified as a fusion protein with nucleophosmin (NPM-ALK) in CD30(ki1)-anaplastic lymphoma.1 Soda and colleagues2 discovered the EML4ALK fusion protein in 6·7% (five of 75) of patients with non-small-cell lung cancer (NSCLC) and showed that EML4-ALK protein was oncogenic in preclinical models. A phase 1 study3 of PF02341066 (crizotinib), a small molecule inhibitor of MET, ALK, and ROS1, enrolled predominantly patients with ALK-rearranged NSCLC and showed an objective response of 60·8% (87 of 143) and median progression-free survival of 9·7 months. A phase 3 randomised study4 further showed the superior progression-free survival of crizotinib over docetaxel or pemetrexed chemotherapy (median progression-free survival 7·7 months vs 3·0 months, hazard ratio 0·49). Despite great advances in the treatment of patients with ALK-rearranged NSCLC, we still face the challenges of primary or acquired resistance to crizotinib. Known resistance mechanisms include the emergence of a gatekeeper mutation Leu1196Met, mutations in the kinase domain of ALK such as Gly1269Ala, Gly1202Arg, and Ser1206Tyr, amplification of the EML4-ALK translocated gene, and appearance of bypass pathways such as EGFR activation, mutated EGFR, mutated KRAS, and amplified KIT gene. The contributions of co-existing driver mutations or amplified pathway genes to the resistance is unclear.5,6 CH5424802 is a small molecule selective ALK inhibitor, a product of rational drug design.7 In vitro, CH5424802 inhibits a variety of resistant ALK mutations such as Leu1196Met, Cys1156Tyr, and Phe1174Leu at low concentrations. CH5424802 does not inhibit MET or other kinases.8 In The Lancet Oncology, a Japanese group report a phase 1–2 study9 of CH5424802 in crizotinibnaive patients with ALK-rearranged NSCLC. The overall response rate in the phase 2 part of the study was 93·5% (43 of 46 patients). Treatment-related adverse events of grade 3 were only noted in around a quarter of patients.9 It seems that CH5424802 is a promising solution for treatment of patients with ALK-rearranged NSCLC. The high response, rapid tumour response, and long response durations in patients with ALK-rearranged NSCLC treated with both crizotinib and CH5424802 suggest that most of the tumour cells in these patients are homogenous and tumour growth is dominated
by ALK-driving pathways. The very high response of CH5424802-treated patients suggest that CH5424802 might have broader coverage of minority clones of denovo crizotinib-resistant ALK mutations or stronger inhibition in NSCLC cells with EML4-ALK amplification. Thus, bypass pathways that cannot be suppressed by selective ALK inhibitors seem to have a minor role in driving the tumour cell growth in ALK inhibitornaive patients. Unfortunately, in most studies, ALKrearrangement was identified by fluorescence in-situ hybridisation. Few studies focused on examining the heterogeneity of rearranged EML4-ALK oncogene sequences or the presence of bypass pathways in tumour specimens. The duration of response is a crucial variable for choosing between crizotinib or novel ALK inhibitors. On the one hand, CH5424802, being more potent in some resistant ALK mutations in vitro,8 might have an advantage over crizotinib in delaying the emergence of crizotinib-resistant ALK mutations. On the other hand, crizotinib could have an advantage insofar as it inhibits MET or ROS1 that might be involved as the bypass pathways of ALK inhibition. It is too early to estimate the duration of response to CH5424802. Additionally, the authors suggest that CH5424802 is effective in controlling brain metastasis. So far, the observation was preliminary and the efficacy in treatment of brain metastasis will need to be further examined. A head-tohead randomised study of crizotinib versus CH5424802 in ALK-rearranged patients and studies of molecular resistance mechanisms of each drug are crucial. Because of Japanese regulations, dose escalation was capped at 300 mg twice daily in the phase 1 study. Whether this is the biologically optimum dose of CH5424802 for patients with ALK-rearranged NSCLC is unknown. The side-effects of CH5424802 at this dose level were minor. There was no visual disturbance, oedema, or vomiting as noted after crizotinib treatment, which might have been related to off-target effects. Higher doses of CH5424802 might better control CNS metastasis and delay the emergence of resistant mutations and amplifications of the ALKtranslocated gene. Whether a high-dose or low-dose strategy can better prevent the emergence of bypass pathways is also unknown. The high response (93·5%), www.thelancet.com/oncology Vol 14 June 2013
Comment
