Clinical Study Chemotherapy 2014;60:143–150 DOI: 10.1159/000369780
Received: April 3, 2014 Accepted after revision: November 7, 2014 Published online: March 7, 2015
Long-Term Everolimus Treatment of Patients with Pancreatic Neuroendocrine Tumors Edward M. Wolin Markey Cancer Center/University of Kentucky, Lexington, Ky., USA
Abstract Background/Aims: Based on the significant prolongation of progression-free survival in a randomized phase III trial, RADIANT-3 (RAD001 in Advanced Neuroendocrine Tumors, Third Trial), everolimus has been approved for the management of advanced, progressive pancreatic neuroendocrine tumors (pNET). Here, we describe 15 participants in RADIANT-3 who were treated with everolimus at our study center. We report the long-term survival of a subset of patients. Methods: Patients with advanced, progressive pNET were randomly assigned to the everolimus arm of RADIANT-3 or received everolimus as open-label treatment after experiencing progression on placebo or during the unblinded phase. Results: Five patients on everolimus (5–10 mg/day) had stable disease for >43 to >76 months after initiating treatment. Three patients achieved stable disease for 19–25 months, but died of progressive malignancy thereafter. Seven patients had stable disease for ≤11 months after initiating everolimus therapy. Conclusion: Patients with advanced, progressive pNET can obtain long-term benefit from daily © 2015 S. Karger AG, Basel oral treatment with everolimus.
© 2015 S. Karger AG, Basel 0009–3157/15/0603–0143$39.50/0 E-Mail [email protected] www.karger.com/che
Introduction
Pancreatic neuroendocrine tumors (pNET), a heterogeneous group of neoplasms of the pancreas, account for approximately 1% of all cases of pancreatic cancer by incidence and 9% of cases by prevalence in the USA, reflecting an increase in incidence and prevalence in the past 30 years [1]. Approximately 65% of pNET are diagnosed at an advanced stage, when the disease has become unresectable or metastatic; this is associated with a poor prognosis [2]. The median survival time is 77 months for patients with regional disease but only 24 months for patients with distant disease [2]. Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), is approved for the treatment of adults with progressive pNET that is unresectable, locally advanced or metastatic [3]. Everolimus has demonstrated efficacy and acceptable tolerability in patients with lowgrade/intermediate-grade advanced pNET in phase II trials [4, 5]. A prospective, randomized, phase III trial, RADIANT-3 (RAD001 in Advanced Neuroendocrine Tumors, Third Trial) evaluated the efficacy and safety of everolimus (10 mg) compared with placebo, both with best supportive care, in patients with advanced, low-grade or intermediate-grade pNET and radiologic progression Edward M. Wolin, MD Markey Cancer Center University of Kentucky, 800 Rose Street Lexington, KY 40536-0093 (USA) E-Mail edward.wolin @ uky.edu
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Key Words Pancreatic cancer · Neuroendocrine tumors · Everolimus
Patients and Methods The methodology of RADIANT-3 has been published in detail [6]. Patients with advanced pNET and radiologic progression within the previous 12 months were randomly assigned to receive everolimus (10 mg once daily) or placebo, both with best supportive care. The primary end point was PFS. All patients enrolled in RADIANT3 signed written informed consent, and the RADIANT-3 protocol was approved by the institutional review board [6].
Results
At our institution, patients with advanced, progressive pNET enrolled in RADIANT-3 were randomly assigned to the everolimus arm (n = 7) or received everolimus as open-label treatment after experiencing progression on 1
At the time of the final overall survival (OS) analysis of the RADIANT-3 trial (after 256 events), everolimus demonstrated a median OS of 44 months, the longest reported for patients with advanced pNET in a phase III study. A clinically relevant improvement in median OS of 6.3 months was observed compared with placebo (37.7 months; HR 0.94 (95% CI, 0.73–1.20); p = 0.30; significance boundary 0.0249). AEs occurring during the extension phase were consistent with those occurring during the blinded phase, most commonly stomatitis (47%), diarrhea (44%), and rash (40%) [7].
