Imatinib in combination with phosphoinositol kinase inhibitor buparlisib in patients with gastrointestinal stromal tumour who failed prior therapy with imatinib and sunitinib: a Phase 1b, multicentre study.
Adult
Aged
Aminopyridines
/ administration & dosage
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Female
Gastrointestinal Neoplasms
/ drug therapy
Gastrointestinal Stromal Tumors
/ drug therapy
Humans
Imatinib Mesylate
/ administration & dosage
Male
Mental Disorders
/ chemically induced
Middle Aged
Morpholines
/ administration & dosage
Phosphoinositide-3 Kinase Inhibitors
/ administration & dosage
Sunitinib
/ administration & dosage
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
04
09
2019
accepted:
12
02
2020
pubmed:
10
3
2020
medline:
31
12
2020
entrez:
10
3
2020
Statut:
ppublish
Résumé
The majority of patients with advanced gastrointestinal stromal tumours (GISTs) develop resistance to imatinib and sunitinib, the standard of care for these patients. This study evaluated the combination of buparlisib, an oral phosphoinositide 3-kinase (PI3K) inhibitor, with imatinib in patients with advanced GIST, who have failed prior therapy with imatinib and sunitinib. This Phase 1b, multicentre, open-label study aimed to determine the maximum tolerated dose (MTD) and/or a recommended Phase 2 dose of buparlisib in combination with 400 mg of imatinib through a dose-escalation part and a dose-expansion part, and also evaluated the clinical profile of the combination. Sixty patients were enrolled, including 25 in the dose-escalation part and 35 in the dose-expansion part. In the combination, MTD of buparlisib was established as 80 mg. No partial or complete responses were observed. The estimated median progression-free survival was 3.5 months in the expansion phase. Overall, 98.3% of patients had treatment-related adverse events (AEs), including 45% with grade 3 or 4 AEs. Buparlisib in combination with imatinib provided no additional benefit compared with currently available therapies. Due to the lack of objective responses, further development of this combination was not pursued for third-line/fourth-line advanced/metastatic GIST. NCT01468688.
Sections du résumé
BACKGROUND
The majority of patients with advanced gastrointestinal stromal tumours (GISTs) develop resistance to imatinib and sunitinib, the standard of care for these patients. This study evaluated the combination of buparlisib, an oral phosphoinositide 3-kinase (PI3K) inhibitor, with imatinib in patients with advanced GIST, who have failed prior therapy with imatinib and sunitinib.
METHODS
This Phase 1b, multicentre, open-label study aimed to determine the maximum tolerated dose (MTD) and/or a recommended Phase 2 dose of buparlisib in combination with 400 mg of imatinib through a dose-escalation part and a dose-expansion part, and also evaluated the clinical profile of the combination.
RESULTS
Sixty patients were enrolled, including 25 in the dose-escalation part and 35 in the dose-expansion part. In the combination, MTD of buparlisib was established as 80 mg. No partial or complete responses were observed. The estimated median progression-free survival was 3.5 months in the expansion phase. Overall, 98.3% of patients had treatment-related adverse events (AEs), including 45% with grade 3 or 4 AEs.
CONCLUSIONS
Buparlisib in combination with imatinib provided no additional benefit compared with currently available therapies. Due to the lack of objective responses, further development of this combination was not pursued for third-line/fourth-line advanced/metastatic GIST.
TRIAL REGISTRATION NUMBER
NCT01468688.
Identifiants
pubmed: 32147671
doi: 10.1038/s41416-020-0769-y
pii: 10.1038/s41416-020-0769-y
pmc: PMC7156686
doi:
Substances chimiques
Aminopyridines
0
Morpholines
0
NVP-BKM120
0
Phosphoinositide-3 Kinase Inhibitors
0
Imatinib Mesylate
8A1O1M485B
Sunitinib
V99T50803M
Banques de données
ClinicalTrials.gov
['NCT01468688']
Types de publication
Clinical Trial, Phase I
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1158-1165Références
Ray-Coquard, I., Cassier, P., Labidi Galy, I., Heudel, P., Tassy, L., Chelghoum, M. et al. Combination therapy for gastrointestinal stromal tumors: evidence from recent clinical trials. Clin. Invest 1, 825–836 (2011).