and adequate plasma level of CH5424802 seem to support the use of this dose level in future development. The dose of CH5424802 is currently being explored in a phase 1 study in North America (ClinicalTrials.gov, number NCT01588028). Finally, whether high-dose or low-dose selective ALK inhibitor treatment is optimum for crizotinib-naive or crizotinib-treated patients remains to be established. CH5424802 has now joined several other selective ALK inhibitors in showing promising activity in patients with ALK-rearranged NSCLC.5 Recently, HSP90 inhibitors also showed good efficacy in ALK-rearranged, crizotinib-resistant patients.10 To develop multiple drugs with a small population of patients is challenging. Individualised and innovative approaches to sequence or combine agents in drug development are urgently needed to achieve the best therapeutic outcome for patients with ALK-rearranged NSCLC. James Chih-Hsin Yang Department of Oncology, National Taiwan University Hospital, National Taiwan University, 7 Chung-Shan South Road, Taipei, Taiwan [email protected]
I serve as a consultant for Roche, Genetech, Pfizer, and Novartis. 1
2
3
4
5 6
7
8
9
10
Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 1994; 263: 1281–84. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007; 448: 561–66. 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: 1011–19. Shaw AT, Kim DW, Nakagawa K, Seto T. Phase III study of crizotinib versus pemetrexed or docetaxel chemotherapy in patients with advanced ALK-positive non-small cell lung cancer (NSCLC) (PROFILE 1007). Ann Oncol 2012; Abstr LBA1_PR. Shaw AT, Engelman JA. ALK in lung cancer: past, present, and future. J Clin Oncol 2013; 31: 1105–11. Doebele RC, Pilling AB, Aisner DL, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 2012; 18: 1472–82. Kinoshita K, Asoh K, Furuichi N, et al. Design and synthesis of a highly selective, orally active and potent anaplastic lymphoma kinase inhibitor (CH5424802). Bioorg Med Chem 2012; 20: 1271–80. Sakamoto H, Tsukaguchi T, Hiroshima S, et al. CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer cell 2011; 19: 679–90. Seto T, Kiura K, Nishio M, Nakagawa K. CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF001JP study): a single-arm, open-label, phase 1–2 study. Lancet Oncol 2013; published online April 30. http://dx.doi.org/10.1016/S14702045(13)70142-6. Sang J, Acquaviva J, Friedland JC, et al. Targeted inhibition of the molecular chaperone Hsp90 overcomes ALK inhibitor resistance in non-small cell lung cancer. Cancer Discov 2013; published online March 26. DOI:10.1158/2159-8290.cd-12-0440.
In the Lancet Oncology, Jie Jin and colleagues1 report results of a randomised study investigating the addition of homoharringtonine to induction treatment of patients younger than 60 years with acute myeloid leukaemia. Homoharringtonine is a natural plant alkaloid derived from Cephalotaxus species and has been assessed by Chinese investigators for treatment of myeloid neoplasms. A semisynthetic version— omacetaxine mepesuccinate—is a highly purified form that has been approved by the US Food and Drug Administration for treatment of advanced chronic myeloid leukaemia. Compared with the standard regimen of daunorubicin and cytarabine, the addition of homoharringtonine to a regimen of cytarabine and aclarubicin increased the number of patients who had complete remission (125/205 [61%] vs 150/206 [73%]; p=0·0108) and 3-year event-free survival (23·1%, 95% CI 17·4–29·3 vs 35·4%, 95% CI 28·6–42·2; p=0·0023). Addition of homoharringtonine to cytarabine and daunorubicin did not significantly affect www.thelancet.com/oncology Vol 14 June 2013
complete remission (133/198 [67%]; p=0·20) or eventfree survival (32·7%, 95% CI 26·1–39·5; p=0·08), leading the investigators to suggest that homoharringtonine might act in synergy with aclarubicin, but not with daunorubicin. Alternatively, the study might not have had enough statistical power to show a lesser, but still important, benefit in the cytarabine and daunorubicin group. This study is one of several to investigate addition of other drugs to the cytarabine and anthracycline induction regimens that are used at present to treat patients with acute myeloid leukaemia. It is both remarkable and disheartening that after 40 years and hundreds of clinical trials, what is referred to by Jin and colleagues as “the gold standard for induction chemotherapy” for acute myeloid leukaemia, is the same regimen of cytarabine plus daunorubicin introduced several decades ago. The absence of progress is not a result of lack of effort. Early studies explored the potential benefit of escalating the cytarabine dose.2,3 Several studies have suggested
Will & Deni McIntyre/Science Photo Library
Is there a standard induction regimen for patients with AML?
