Jayesh Desai

Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial

BACKGROUND No effective therapeutic options for patients with unresectable imatinib-resistant gastrointestinal stromal tumour are available. We did a randomised, double-blind, placebo-controlled, multicentre, international trial to assess tolerability and anticancer efficacy of sunitinib, a multitargeted tyrosine kinase inhibitor, in patients with advanced gastrointestinal stromal tumour who were resistant to or intolerant of previous treatment with imatinib. METHODS Blinded sunitinib or placebo was given orally once daily at a 50-mg starting dose in 6-week cycles with 4 weeks on and 2 weeks off treatment. The primary endpoint was time to tumour progression. Intention-to-treat, modified intention-to-treat, and per-protocol analyses were done. This study is registered at ClinicalTrials.gov, number NCT00075218. FINDINGS 312 patients were randomised in a 2:1 ratio to receive sunitinib (n=207) or placebo (n=105); the trial was unblinded early when a planned interim analysis showed significantly longer time to tumour progression with sunitinib. Median time to tumour progression was 27.3 weeks (95% CI 16.0-32.1) in patients receiving sunitinib and 6.4 weeks (4.4-10.0) in those on placebo (hazard ratio 0.33; p<0.0001). Therapy was reasonably well tolerated; the most common treatment-related adverse events were fatigue, diarrhoea, skin discolouration, and nausea. INTERPRETATION We noted significant clinical benefit, including disease control and superior survival, with sunitinib compared with placebo in patients with advanced gastrointestinal stromal tumour after failure and discontinuation of imatinab. Tolerability was acceptable.

Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib

BACKGROUND Sunitinib, a multitargeted tyrosine-kinase inhibitor, which is approved by both US and European Commission regulatory agencies for clinical use, extends survival of patients with metastatic renal-cell carcinoma and gastrointestinal stromal tumours, but concerns have arisen about its cardiac safety. We therefore assessed the cardiovascular risk associated with sunitinib in patients with metastatic gastrointestinal stromal tumours. METHODS We retrospectively reviewed all cardiovascular events in 75 patients with imatinib-resistant, metastatic, gastrointestinal stromal tumours who had been enrolled in a phase I/II trial investigating the efficacy of sunitinib. The composite cardiovascular endpoint was cardiac death, myocardial infarction, and congestive heart failure. We also examined sunitinibs effects on left ventricular ejection fraction (LVEF) and blood pressure. We investigated potential mechanisms of sunitinib-associated cardiac effects by studies in isolated rat cardiomyocytes and in mice. FINDINGS Eight of 75 (11%) patients given repeating cycles of sunitinib in the phase I/II trial had a cardiovascular event, with congestive heart failure recorded in six of 75 (8%). Ten of 36 (28%) patients treated at the approved sunitinib dose had absolute LVEF reductions in ejection fraction (EF) of at least 10%, and seven of 36 (19%) had LVEF reductions of 15 EF% or more. Sunitinib induced increases in mean systolic and diastolic blood pressure, and 35 of 75 (47%) individuals developed hypertension (>150/100 mm Hg). Congestive heart failure and left ventricular dysfunction generally responded to sunitinib being withheld and institution of medical management. Sunitinib caused mitochondrial injury and cardiomyocyte apoptosis in mice and in cultured rat cardiomyocytes. INTERPRETATION Left ventricular dysfunction might be due, in part, to direct cardiomyocyte toxicity, exacerbated by hypertension. Patients treated with sunitinib should be closely monitored for hypertension and LVEF reduction, especially those with a history of coronary artery disease or cardiac risk factors.