Cassier, P. A., Ducimetiere, F., Lurkin, A., Ranchere-Vince, D., Scoazec, J. Y., Bringuier, P. P. et al. A prospective epidemiological study of new incident GISTs during two consecutive years in Rhone Alpes region: incidence and molecular distribution of GIST in a European region. Br. J. Cancer 103, 165–170 (2010).
pubmed: 20588273
pmcid: 2906738
Nilsson, B., Bumming, P., Meis-Kindblom, J. M., Oden, A., Dortok, A., Gustavsson, B. et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era-a population-based study in western Sweden. Cancer 103, 821–829 (2005).
pubmed: 15648083
Corless, C. L. & Heinrich, M. C. Molecular pathobiology of gastrointestinal stromal sarcomas. Annu Rev. Pathol. 3, 557–586 (2008).
pubmed: 18039140
Corless, C. L., McGreevey, L., Haley, A., Town, A. & Heinrich, M. C. KIT mutations are common in incidental gastrointestinal stromal tumors one centimeter or less in size. Am. J. Pathol. 160, 1567–1572 (2002).
pubmed: 12000708
pmcid: 1850861
Corless, C. L., Schroeder, A., Griffith, D., Town, A., McGreevey, L., Harrell, P. et al. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J. Clin. Oncol. 23, 5357–5364 (2005).
pubmed: 15928335
DeMatteo, R. P., Lewis, J. J., Leung, D., Mudan, S. S., Woodruff, J. M. & Brennan, M. F. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann. Surg. 231, 51–58 (2000).
pubmed: 10636102
pmcid: 1420965
Mazzocca, A., Napolitano, A., Silletta, M., Spalato Ceruso, M., Santini, D., Tonini, G. et al. New frontiers in the medical management of gastrointestinal stromal tumours. Ther Adv. Med. Oncol. https://doi.org/10.1177/1758835919841946 (2019).
Cohen, M. H., Johnson, J. R., Justice, R. & Pazdur, R. Approval summary: imatinib mesylate for one or three years in the adjuvant treatment of gastrointestinal stromal tumors. Oncologist 17, 992–997 (2012).
pubmed: 22643537
pmcid: 3399657
Demetri, G. D., van Oosterom, A. T., Garrett, C. R., Blackstein, M. E., Shah, M. H., Verweij, J. et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 368, 1329–1338 (2006).
pubmed: 17046465
Mei, L., Du, W., Idowu, M., von Mehren, M. & Boikos, S. A. Advances and challenges on management of gastrointestinal stromal tumors. Front Oncol. 8, 135 (2018).
pubmed: 29868467
pmcid: 5949718
Demetri, G. D., von Mehren, M., Blanke, C. D., Van den Abbeele, A. D., Eisenberg, B., Roberts, P. J. et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N. Engl. J. Med 347, 472–480 (2002).
pubmed: 12181401
Serrano, C. & George, S. Recent advances in the treatment of gastrointestinal stromal tumors. Ther. Adv. Med Oncol. 6, 115–127 (2014).
pubmed: 24790651
pmcid: 3987653
ESMO / European Sarcoma Network Working Group. Gastrointestinal stromal tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 23(Suppl 7), vii49–vii55 (2012).