Published Online May 9, 2013 http://dx.doi.org/10.1016/ S1470-2045(13)70183-9 See Articles page 599
565
Eye of Science/Science Photo Library
A selective ALK inhibitor in ALK-rearranged patients
Published Online April 30, 2013 http://dx.doi.org/10.1016/ S1470-2045(13)70170-0 See Articles page 590
564
ALK was first identified as a fusion protein with nucleophosmin (NPM-ALK) in CD30(ki1)-anaplastic lymphoma.1 Soda and colleagues2 discovered the EML4ALK fusion protein in 6·7% (five of 75) of patients with non-small-cell lung cancer (NSCLC) and showed that EML4-ALK protein was oncogenic in preclinical models. A phase 1 study3 of PF02341066 (crizotinib), a small molecule inhibitor of MET, ALK, and ROS1, enrolled predominantly patients with ALK-rearranged NSCLC and showed an objective response of 60·8% (87 of 143) and median progression-free survival of 9·7 months. A phase 3 randomised study4 further showed the superior progression-free survival of crizotinib over docetaxel or pemetrexed chemotherapy (median progression-free survival 7·7 months vs 3·0 months, hazard ratio 0·49). Despite great advances in the treatment of patients with ALK-rearranged NSCLC, we still face the challenges of primary or acquired resistance to crizotinib. Known resistance mechanisms include the emergence of a gatekeeper mutation Leu1196Met, mutations in the kinase domain of ALK such as Gly1269Ala, Gly1202Arg, and Ser1206Tyr, amplification of the EML4-ALK translocated gene, and appearance of bypass pathways such as EGFR activation, mutated EGFR, mutated KRAS, and amplified KIT gene. The contributions of co-existing driver mutations or amplified pathway genes to the resistance is unclear.5,6 CH5424802 is a small molecule selective ALK inhibitor, a product of rational drug design.7 In vitro, CH5424802 inhibits a variety of resistant ALK mutations such as Leu1196Met, Cys1156Tyr, and Phe1174Leu at low concentrations. CH5424802 does not inhibit MET or other kinases.8 In The Lancet Oncology, a Japanese group report a phase 1–2 study9 of CH5424802 in crizotinibnaive patients with ALK-rearranged NSCLC. The overall response rate in the phase 2 part of the study was 93·5% (43 of 46 patients). Treatment-related adverse events of grade 3 were only noted in around a quarter of patients.9 It seems that CH5424802 is a promising solution for treatment of patients with ALK-rearranged NSCLC. The high response, rapid tumour response, and long response durations in patients with ALK-rearranged NSCLC treated with both crizotinib and CH5424802 suggest that most of the tumour cells in these patients are homogenous and tumour growth is dominated
by ALK-driving pathways. The very high response of CH5424802-treated patients suggest that CH5424802 might have broader coverage of minority clones of denovo crizotinib-resistant ALK mutations or stronger inhibition in NSCLC cells with EML4-ALK amplification. Thus, bypass pathways that cannot be suppressed by selective ALK inhibitors seem to have a minor role in driving the tumour cell growth in ALK inhibitornaive patients. Unfortunately, in most studies, ALKrearrangement was identified by fluorescence in-situ hybridisation. Few studies focused on examining the heterogeneity of rearranged EML4-ALK oncogene sequences or the presence of bypass pathways in tumour specimens. The duration of response is a crucial variable for choosing between crizotinib or novel ALK inhibitors. On the one hand, CH5424802, being more potent in some resistant ALK mutations in vitro,8 might have an advantage over crizotinib in delaying the emergence of crizotinib-resistant ALK mutations. On the other hand, crizotinib could have an advantage insofar as it inhibits MET or ROS1 that might be involved as the bypass pathways of ALK inhibition. It is too early to estimate the duration of response to CH5424802. Additionally, the authors suggest that CH5424802 is effective in controlling brain metastasis. So far, the observation was preliminary and the efficacy in treatment of brain metastasis will need to be further examined. A head-tohead randomised study of crizotinib versus CH5424802 in ALK-rearranged patients and studies of molecular resistance mechanisms of each drug are crucial. Because of Japanese regulations, dose escalation was capped at 300 mg twice daily in the phase 1 study. Whether this is the biologically optimum dose of CH5424802 for patients with ALK-rearranged NSCLC is unknown. The side-effects of CH5424802 at this dose level were minor. There was no visual disturbance, oedema, or vomiting as noted after crizotinib treatment, which might have been related to off-target effects. Higher doses of CH5424802 might better control CNS metastasis and delay the emergence of resistant mutations and amplifications of the ALKtranslocated gene. Whether a high-dose or low-dose strategy can better prevent the emergence of bypass pathways is also unknown. The high response (93·5%), www.thelancet.com/oncology Vol 14 June 2013