Surgical Management of Advanced Gastrointestinal Stromal Tumors After Treatment With Targeted Systemic Therapy Using Kinase Inhibitors

PURPOSE While targeted inhibitors of tyrosine kinase activity demonstrate dramatic efficacy in the majority of patients with advanced gastrointestinal stromal tumors (GISTs), cure remains elusive and resistance to systemic therapy is a challenge. To assess the role of surgery in multimodality management of GISTs, we studied postoperative outcomes in patients treated with targeted kinase inhibitors for advanced GIST. METHODS We evaluated outcomes in a single institution series of 69 consecutive patients who underwent surgery for advanced GISTs while receiving kinase inhibitors. Patients were categorized based on extent of disease before surgery (stable disease, limited disease progression, generalized disease progression) and surgical result (no evidence of disease, minimal residual disease, bulky residual disease). RESULTS Disease status before surgery was associated with surgical result (P < .0001; median follow-up, 14.6 months). After surgery, there was no evidence of disease in 78%, 25%, and 7% of patients with stable disease, limited progression, and generalized progression, respectively. Bulky residual disease remained after surgery in 4%, 16%, and 43% of the patients with stable disease, limited progression, and generalized progression. Twelve-month progression-free survival was 80%, 33%, and 0% for patients with stable disease, limited progression, and generalized progression (P < .0001). Twelve-month overall survival was 95%, 86%, and 0% for patients with stable disease, limited progression, and generalized progression (P < .0001). CONCLUSION Patients with advanced GISTs exhibiting stable disease or limited progression on kinase inhibitor therapy have prolonged overall survival after debulking procedures. Surgery has little to offer in the setting of generalized progression.

Hypothyroidism after Sunitinib Treatment for Patients with Gastrointestinal Stromal Tumors