Kang, Y. K., Kang, H. J., Kim, K. M., Sohn, T., Choi, D., Ryu, M. H. et al. Clinical practice guideline for accurate diagnosis and effective treatment of gastrointestinal stromal tumor in Korea. Cancer Res. Treat. 44, 85–96 (2012).
pubmed: 22802746
pmcid: 3394868
Bauer, S., Duensing, A., Demetri, G. D. & Fletcher, J. A. KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway. Oncogene 26, 7560–7568 (2007).
pubmed: 17546049
Duensing, A., Heinrich, M. C., Fletcher, C. D. & Fletcher, J. A. Biology of gastrointestinal stromal tumors: KIT mutations and beyond. Cancer Invest 22, 106–116 (2004).
pubmed: 15069768
Maira, S. M., Pecchi, S., Huang, A., Burger, M., Knapp, M., Sterker, D. et al. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol. Cancer Ther. 11, 317–328 (2012).
pubmed: 22188813
Maira, M., Schnell, C., Lollini, P., Chouaid, C., Schmid, P., Nanni, P. et al. Preclinical and preliminary clinical activity of NVP-BKM120, an oral pan-class I PI3K inhibitor, in the brain. Ann. Oncol. 23(suppl 9), ix537 (2012).
Van, Looy, T., Wozniak, A., Floris, G., Sciot, R., Li, H., Wellens, J. et al. Phosphoinositide 3-kinase inhibitors combined with imatinib in patient-derived xenograft models of gastrointestinal stromal tumors: rationale and efficacy. Clin. Cancer Res 20, 6071–6082 (2014).
pubmed: 25316817
Spitzer, R. L., Kroenke, K., Williams, J. B. & Lowe, B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch. Intern Med 166, 1092–1097 (2006).
pubmed: 16717171
Kroenke, K., Spitzer, R. L. & Williams, J. B. The PHQ-9: validity of a brief depression severity measure. J. Gen. Intern Med 16, 606–613 (2001).
pubmed: 11556941
pmcid: 1495268
Wozniak, A., Gebreyohannes, Y. K., Debiec-Rychter, M. & Schoffski, P. New targets and therapies for gastrointestinal stromal tumors. Expert Rev. Anticancer Ther. 17, 1117–1129 (2017).
pubmed: 29110548
Quattrone, A., Wozniak, A., Dewaele, B., Floris, G., Vanspauwen, V., Van Looy, T. et al. Frequent mono-allelic loss associated with deficient PTEN expression in imatinib-resistant gastrointestinal stromal tumors. Mod. Pathol. 27, 1510–1520 (2014).
pubmed: 24743220
Floris, G., Wozniak, A., Sciot, R., Li, H., Friedman, L., Van Looy, T. et al. A potent combination of the novel PI3K Inhibitor, GDC-0941, with imatinib in gastrointestinal stromal tumor xenografts: long-lasting responses after treatment withdrawal. Clin. Cancer Res 19, 620–630 (2013).
pubmed: 23231951
Bosbach B., Rossi F., Yozgat Y., Loo J., Zhang J. Q., Berrozpe G. et al. Direct engagement of the PI3K pathway by mutant KIT dominates oncogenic signaling in gastrointestinal stromal tumor. Proc. Natl Acad. Sci. USA 114, E8448–E8457 (2017).
Massacesi, C., Di Tomaso, E., Urban, P., Germa, C., Quadt, C., Trandafir, L. et al. PI3K inhibitors as new cancer therapeutics: implications for clinical trial design. Onco Targets Ther. 9, 203–210 (2016).
pubmed: 26793003
pmcid: 4708174
Zook, P., Pathak, H. B., Belinsky, M. G., Gersz, L., Devarajan, K., Zhou, Y. et al. Combination of imatinib mesylate and AKT inhibitor provides synergistic effects in preclinical study of gastrointestinal stromal tumor. Clin. Cancer Res 23, 171–180 (2017).
pubmed: 27370604
Verweij, J., Casali, P. G., Zalcberg, J., LeCesne, A., Reichardt, P., Blay, J. Y. et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 364, 1127–1134 (2004).
pubmed: 15451219
Blanke, C. D., Rankin, C., Demetri, G. D., Ryan, C. W., von Mehren, M., Benjamin, R. S. et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J. Clin. Oncol. 26, 626–632 (2008).
