|Year : 2015 | Volume
| Issue : 3 | Page : 320-323
Sunitinib in patients with imatinib-resistant gastrointestinal stromal tumor: A single center experiencep-190 chronic myelogenous leukemia presenting as extramedullary blast crisis
A Sahu1, S Godbole1, P Jain1, J Ghosh1, S Shrikhande2, M Ramadwar3, M Goyal2, S Gulia1, J Bajpai1, Y Kembhavi1, S Gupta1
1 Department of Medical Oncology, Tata Memorial Centre, Mumbai, Maharashtra, India
2 Department of Surgical Oncology, Tata Memorial Centre, Mumbai, Maharashtra, India
3 Department of Pathology, Tata Memorial Centre, Mumbai, Maharashtra, India
|Date of Web Publication||18-Feb-2016|
Department of Medical Oncology, Tata Memorial Centre, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Aim: The outcome of patients with advanced gastrointestinal stromal tumor (GIST) has improved with the use of imatinib. Despite high response rates with this drug resistance eventually develops in nearly all patients. We present an analysis of prospectively collected data on sunitinib efficacy and safety in patients with imatinib-resistant GIST. Subjects And Methods: Between November 2006 and October 2007, patients with GIST were accrued in an approved sunitinib patient access protocol. Key eligibility criteria included tumor resistance to imatinib and/or patient intolerance to this drug. Patients received sunitinib at a starting dose of 50 mg once daily for 4 weeks in a 6 week cycle, with standardized dose modification titrated to toxicity. Patients were continued on sunitinib until disease progression or unacceptable toxicity. The endpoints were safety, overall survival (OS) and objective response rate (ORR). Results: Fifteen patients, all of whom had imatinib resistance and none intolerance, with median age of 48 (26–69) years, were treated on the protocol. The most common sites of primary disease were small intestine (40%), stomach (26.7%) and retroperitoneal (26.7%). A median of 10 (1–47) cycles of sunitinib were delivered, 9 (60%) patients required dose reductions due to toxicity whereas dose delay of > 2 weeks was required in only one (6.7%) patient. There were no toxicity-related drug discontinuations. Hypothyroidism (n = 4; 26.7%) and hand-foot syndrome (n = 3; 20%) were the most common toxicities. There were no complete and 4 (26.7%) partial responses while prolonged disease stability was seen in 8 (53.3%) patients. At a median follow-up of 81 months in surviving patients, the median progression-free and overall survivals were 15.5 and 18.7 months, respectively. Conclusions: Sunitinib appears to be an effective and well-tolerated treatment for Indian patients with imatinib-resistant GIST with outcomes similar to that reported previously. Adverse effects can be reasonably well managed using a dose modification strategy.
Keywords: Gastrointestinal stromal tumor, imatinib resistance gastrointestinal stromal tumor, sunitinib, sunitinib adverse effects
|How to cite this article:|
Sahu A, Godbole S, Jain P, Ghosh J, Shrikhande S, Ramadwar M, Goyal M, Gulia S, Bajpai J, Kembhavi Y, Gupta S. Sunitinib in patients with imatinib-resistant gastrointestinal stromal tumor: A single center experiencep-190 chronic myelogenous leukemia presenting as extramedullary blast crisis. Indian J Cancer 2015;52:320-3
|How to cite this URL:|
Sahu A, Godbole S, Jain P, Ghosh J, Shrikhande S, Ramadwar M, Goyal M, Gulia S, Bajpai J, Kembhavi Y, Gupta S. Sunitinib in patients with imatinib-resistant gastrointestinal stromal tumor: A single center experiencep-190 chronic myelogenous leukemia presenting as extramedullary blast crisis. Indian J Cancer [serial online] 2015 [cited 2019 Sep 20];52:320-3. Available from: http://www.indianjcancer.com/text.asp?2015/52/3/320/176747
| » Introduction|| |
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. There have been unprecedented advances in understanding the molecular aberrations in GIST, especially the important role of activating mutations in KIT and platelet-derived growth factor receptor-alpha (PDGFRA) genes. Approximately, 85% of patients with GIST display activating mutations of KIT , and another 5–7% have activating mutations in PDGFRA while 12–15% patients do not have detectable mutations in either kinase. After investigators reported in vitro evidence of antitumor activity of small-molecule KIT kinase inhibitor imatinib mesylate against KIT mutant cell lines,, clinical trials established this drug as first-line medical therapy for patients with advanced stage disease.,,, However, despite remarkable results in a hitherto untreatable condition, clinical resistance to imatinib has proved to be a significant problem with more prolonged follow-up. Approximately 12–14% of patients have primary resistance to imatinib ,, and more than 40% of initially responsive patients develop secondary resistance at a median of 18–26 months of treatment. Sunitinib malate, another small-molecule tyrosine kinase inhibitor with selectivity for KIT and PDGFRA (and for PDGFRB, all three isoforms of vascular endothelial growth factor receptor, FMS-like tyrosine kinase 3, colony-stimulating factor 1 receptor and glial cell line-derived neurotrophic factor) has demonstrated clinical benefit in imatinib-resistant patients.,,