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placebo (n = 7) or after unblinding (n = 1). Of the 15 patients, 8 demonstrated responses to everolimus of ≥19 months and 7 demonstrated responses of ≤11 months. The baseline characteristics of patients who responded to everolimus for ≥19 months are presented in table 1 (patients 1–8). The baseline characteristics of patients who responded to everolimus for ≤11 months are presented in table 2 (patients 9–15). All 15 patients had previously received therapy with somatostatin analogs. Patients Who Responded to Everolimus for Approximately 19 to >76 Months Patient 1 A 36-year-old Caucasian woman with well-differentiated pNET and involvement of the liver, diagnosed on June 4, 2008, entered RADIANT-3 and was assigned to the everolimus arm on August 15, 2008. She had a World Health Organization (WHO) performance status (PS) of 1 at baseline and received an everolimus dose of 10 mg/ day. AEs possibly related to treatment were of grade 1/2 and included chills, night sweats, rash, epistaxis, stomatitis, hair and weight loss, hyperglycemia and peripheral edema. Concomitant medications were administered for hyperglycemia, rash and stomatitis. The patient experienced grade 3 pneumonitis requiring a temporary dose interruption for 10 days; subsequently, the study medication was resumed at the previous dose. She received everolimus for 19 months, from August 2008 until disease progression in March 2010. She was subsequently treated with temozolomide and capecitabine, and with etoposide and carboplatin. The patient died on June 1, 2011, of progressive disease. Patient 2 A 40-year-old Caucasian woman with well-differentiated pNET and involvement of the liver and abdominal lymph nodes enrolled in RADIANT-3 on March 6, 2008, and was assigned to placebo. She had a WHO PS of 1 at baseline. In October 2008, because of disease progression at day 169 of the study, she received open-label everolimus (10 mg/day). AEs possibly related to treatment were grade 1/2 and included fatigue, asthenia, erythema, rash, peripheral edema, pruritus and anemia. The patient received everolimus for 25 months without dose modification but died of progressive disease on November 11, 2010. Patient 3 A 71-year-old Caucasian woman with well-differentiated pNET and involvement of the liver, lymph nodes and abdomen entered RADIANT-3 on March 12, 2008, Wolin
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within the previous 12 months [6]. Median progressionfree survival (PFS) was 11.0 months with everolimus and 4.6 months with placebo [hazard ratio (HR) 0.35; 95% confidence interval (CI) 0.27–0.45; p < 0.001] based on assessments by the local investigators. The estimated proportion of patients who were alive and progression-free at 18 months was 34% (95% CI 26–43) with everolimus compared with 9% (95% CI 4–16) with placebo.1 Confirmed objective tumor responses (all partial responses) as assessed by local investigators were observed in 10 patients receiving everolimus (5%) compared with 4 patients receiving placebo (2%). Stable disease was achieved in 73% of the patients who received everolimus compared with 51% of the patients who received placebo. Tumor shrinkage was observed in 64% of the patients who received everolimus compared with 21% of the patients who received placebo. The safety profile of everolimus was consistent with that of previous reports from other trials, and most adverse events (AEs) were grade 1 or 2, allowing for potential long-term daily use [4–6]. At the time of publication of RADIANT-3 results, treatment was ongoing for 32% and 13% of patients in the everolimus and placebo groups, respectively. Here, we describe the outcomes of everolimus treatment including long-term survival for 15 patients with pNET enrolled in RADIANT-3 at our study center.
Table 1. Baseline characteristics of patients who responded to treatment with everolimus for ≥19 months Patient
WHO PSa
Clinical presentation
Previous surgery
Treatment
No.