Context Sunitinib, a tyrosine kinase inhibitor, has recently been approved for the treatment of gastrointestinal stromal tumors and renal cell carcinoma. Contribution In a series of imatinib-resistant patients treated with sunitinib for gastrointestinal stromal tumors, 36% developed hypothyroidism during the course of treatment. Incidence of hypothyroidism increased progressively with duration of treatment. Implications Disruption of specific cellular signaling pathways by kinase inhibitors that are intended to interfere with malignant cell growth may have profound and unanticipated metabolic consequences. Patients receiving kinase inhibitors should be closely monitored for the occurrence of adverse effects on other organ systems. The Editors Tyrosine kinase inhibitors are beneficial for the treatment of numerous malignant conditions. Although each small molecule is modeled to block the activity of selected kinase signaling enzymes, it is increasingly evident that many have overlapping effects on several kinase pathways. Sunitinib malate (Sutent [previously known as SU11248], Pfizer, Inc., New York, New York), a multitargeted small-molecule tyrosine kinase inhibitor with proven antitumor activity against gastrointestinal stromal tumors and renal cell carcinoma, has recently been approved in the United States and Europe for treatment of patients with metastatic or surgically unresectable disease (14). Although the drug is usually well tolerated, patient-reported fatigue noted during clinical trials led to the monitoring of serum thyroid-stimulating hormone (TSH) concentrations to rule out primary hypothyroidism. After the identification of 2 index case-patients who developed primary hypothyroidism, we expanded our observations in patients receiving sunitinib therapy to further define this association. Index case-patient 1, a 39-year-old woman, presented with lower gastrointestinal bleeding and was found to have a gastrointestinal stromal tumor of the stomach wall with several liver metastases. Following surgery to resect the bleeding lesion, she was treated with imatinib mesylate. Within months, serial imaging confirmed disease progression. Imatinib was withdrawn, and she enrolled in a phase I/II clinical study investigating the safety and efficacy of sunitinib. She received sunitinib in repeated 4-week cycles (50 mg/d for 2 weeks, followed by a 2-week washout phase). At initiation of therapy, the patient had an Eastern Cooperative Oncology Group performance status of zero and had no cold intolerance, constipation, fatigue, or other signs of hypothyroidism. Baseline serum TSH concentration was 1.6 mU/L (normal range, 0.5 to 5.0 mU/L). The patient was treated with sunitinib for more than 1 year and had normal serum TSH concentration during this time, except 1 value of 8.8 mU/L at 38 weeks of therapy (Figure 1). During the 60th week of sunitinib therapy, she reported progressive fatigue, confusion, and cold intolerance. Physical examination was notable for myxedema. The results of thyroid function testing showed a serum TSH value of 288 mU/L. l-Thyroxine was administered, and a normal TSH value was achieved, resulting in resolution of symptoms. Figure 1. Biochemical findings of thyroid dysfunction in a patient treated with sunitinib for recurrence of gastrointestinal stromal tumor. The figure depicts sequential thyroid-stimulating hormone (TSH) measurements during 2 years of sunitinib therapy. l-Thyroxine therapy was initiated at week 74. At 92 weeks, the patient was referred from the oncology program to the Division of Endocrinology for consultation at the Brigham and Womens Hospital, Boston, Massachusetts. At that time, the patient appeared clinically euthyroid, and results of thyroid function tests were normal while she was receiving 150 g of l-thyroxine per day. Her thyroid was not palpable, and results on neck ultrasonography showed minimal thyroid tissue. Index case-patient 2, a 38-year-old woman, presented with a metastatic gastrointestinal stromal tumor. She had previously been treated with imatinib for 18 months before developing refractory disease. Imatinib was withdrawn, and the patient began receiving sunitinib in repeated 6-week cycles (50 mg/d for 4 weeks, followed by a 2-week washout period) at a different cancer center. After she developed diarrhea and fatigue, her dose was reduced to 37.5 mg/d. Following 24 weeks of sunitinib therapy, she noted heart palpitations, heat intolerance, dysphagia, and anterior neck pain lasting several weeks. After approximately 30 weeks of therapy, the patient developed progressive fatigue, cold intolerance, hoarseness, and constipation. These symptoms were initially attributed to direct effects of sunitinib in conjunction with systemic effects of her tumor. After 51 weeks of sunitinib therapy, she was referred to the Dana Farber Cancer Institute, Boston, Massachusetts, and her persistent symptoms suggesting hypothyroidism prompted an endocrine consultation. She was extremely hypothyroid, with dry skin, nonpitting edema, absence of palpable thyroid tissue, and delayed relaxation of deep tendon reflexes. The results of a neck ultrasonography showed no visible thyroid tissue (Figure 2). Her TSH level was 101 mU/L; serum thyroxine concentration was 21 nmol/L (1.6 g/dL) (normal range, 64 to 142 nmol/L [5 to 11 g/dL]), her thyroid hormone binding ratio was 0.48 (normal range, 0.8 to 1.2), her free thyroxine index was 0.8 (normal range, 5 to 11), and her thyroid peroxidase antibody was 17.6 U/mL (normal range, 0 to 20 U/mL). The patient was treated with l-thyroxine, 88 g/d, resulting in complete resolution of her symptoms. On the basis of these initial findings in 2 patients receiving sunitinib, we sought to prospectively evaluate thyroid function in patients enrolled in a phase I/II study investigating sunitinib as a treatment for patients with imatinib-resistant gastrointestinal stromal tumors at the Dana Farber Cancer Institute. Methods Patients Between April 2002 and December 2004, 79 patients were treated in a phase I/II trial investigating sunitinib therapy for the treatment of imatinib-resistant gastrointestinal stromal tumors. Most received 50 mg of sunitinib per day in repeated 4- or 6-week cycles, each consisting of 2 to 4 weeks of sunitinib followed by 2 weeks with no therapy. Patients enrolled in this study had stopped receiving imatinib therapy at least 14 days before starting sunitinib therapy. Between April 2002 and September 2002, thyroid function tests were performed only if there was a clinical suspicion of hypothyroidism. Beginning in October 2002, the study protocol was modified to include measurements of serum TSH at the beginning of each sunitinib treatment cycle. In December 2004, the Endocrinology Division began collaborative evaluation of this population. Serum TSH values were available for 69 of 79 patients (87%), 20 of whom were excluded from primary analysis because of abnormal thyroid function or l-thyroxine therapy preceding initiation of sunitinib or because baseline data were not available. Of these 20 patients, 8 patients were receiving l-thyroxine therapy at study entry (6 had begun l-thyroxine therapy before either imatinib or sunitinib therapy, and 3 patients were first tested for thyroid function after treatment with 5 cycles of sunitinib; 9 other patients had abnormal baseline thyroid function (7 had elevated TSH concentrations, and 2 had suppressed TSH concentrations). Seven additional patients with normal baseline thyroid function received sunitinib therapy for less than 3 cycles because of progressive disease or drug intolerance and were also excluded. No participants received medications known to cause thyroid dysfunction, such as iodinated compounds, lithium, or interferon. Thus, we evaluated results in 42 patients with normal baseline thyroid function treated with sunitinib for at least 3 cycles. These 42 patients were treated for a median of 37 weeks (range, 10 to 167 weeks). Biochemical Evaluation and Treatment Patients were screened for thyroid dysfunction by monitoring serum TSH concentration (5, 6). A TSH concentration greater than 5.0 mU/L was considered abnormal. Patients with substantial increases in TSH were further evaluated, and treatment with l-thyroxine was initiated as indicated. Role of the Funding Source The phase I/II trial of sunitinib was funded in part by Pfizer, Inc., and the results of the trial have been reported elsewhere. There was no separate industry funding source for this investigation, and funding played no role in the collection, analysis, and interpretation of these data or in the decision to submit this paper for publication. The institutional review board of the Dana Farber Cancer Institute granted permission to perform these investigations. Results During the phase I/II trial of sunitinib, 15 of 42 (36%) patients developed hypothyroidism after an average of 50 weeks of therapy (range, 12 to 94 weeks) (Table). Of these, 9 had TSH concentrations more than 20 mU/L (mean maximal serum TSH concentration, 100 mU/L) and 6 had TSH concentrations between 7.0 and 20 mU/L. Seven additional patients (17%) had at least 1 TSH concentration between 5.0 and 7.0 mU/L while receiving sunitinib that subsequently normalized. Four patients developed TSH suppression while receiving sunitinib but discontinued the study protocol before repeated thyroid function studies could be performed. In summary, abnormal serum TSH values were documented in 26 of 42 (62%) patients receiving sunitinib. Eastern Cooperative Oncology Group functional status was similar in patients with normal thyroid function and in those who were hypothyroid, suggesting that acute illness did not selectively influence thyroid function in affected patients. Table. Serum Thyroid-Stimulating Hormone Concentrations in 15 Patients Who Developed Hypothyroidism during Sunitinib Therapy for the Treatment of Gastrointestinal Stromal Tumors Six of the 15 (40%

Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer.

It is hypothesized that BRAF mutant cancers represent a discrete subset of metastatic colorectal cancer (CRC) defined by poorer survival. This study investigates whether BRAF mutant CRC is further defined by a distinct pattern of metastatic spread and explores the impact of BRAF mutation and microsatellite instability (MSI) on prognosis in metastatic CRC.

Metastasis-Associated Gene Expression Changes Predict Poor Outcomes in Patients with Dukes Stage B and C Colorectal Cancer.

Purpose: Colorectal cancer prognosis is currently predicted from pathologic staging, providing limited discrimination for Dukes stage B and C disease. Additional markers for outcome are required to help guide therapy selection for individual patients. Experimental Design: A multisite single-platform microarray study was done on 553 colorectal cancers. Gene expression changes were identified between stage A and D tumors (three training sets) and assessed as a prognosis signature in stage B and C tumors (independent test and external validation sets). Results: One hundred twenty-eight genes showed reproducible expression changes between three sets of stage A and D cancers. Using consistent genes, stage B and C cancers clustered into two groups resembling early-stage and metastatic tumors. A Prediction Analysis of Microarray algorithm was developed to classify individual intermediate-stage cancers into stage A–like/good prognosis or stage D–like/poor prognosis types. For stage B patients, the treatment adjusted hazard ratio for 6-year recurrence in individuals with stage D–like cancers was 10.3 (95% confidence interval, 1.3-80.0; P = 0.011). For stage C patients, the adjusted hazard ratio was 2.9 (95% confidence interval, 1.1-7.6; P = 0.016). Similar results were obtained for an external set of stage B and C patients. The prognosis signature was enriched for downregulated immune response genes and upregulated cell signaling and extracellular matrix genes. Accordingly, sparse tumor infiltration with mononuclear chronic inflammatory cells was associated with poor outcome in independent patients. Conclusions: Metastasis-associated gene expression changes can be used to refine traditional outcome prediction, providing a rational approach for tailoring treatments to subsets of patients. (Clin Cancer Res 2009;15(24):7642–51)