There are no studies from India analyzing the outcome of advanced imatinib-resistant GIST. We performed an analysis of prospectively collected data in the imatinib intolerant/resistant patients with GIST who were treated on a patient access protocol.
| » Subjects and Methods|| |
This is an analysis of prospectively collected single center data of patients with advanced imatinib resistant and/or intolerant GIST who were enrolled in a patient access clinical protocol conducted at many centers worldwide subsequent to approval of sunitinib for this indication. The protocol was approved by the institutional ethics committee and permission to undertake and report this analysis has been obtained from the study sponsor. All patients gave written informed consent to participate in the study.
Screening procedures included physical examination, routine hematology, biochemistry, urinalysis and a 12 lead electrocardiogram. Patients were required to have adequate hematological (absolute neutrophil count ≥1000/μL, platelets ≥75,000/μL, hemoglobin ≥8.0 g/dL) and liver functions (serum bilirubin ≤2× upper limit of normal (ULN) and serum transaminases <5 × ULN). The main eligibility criteria included resistance or intolerance to first-line treatment with imatinib mesylate that were defined as either disease progression or significant drug toxicity that precluded further treatment. Significant toxicity was defined as either life-threatening adverse event at any dose or unacceptable toxicity at moderate doses (e.g., 400 mg of imatinib per day) that persisted despite standard measures.
Enrolled patients received tablet sunitinib at a starting dose of 50 mg once per day for 28 days, followed by 14 days of the rest period, which constituted one cycle of treatment. Dose modification for toxicity was done in a standardized protocol defined manner.
Assessments for tumor response and progression were performed as per institutional standards. Minimal disease evaluation data (best response and date of progression) were required to be collected within this protocol. Follow-up survival information was collected by clinic visit or telephone contact every 2 months for up to 2 years from the date of the last dose of sunitinib.
The primary objective of this protocol was to provide access to sunitinib to patients who fulfilled the eligibility criteria. Other endpoints were OS, ORR and safety profile of sunitinib. Assessment of response was performed using serial clinical examination and either contrast-enhanced computed tomography (CT) scan or positron emission tomography-CT scans, with the same modality being used serially in a single patient. Response was categorized as complete, partial and stable disease (SD) as per RECIST 1.1 criteria. OS was calculated as the time interval from the initiation of therapy until death or date of last follow-up and computed according to Kaplan–Meier method. For the purpose of this analysis we also calculated the progression-free survival (PFS), defined as the time interval from the initiation of therapy until disease progression or death, whichever was earlier. Toxicity was evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.
| » Results|| |
Fifteen eligible patients were enrolled in the study between November 2006 and October 2007. The baseline patient characteristics are shown in [Table 1]. Key features included good performance status (Eastern Cooperative Oncology Group 0 or 1) in the majority (80%) of patients and well-controlled hypertension in 26.7%. Small intestine was the most common primary site (40%) followed by the stomach and retroperitoneal (26.7% each). Surgery had been previously performed in 9 (60%) patients and the other 6 (40%) had inoperable disease. All 15 patients had documented disease progression on imatinib at a median of 29 (6–46) months and no patient had imatinib intolerance. Twelve (80%) patients had been treated with a starting imatinib dose of 400 mg/day and 3 (20%) on 600 mg/day. In 8 (53.3%) patients imatinib dose had been escalated from 400 mg to 600 mg/day and in 2 (13.3%) this drug had been deescalated from 600 mg to 400 mg due to toxicity.