age, years
sex
race
arm
period on everolimus, months
1
36
F
C
1
Well-differentiated pNET with involvement of the liver
–
E
19
2
40
F
C
1
Well-differentiated pNET with involvement of the liver and lymph nodes, including those in the abdomen
Excision of left portal lymph node; whipple procedure; pancreatic duodenectomy
P
25
3
71
F
C
0
Well-differentiated pNET with involvement of the liver, lymph nodes and abdomen
Radical resection distal tail pancreas; splenectomy; radical left nephrectomy; removal of intraportal tumor and repair of portal vein; partial gastrectomy; hepatic lymph node excision; adrenalectomy, left; resection of small cell carcinoma, upper lip
P
>50
4
58
F
A
0
Well-differentiated pNET with involvement of the liver
Hepatic left lateral segmentectomy; subtotal pancreatectomy; splenectomy; cholecystectomy
P
>56b
5
51
M
C
1
Well-differentiated grade 2 pNET with involvement of the retroperitoneum
Distal pancreatectomy; splenectomy
E
>72c
6
54
M
C
0
Well-differentiated grade 2 pNET with involvement of the liver and paraaortic lymph node
Splenectomy; distal pancreatectomy; orchiectomy; left upper lobectomy; retroperitoneal mass/lymph node
E
>76c
7
54
M
C
1
Well-differentiated pNET with involvement of the liver and paraaortic lymph node
–
E
>43c, d
8
65
M
C
0
Well-differentiated pNET with involvement of the bone, liver, pancreas, lymph nodes and peritoneum
–
P
22
A = Asian; C = Caucasian; E = everolimus; F = female; M = male; P = placebo. a WHO PS at baseline. b The patient received everolimus for approximately 10 months and then discontinued it because of grade 4 hyponatremia. She has subsequently received octreotide (long-acting repeatable, 30 mg i.m. every 4 weeks) for approximately 3 years and, as of August 2014, has had stable disease for >46 months. c As of August 2014, these patients were receiving ongoing everolimus treatment. d The patient voluntarily interrupted everolimus treatment after experiencing 20.7 months of stable disease; 43 months reflects the duration of treatment/ stable disease since the patient resumed everolimus after treatment interruption and disease progression.
Long-Term Everolimus in pNET
off the study because of disease progression, after having received everolimus 5 mg/day for >50 months with stable disease since the initiation of everolimus treatment in September 2008. Patient 4 A 58-year-old Asian woman had well-differentiated pNET and involvement of the liver. She entered RADIANT-3 on April 7, 2009, and was assigned to the placebo arm. She had a WHO PS of 0 at baseline. At disease progression after 228 days (December 2009), she received open-label everolimus 10 mg/day. After 6 days on Chemotherapy 2014;60:143–150 DOI: 10.1159/000369780
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and was assigned to the placebo arm. She had a WHO PS of 0 at baseline. Due to disease progression at day 169 of the study, she began treatment with open-label everolimus 10 mg/day on September 15, 2008. AEs possibly related to treatment were grade 1/2 rash, alopecia, nail disorder, hyperglycemia, hypertension and pruritus. The alopecia resolved spontaneously. Hypertension and hyperglycemia, thought to be related to the study drug, developed 160 and 491 days after the start of the everolimus treatment, respectively. Pneumonitis in March 2012 necessitated a dose reduction to 5 mg/day. On December 5, 2012, the patient went
Table 2. Baseline characteristics of patients who responded to treatment with everolimus for ≤11 months Patient No.
WHO PSa
age, years
sex
race
9
49
F
C
0
10
47
F
C
11
64
F
12
59
13
Clinical presentation
Previous surgery
Treatment arm
period on everolimus
Well-differentiated pNET with involvement Peripancreatic and mediastinal lymph node of the liver and abdominal lymph nodes (fine-needle aspiration)
E
11 months
1
Well-differentiated pNET with involvement Omentum nodule excision; celiac and portal of the liver lymph node excision; peripancreatic and bile duct lymph node excision; portal lymph node excision
E
84 days
C
0
Well-differentiated pNET with involvement Peripancreatic neuroendocrine mass resection of the liver and lung
P
5 months
M
C
0
Well-differentiated pNET with involvement Cholecystectomy of the liver, lymph nodes and mediastinum
P
8 months
71
M
C
1
Well-differentiated pNET with involvement – of the bone, liver and lymph nodes
P
76 days
14
73
M
C
0
Well-differentiated pNET with involvement Thoracotomy; mediastinal lymph node of the bone, liver and lymph nodes dissection; right pneumonectomy
P
11 months
15
81
M
C
0
Well-differentiated pNET with involvement – of the lung, liver and kidneys
E
85 days
C = Caucasian; F = female; M = male; E = everolimus; P = placebo. baseline.