Blood-Based Biomarkers of SU11248 Activity and Clinical Outcome in Patients with Metastatic Imatinib-Resistant Gastrointestinal Stromal Tumor

Purpose: There is an unmet need for noninvasive markers to measure the biological effects of targeted agents, particularly those inhibiting the vascular endothelial growth factor (VEGF) receptor (VEGFR) pathway, and identify patients most likely to benefit from treatment. In this study, we investigated potential blood-based biomarkers for SU11248 (sunitinib malate), a multitargeted tyrosine kinase inhibitor, in patients with metastatic imatinib-refractory gastrointestinal stromal tumors. Experimental Design: Patients (n = 73) enrolled in a phase I/II trial received SU11248 daily for 14 or 28 days followed by 14 days without treatment per cycle. Clinical benefit was defined as progression-free survival of >6 months. We assessed plasma markers, including VEGF and soluble VEGFR-2 (sVEGFR-2), and two cellular populations bearing VEGF receptors: monocytes and, in a subset of patients, mature circulating endothelial cells (CEC). Results: Compared to patients with progressive disease, patients with clinical benefit had significantly greater increases in CECs (0.52 versus −−0.01 CEC/μL/d, P = 0.03) and smaller decreases in monocyte levels (47% versus 60%, P = 0.007) during cycle 1. VEGF increased by 2.2-fold and sVEGFR-2 decreased 25% during the first 2 weeks of treatment. Neither plasma marker correlated with clinical outcome although a modest inverse correlation was observed between sVEGFR-2 changes and plasma drug levels. Monocytes, VEGF, and sVEGFR-2 all rebounded towards baseline off treatment. Conclusions: Monocytes, VEGF, and sVEGFR-2 were consistently modulated by treatment, suggesting that they may serve as pharmacodynamic markers for SU11248. Changes in CECs and monocytes, but not the plasma markers, differed between the patients with clinical benefit and those with progressive disease. These end points merit further investigation in future trials to determine their utility as markers of SU11248 activity and clinical benefit in gastrointestinal stromal tumors and other tumor types.

Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer

Detection of circulating tumor DNA in patients with resected stage II colon cancer provides evidence of residual disease. Footprints of persistent cancer Stage II colon cancer, which has spread through the wall of the colon but has not metastasized to the lymph nodes, can present a therapeutic dilemma. On one hand, these tumors can usually be completely removed by surgery, and the majority does not recur even without chemotherapy. On the other hand, it is difficult to determine which of these tumors will recur and to identify patients who would benefit from adjuvant chemotherapy after surgery. Tie et al. show that the presence of circulating tumor DNA in a patient’s blood after surgery is a sign of persistent tumor and a greatly increased risk of relapse, suggesting that this group of patients may require chemotherapy to prevent recurrence. Detection of circulating tumor DNA (ctDNA) after resection of stage II colon cancer may identify patients at the highest risk of recurrence and help inform adjuvant treatment decisions. We used massively parallel sequencing–based assays to evaluate the ability of ctDNA to detect minimal residual disease in 1046 plasma samples from a prospective cohort of 230 patients with resected stage II colon cancer. In patients not treated with adjuvant chemotherapy, ctDNA was detected postoperatively in 14 of 178 (7.9%) patients, 11 (79%) of whom had recurred at a median follow-up of 27 months; recurrence occurred in only 16 (9.8 %) of 164 patients with negative ctDNA [hazard ratio (HR), 18; 95% confidence interval (CI), 7.9 to 40; P < 0.001]. In patients treated with chemotherapy, the presence of ctDNA after completion of chemotherapy was also associated with an inferior recurrence-free survival (HR, 11; 95% CI, 1.8 to 68; P = 0.001). ctDNA detection after stage II colon cancer resection provides direct evidence of residual disease and identifies patients at very high risk of recurrence.