The details of sunitinib treatment are shown in [Table 2]. A median of 10 (1–47) cycles were delivered. Nine (60%) patients required dose modification due to toxicity after having received a median of 5 (1–40) cycles of treatment. Sunitinib could be delivered at a median dose intensity of 29.8 mg/day. Considering a target dose intensity of 33.3 mg/day (50 mg/day for 28 days of the 42 day cycle) the median delivered relative dose intensity was 0.89.
The toxicity profile of sunitinib is shown in [Table 3]. Grade 3 toxicity attributable to sunitinib was seen in 6 (40%) patients but in no patient did this lead to permanent discontinuation of this drug. No grade 4 toxicity attributable to sunitinib was documented, and no patient required hospitalization due to drug-related complications. Of note, grade 3 hypothyroidism was noted in 1(6.7%), and grade 3 hand-foot syndrome in 3 (20%) patients and 2 (13.3%) patient had grade 3 hypertension. No patient had renal or cardiac adverse effects due to sunitinib.
The response rates are shown in [Table 4]. One patient died due to disease progression during the first cycle of treatment due to disease progression. Of the remaining patients, no patient had complete response (CR), 4 (26.7%) achieved partial response (PR), 8 (53.3%) had stable disease (SD) and 2 (13.3%) had progressive disease as their best response. The overall clinical benefit rate (CR + PR + SD) was 80%.
At the time of last follow-up, 14 patients have died, and one patient is surviving in disease progression. At a median follow-up of 81 months in surviving patients, the median PFS is 15.5 months [Figure 1] and median OS is 18.7 months [Figure 2].
| » Discussion|| |
To our knowledge, this is the first report of the use of sunitinib in a well-defined cohort of Indian patients with imatinib resistant GIST. Although no patient achieved CR the clinical benefit rate was high (80%). Taken together with the reasonably good PFS and OS (15.5 and 18.7 months respectively), these data suggest that radiological disease stability is consistent with good outcome in advanced-stage patients. Physicians should, therefore, avoid premature discontinuation of sunitinib based only on the lack of objective tumor shrinkage in these patients. Our efficacy results are consistent with or better than those reported earlier, including the pivotal phase 3 trial that led to approval of sunitinib for this indication.,,,
Our data also suggests that sunitinib is well-tolerated in our patient population. There were no toxicity-related treatment discontinuations or deaths and almost 90% of the target sunitinib dose intensity could be delivered to our patients. Of note, hand-foot syndrome was a prominent toxicity of sunitinib in our patients, which is unlike that reported from Western studies. This pattern of toxicity is consistent with other Indian studies with this drug in renal carcinoma. Although the exact reasons are unknown, this observation is consistent with others that have reported differing patterns of drug toxicity in Asian populations. It is possible that pharmacogenomic and pharmacokinetic variables are responsible for the toxicity pattern seen in our study. We would also like to emphasize the excellent patient compliance in our protocol. Our data attests to the importance of close patient monitoring and protocol defined dose modifications to minimize toxicity and maximize patient compliance and outcome.
The chief limitation of our study is the small number of patients with consequent wide confidence intervals of all results. However, because of prospective, standardized, protocol defined data collection, long and complete follow-up and high event rate in our study population, we believe our data to be representative of any larger patient cohort.
In conclusion, sunitinib seems to an effective and safe treatment option for Indian patients with advanced imatinib resistant GIST. These data, along with those reported earlier, can be used by Indian physicians to counsel their patients with this disease.
| » References|| |
Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, et al.
Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998;279:577-80.
Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol 2004;22:3813-25.
Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, et al.
Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 2003;21:4342-9.
Blanke CD, Corless CL. State-of-the art therapy for gastrointestinal stromal tumors. Cancer Invest 2005;23:274-80.
Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 2000;96:925-32.
Tuveson DA, Willis NA, Jacks T, Griffin JD, Singer S, Fletcher CD, et al.
STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: Biological and clinical implications. Oncogene 2001;20:5054-8.
Joensuu H, Roberts PJ, Sarlomo-Rikala M, Andersson LC, Tervahartiala P, Tuveson D, et al.
Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 2001;344:1052-6.
van Oosterom AT, Judson I, Verweij J, Stroobants S, Donato di Paola E, Dimitrijevic S, et al.
Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: A phase I study. Lancet 2001;358:1421-3.
Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, et al.
Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472-80.
Blanke CD, Demetri GD, von Mehren M, Heinrich MC, Eisenberg B, Fletcher JA, 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;26:620-5.
von Mehren M, Heinrich MC, Joensuu H, et al
. Follow-up results after 9 years (yrs) of the ongoing, phase II B2222 trial of imatinib mesylate (IM) in patients (pts) with metastatic or unresectable KIT + gastrointestinal stromal tumors (GIST). J Clin Oncol 2011;29:609s. [suppl; abstr 10016].
Demetri DG, van Oosterom A, Blackstein M, et al
. Phase 3 Multicenter, Randomized, Double-Bind, Placebo-Controlled Trial of SU11248 in Patients Following Failure of Imatinib for Metastatic GIST. Orlando, Florida, USA: American Society of Clinical Oncology 41st
Annual Meeting. 13-17 May, 2005.
Van Glabbeke M, Verweij J, Casali PG, Le Cesne A, Hohenberger P, Ray-Coquard I, et al.
Initial and late resistance to imatinib in advanced gastrointestinal stromal tumors are predicted by different prognostic factors: A European Organisation for Research and Treatment of Cancer-Italian Sarcoma Group-Australasian Gastrointestinal Trials Group study. J Clin Oncol 2005;23:5795-804.
Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY, et al.
Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: Randomised trial. Lancet 2004;364:1127-34.
Maki RG, Fletcher JA, Heinrich MC, et al
. Results from a continuation trial of SU11248 in patients with imatinib-resistant gastrointestinal stromal tumor (GIST). J Clin Oncol 2005;23:818s. [suppl; abstr 9011].
Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, 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 2006;368:1329-38.
Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N, et al.
Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 2006;24:25-35.
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al.
New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205-16.
Heinrich MC, Maki RG, Corless CL, Antonescu CR, Harlow A, Griffith D, et al.
Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol 2008;26:5352-9.
Chen YY, Yeh CN, Cheng CT, Chen TW, Rau KM, Jan YY, et al.
Sunitinib for Taiwanese patients with gastrointestinal stromal tumor after imatinib treatment failure or intolerance. World J Gastroenterol 2011;17:2113-9.
Liu X, Jiang WZ, Guan GX, Chen ZF, Chi P, Lu HS. Efficacy and safety of sunitinib on patients with imatinib-resistant gastrointestinal stromal tumor. Zhonghua Wei Chang Wai Ke Za Zhi 2013;16:221-5.
Krishna VM, Noronha V, Prabhash K, Joshi A, Patil V, Bhosale B, et al.
Sunitinib in metastatic renal cell carcimoma: A single-center experience. Indian J Cancer 2013;50:268-73.
Swain SM, Im YH, Im SA, Chan V, Miles D, Knott A, et al
. Safety profile of Pertuzumab with Trastuzumab and Docetaxel in patients from Asia with human epidermal growth factor receptor 2-positive metastatic breast cancer: Results from the phase III trial CLEOPATRA. Oncologist 2014;19:693-701.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]
|This article has been cited by|
||Complete response to second-line chemotherapy with sunitinib of a gastrointestinal stromal tumor: A case report
| ||Tsuyoshi Shirakawa,Tomoya Hirata,Kosuke Maemura,Toshiyuki Goto,Yoshiya Shimao,Kosuke Marutsuka,Yuji Ueda,Ikuo Kikuchi |
| ||Molecular and Clinical Oncology. 2017; 7(1): 93 |
|[Pubmed] | [DOI]|