a At
Patient 5 A 51-year-old Caucasian man with a well-differentiated, grade 2 pNET and involvement of the retroperitoneum entered RADIANT-3 on August 8, 2008, and was assigned to the everolimus arm. He had a WHO PS of 1 at baseline. Grade 1/2 AEs in the course of his everolimus therapy suspected to be related to treatment were headache, dysgeusia, stomatitis, rash, palpitations, viral infec146
Chemotherapy 2014;60:143–150 DOI: 10.1159/000369780
tion, peripheral edema, peripheral neuropathy, eczema and stomatitis. The stomatitis was controlled with topical therapy. The eczema resolved spontaneously, and the edema responded to diuretics. He experienced a grade 3 pulmonary embolism for 6 days that necessitated hospitalization, anticoagulant therapy and a 4-day dose interruption. Subsequently, the study drug was resumed at the full dose. As of August 2014, the patient is continuing with everolimus 10 mg/day and has had stable disease for >72 months since treatment initiation in August 2008. Patient 6 A 54-year-old Caucasian man with well-differentiated, grade 2 pNET and involvement of the liver and paraaortic lymph nodes began RADIANT-3 on April 10, 2008, and was randomly assigned to the everolimus arm. He had a WHO PS of 0 at baseline. During the course of the everolimus therapy, he experienced grade 1/2 AEs, including headache, dyspnea, erythematous rash, stomatitis, herpes zoster, upper respiratory tract infection, peripheral edema, hyperglycemia and joint swelling, suspected to be related to treatment. After 72 days on study medication, he experienced grade 3 fatigue and asthenia lasting 154 days; these symptoms improved to grade 1 without intervenWolin
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the study drug, she experienced grade 3 stomatitis and asthenia for 31 and 42 days, respectively, and required a dose interruption for 10 days and a dose reduction to 5 mg/day for 32 days. She then experienced grade 1/2 AEs, including dry skin, rash, increased blood cholesterol, dyspnea, stomatitis, hyperglycemia and hypertension, suspected to be related to the treatment. The hypertension was medically controlled. All other conditions resolved 36–42 days after the dose interruption and reduction. The patient received everolimus for 10 months, but was removed from the study on October 18, 2010, because of grade 4 hyponatremia. She has subsequently received octreotide (long-acting repeatable, 30 mg i.m. every 4 weeks) and, as of August 2014, has had stable disease for >56 months.
Patient 7 A 54-year-old Caucasian man with well-differentiated pNET and involvement of the liver and paraaortic lymph nodes entered RADIANT-3 on January 7, 2009, and was assigned to the everolimus arm. He had a WHO PS of 1 at baseline. Grade 1/2 AEs suspected to be related to treatment, and beginning in the first month of therapy, were stomatitis, rash and dermatitis. These did not require a dose adjustment, but medical treatment was needed for the rash and the dermatitis. After experiencing stable disease for 21 months since the initiation of everolimus in January 2009, he withdrew from the study on October 6, 2010, to use somatostatin analog therapy only. However, on January 24, 2011, he resumed the everolimus treatment, off trial, because of disease progression. As of August 2014, >43 months since resuming everolimus 10 mg/day plus octreotide, the patient has had stable disease. Patient 8 A 65-year-old Caucasian man with well-differentiated pNET and involvement of bone, liver, pancreas, lymph nodes and peritoneum entered RADIANT-3 on December 4, 2008, and was assigned to the placebo arm. He had a WHO PS of 0 at baseline and did not experience disease progression for >14 months on placebo. He then began open-label everolimus 10 mg/day after discontinuing placebo therapy on June 28, 2010. After experiencing stable disease on everolimus for almost 22 months, he voluntarily withdrew from the study on December 14, 2011, because of grade 2 weakness and fatigue, which he felt were interfering with the quality of his life. The patient died on May 10, 2012, of progressive cancer. Patients Who Responded to Everolimus for ≤11 Months Patient 9 A 49-year-old Caucasian woman with well-differentiated pNET and involvement of the liver and abdominal Long-Term Everolimus in pNET