Comment
and adequate plasma level of CH5424802 seem to support the use of this dose level in future development. The dose of CH5424802 is currently being explored in a phase 1 study in North America (ClinicalTrials.gov, number NCT01588028). Finally, whether high-dose or low-dose selective ALK inhibitor treatment is optimum for crizotinib-naive or crizotinib-treated patients remains to be established. CH5424802 has now joined several other selective ALK inhibitors in showing promising activity in patients with ALK-rearranged NSCLC.5 Recently, HSP90 inhibitors also showed good efficacy in ALK-rearranged, crizotinib-resistant patients.10 To develop multiple drugs with a small population of patients is challenging. Individualised and innovative approaches to sequence or combine agents in drug development are urgently needed to achieve the best therapeutic outcome for patients with ALK-rearranged NSCLC. James Chih-Hsin Yang Department of Oncology, National Taiwan University Hospital, National Taiwan University, 7 Chung-Shan South Road, Taipei, Taiwan [email protected]
I serve as a consultant for Roche, Genetech, Pfizer, and Novartis. 1
2
3
4
5 6
7
8
9
10
Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 1994; 263: 1281–84. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007; 448: 561–66. 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: 1011–19. Shaw AT, Kim DW, Nakagawa K, Seto T. Phase III study of crizotinib versus pemetrexed or docetaxel chemotherapy in patients with advanced ALK-positive non-small cell lung cancer (NSCLC) (PROFILE 1007). Ann Oncol 2012; Abstr LBA1_PR. Shaw AT, Engelman JA. ALK in lung cancer: past, present, and future. J Clin Oncol 2013; 31: 1105–11. Doebele RC, Pilling AB, Aisner DL, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 2012; 18: 1472–82. Kinoshita K, Asoh K, Furuichi N, et al. Design and synthesis of a highly selective, orally active and potent anaplastic lymphoma kinase inhibitor (CH5424802). Bioorg Med Chem 2012; 20: 1271–80. Sakamoto H, Tsukaguchi T, Hiroshima S, et al. CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer cell 2011; 19: 679–90. Seto T, Kiura K, Nishio M, Nakagawa K. CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF001JP study): a single-arm, open-label, phase 1–2 study. Lancet Oncol 2013; published online April 30. http://dx.doi.org/10.1016/S14702045(13)70142-6. Sang J, Acquaviva J, Friedland JC, et al. Targeted inhibition of the molecular chaperone Hsp90 overcomes ALK inhibitor resistance in non-small cell lung cancer. Cancer Discov 2013; published online March 26. DOI:10.1158/2159-8290.cd-12-0440.
In the Lancet Oncology, Jie Jin and colleagues1 report results of a randomised study investigating the addition of homoharringtonine to induction treatment of patients younger than 60 years with acute myeloid leukaemia. Homoharringtonine is a natural plant alkaloid derived from Cephalotaxus species and has been assessed by Chinese investigators for treatment of myeloid neoplasms. A semisynthetic version— omacetaxine mepesuccinate—is a highly purified form that has been approved by the US Food and Drug Administration for treatment of advanced chronic myeloid leukaemia. Compared with the standard regimen of daunorubicin and cytarabine, the addition of homoharringtonine to a regimen of cytarabine and aclarubicin increased the number of patients who had complete remission (125/205 [61%] vs 150/206 [73%]; p=0·0108) and 3-year event-free survival (23·1%, 95% CI 17·4–29·3 vs 35·4%, 95% CI 28·6–42·2; p=0·0023). Addition of homoharringtonine to cytarabine and daunorubicin did not significantly affect www.thelancet.com/oncology Vol 14 June 2013
complete remission (133/198 [67%]; p=0·20) or eventfree survival (32·7%, 95% CI 26·1–39·5; p=0·08), leading the investigators to suggest that homoharringtonine might act in synergy with aclarubicin, but not with daunorubicin. Alternatively, the study might not have had enough statistical power to show a lesser, but still important, benefit in the cytarabine and daunorubicin group. This study is one of several to investigate addition of other drugs to the cytarabine and anthracycline induction regimens that are used at present to treat patients with acute myeloid leukaemia. It is both remarkable and disheartening that after 40 years and hundreds of clinical trials, what is referred to by Jin and colleagues as “the gold standard for induction chemotherapy” for acute myeloid leukaemia, is the same regimen of cytarabine plus daunorubicin introduced several decades ago. The absence of progress is not a result of lack of effort. Early studies explored the potential benefit of escalating the cytarabine dose.2,3 Several studies have suggested
Will & Deni McIntyre/Science Photo Library
Is there a standard induction regimen for patients with AML?
Published Online May 9, 2013 http://dx.doi.org/10.1016/ S1470-2045(13)70183-9 See Articles page 599
565