Resistance to BRAF Inhibition in BRAF-Mutant Colon Cancer Can Be Overcome with PI3K Inhibition or Demethylating Agents

Purpose: Vemurafenib, a selective inhibitor of BRAFV600, has shown significant activity in BRAFV600 melanoma but not in less than 10% of metastatic BRAFV600 colorectal cancers (CRC), suggesting that studies of the unique hypermethylated phenotype and concurrent oncogenic activation of BRAFmut CRC may provide combinatorial strategies. Experimental Design: We conducted comparative proteomic analysis of BRAFV600E melanoma and CRC cell lines, followed by correlation of phosphoinositide 3-kinase (PI3K) pathway activation and sensitivity to the vemurafenib analogue PLX4720. Pharmacologic inhibitors and siRNA were used in combination with PLX4720 to inhibit PI3K and methyltransferase in cell lines and murine models. Results: Compared with melanoma, CRC lines show higher levels of PI3K/AKT pathway activation. CRC cell lines with mutations in PTEN or PIK3CA were less sensitive to growth inhibition by PLX4720 (P = 0.03), and knockdown of PTEN expression in sensitive CRC cells reduced growth inhibition by the drug. Combined treatment of PLX4720 with PI3K inhibitors caused synergistic growth inhibition in BRAF-mutant CRC cells with both primary and secondary resistance. In addition, methyltransferase inhibition was synergistic with PLX4720 and decreased AKT activation. In vivo, PLX4720 combined with either inhibitors of AKT or methyltransferase showed greater tumor growth inhibition than PLX4720 alone. Clones with acquired resistance to PLX4720 in vitro showed PI3K/AKT activation with EGF receptor (EGFR) or KRAS amplification. Conclusions: We show that activation of the PI3K/AKT pathway is a mechanism of both innate and acquired resistance to BRAF inhibitors in BRAFV600E CRC and suggest combinatorial approaches to improve outcomes in this poor prognosis subset of patients. Clin Cancer Res; 19(3); 657–67. ©2012 AACR.

Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study

BACKGROUND Metastatic DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer has a poor prognosis after treatment with conventional chemotherapy and exhibits high levels of tumour neoantigens, tumour-infiltrating lymphocytes, and checkpoint regulators. All of these features are associated with the response to PD-1 blockade in other tumour types. Therefore, we aimed to study nivolumab, a PD-1 immune checkpoint inhibitor, in patients with dMMR/MSI-H metastatic colorectal cancer. METHODS In this ongoing, multicentre, open-label, phase 2 trial, we enrolled adults (aged ≥18 years) with histologically confirmed recurrent or metastatic colorectal cancer locally assessed as dMMR/MSI-H from 31 sites (academic centres and hospitals) in eight countries (Australia, Belgium, Canada, France, Ireland, Italy, Spain, and the USA). Eligible patients had progressed on or after, or been intolerant of, at least one previous line of treatment, including a fluoropyrimidine and oxaliplatin or irinotecan. Patients were given 3 mg/kg nivolumab every 2 weeks until disease progression, death, unacceptable toxic effects, or withdrawal from study. The primary endpoint was investigator-assessed objective response as per Response Evaluation Criteria in Solid Tumors (version 1.1). All patients who received at least one dose of study drug were included in all analyses. This trial is registered with ClinicalTrials.gov, number NCT02060188. FINDINGS Of the 74 patients who were enrolled between March 12, 2014, and March 16, 2016, 40 (54%) had received three or more previous treatments. At a median follow-up of 12·0 months (IQR 8·6-18·0), 23 (31·1%, 95% CI 20·8-42·9) of 74 patients achieved an investigator-assessed objective response and 51 (69%, 57-79) patients had disease control for 12 weeks or longer. Median duration of response was not yet reached; all responders were alive, and eight had responses lasting 12 months or longer (Kaplan-Meier 12-month estimate 86%, 95% CI 62-95). The most common grade 3 or 4 drug-related adverse events were increased concentrations of lipase (six [8%]) and amylase (two [3%]). 23 (31%) patients died during the study; none of these deaths were deemed to be treatment related by the investigator. INTERPRETATION Nivolumab provided durable responses and disease control in pre-treated patients with dMMR/MSI-H metastatic colorectal cancer, and could be a new treatment option for these patients. FUNDING Bristol-Myers Squibb.