pubmed: 18235122
Dematteo, R. P., Ballman, K. V., Antonescu, C. R., Maki, R. G., Pisters, P. W., Demetri, G. D. et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet 373, 1097–1104 (2009).
pubmed: 19303137
pmcid: 2915459
Kang, Y. K., Ryu, M. H., Yoo, C., Ryoo, B. Y., Kim, H. J., Lee, J. J. et al. Resumption of imatinib to control metastatic or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib (RIGHT): a randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 14, 1175–1182 (2013).
pubmed: 24140183
pmcid: 4347867
Patrikidou, A., Chabaud, S., Ray-Coquard, I., Bui, B. N., Adenis, A., Rios, M. et al. Influence of imatinib interruption and rechallenge on the residual disease in patients with advanced GIST: results of the BFR14 prospective French Sarcoma Group randomised, phase III trial. Ann. Oncol. 24, 1087–1093 (2013).
pubmed: 23175622
Vincenzi B., Nannini M., Badalamenti G., Grignani G., Fumagalli E., Gasperoni S. et al. Imatinib rechallenge in patients with advanced gastrointestinal stromal tumors following progression with imatinib, sunitinib and regorafenib. Ther. Adv. Med. Oncol. https://doi.org/10.1177/1758835918794623 (2018).
Rutkowski, P. & Stepniak, J. The safety of regorafenib for the treatment of gastrointestinal stromal tumors. Expert Opin. Drug Saf. 15, 105–116 (2016).
pubmed: 26651387
Demetri, G. D., Reichardt, P., Kang, Y. K., Blay, J. Y., Rutkowski, P., Gelderblom, H. et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381, 295–302 (2013).
pubmed: 23177515
George, S., Wang, Q., Heinrich, M. C., Corless, C. L., Zhu, M., Butrynski, J. E. et al. Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial. J. Clin. Oncol. 30, 2401–2407 (2012).
pubmed: 22614970
pmcid: 3675695
Schoffski, P., Reichardt, P., Blay, J. Y., Dumez, H., Morgan, J. A., Ray-Coquard, I. et al. A phase I-II study of everolimus (RAD001) in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors. Ann. Oncol. 21, 1990–1998 (2010).
pubmed: 20507881
Montemurro, M., Gelderblom, H., Bitz, U., Schutte, J., Blay, J. Y., Joensuu, H. et al. Sorafenib as third- or fourth-line treatment of advanced gastrointestinal stromal tumour and pretreatment including both imatinib and sunitinib, and nilotinib: a retrospective analysis. Eur. J. Cancer 49, 1027–1031 (2013).
pubmed: 23140824
Blanke, C. D., Demetri, G. D., von Mehren, M., Heinrich, M. C., Eisenberg, B., Fletcher, J. A. 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. 26, 620–625 (2008).
pubmed: 18235121
Bendell, J. C., Rodon, J., Burris, H. A., de Jonge, M., Verweij, J., Birle, D. et al. Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. J. Clin. Oncol. 30, 282–290 (2012).
Patsouris, A., Augereau, P., Frenel, J. S., Robert, M., Gourmelon, C., Bourbouloux, E. et al. Benefits versus risk profile of buparlisib for the treatment of breast cancer. Expert Opin. Drug Saf. 18, 553–562 (2019).
pubmed: 31159599
Nanni, P., Nicoletti, G., Palladini, A., Croci, S., Murgo, A., Ianzano, M. L. et al. Multiorgan metastasis of human HER-2+ breast cancer in Rag2-/-;Il2rg-/- mice and treatment with PI3K inhibitor. PLoS ONE 7, e39626 (2012).
pubmed: 22737248
pmcid: 3380859
Blay, J. Y., Perol, D. & Le Cesne, A. Imatinib rechallenge in patients with advanced gastrointestinal stromal tumors. Ann. Oncol. 23, 1659–1665 (2012).
pubmed: 22357253