lymph nodes began RADIANT-3 on January 6, 2009, and was randomly assigned to everolimus. She had a WHO PS of 0 at baseline. While taking everolimus 10 mg/day, starting in the first month of therapy, the patient experienced grade 1/2 AEs, probably related to treatment, including rash, stomatitis, dyspepsia, pruritus and anemia. Intravenous iron was administered for the anemia. Two brief episodes of facial rash resolved spontaneously, the first after 22 days and the second after 13 days. An episode of dyspepsia also resolved spontaneously after 15 days. Short episodes of oral mucositis and pruritus resolved without medical treatment. The patient continued to receive everolimus 10 mg/day for 11 months before leaving the study on December 13, 2009, because of disease progression. She was subsequently treated with octreotide (long-acting repeatable) and peptide receptor radionuclide therapy (PRRT). The patient died on April 18, 2012, of biliary sepsis after PRRT. Patient 10 A 47-year-old Caucasian woman with well-differentiated pNET and involvement of the liver entered RADIANT-3 on August 5, 2008, and was randomly assigned to the everolimus arm. She had a WHO PS of 1 at baseline. Grade 1/2 AEs suspected to be related to treatment included headache, nausea, urinary tract infection, stomatitis, diarrhea, peripheral edema and paronychia. The headache, rash, diarrhea and urinary tract infections required medical therapy. She received everolimus treatment for 84 days before discontinuation on October 30, 2008, due to progressive disease. She was subsequently treated with PRRT but died of progressive cancer on March 18, 2011. Patient 11 A 64-year-old Caucasian woman with well-differentiated pNET and involvement of the liver and lung entered RADIANT-3 on April 3, 2009, and was assigned to the placebo arm. She had a WHO PS of 0 at baseline. Because of disease progression after 85 days, she crossed over to treatment with open-label everolimus 10 mg/day. AEs after the cross-over suspected to be related to treatment were grade 1/2 rash, stomatitis and cachexia. After 4.6 months of everolimus therapy, grade 3 aspiration pneumonia developed that was unrelated to the study drug, lasted 12 days and resolved with antibiotic therapy, necessitating a dose interruption of 18 days. There was no indication of everolimus pneumonitis. Concomitantly and not related to the study drug, a pulmonary embolus developed for 37 days, resulting in a dose of 5 mg/day for 15 Chemotherapy 2014;60:143–150 DOI: 10.1159/000369780
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tion. The patient responded to medical treatment for herpes zoster, peripheral edema and joint swelling. No dose reduction was necessary. The patient developed hyperglycemia, probably related to the study drug, after 317 days of everolimus and required medical treatment with oral hypoglycemic agents. He withdrew from the study on May 9, 2012, because of the inconvenience of the longdistance travel (>1,000 miles to our center) but continued to receive everolimus 10 mg/day. As of August 2014, he has had stable disease for >76 months since the initiation of everolimus treatment in April 2008.
Patient 12 A 59-year-old Caucasian man with well-differentiated pNET and involvement of the liver, lymph nodes and mediastinum entered RADIANT-3 on January 22, 2009, and was assigned to the placebo arm. He had a WHO PS of 0 at baseline. He experienced disease progression after 85 days in the study and switched to open-label everolimus 10 mg/day on May 1, 2009. AEs possibly related to treatment were grade 1/2 and included upper abdominal pain, weight loss, decreased appetite, gastrointestinal reflux disease, dermatitis, hyperglycemia, pruritus and stomatitis. On study day 245, he experienced acute, grade 3 cholangitis with biliary stent occlusion, lasting 5 and 2 days, respectively, and was admitted to the hospital and administered concomitant medications. The patient continued to take everolimus 10 mg/day for 90 additional days. Overall, he received everolimus treatment for 8 months, but left the study on December 30, 2009, because of disease progression. He received no further therapy and died on June 30, 2010, of progressive malignancy complicated by acute renal failure. Patient 13 A 71-year-old Caucasian man with well-differentiated pNET and involvement of the bone, liver and lymph nodes entered RADIANT-3 on May 1, 2008, and was randomly assigned to the placebo arm. He had a WHO PS of 1 at baseline. Due to disease progression on day 90, he crossed over to open-label treatment with everolimus on September 4, 2008, at a dose of 10 mg/day. Grade 1/2 AEs suspected to be related to treatment started in the first month of therapy and included nausea, diarrhea, headache and cachexia. The diarrhea and cachexia responded to medical management. While in the study, the patient was admitted to the hospital for 3 days for anemia, not suspected to be related to everolimus treatment. After 72 days on the study drug, grade 2 pneumonitis developed that was suspected to be related to treatment. Everolimus treatment was interrupted 4 days later, on November 18, 2008, and was not resumed because the patient was again 148
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in hospital, this time for hypercalcemia, metabolic encephalopathy and cerebrovascular accident. He was taken off the study on November 25, 2008, for progressive metastatic disease in the liver, periportal lymph nodes and retroperitoneal lymph nodes. He had received everolimus for 76 days in total. The patient moved out of state and was then treated with gemcitabine, 5-fluorouracil, irinotecan and platinum. He died of progressive malignancy on May 25, 2010. Patient 14 A 73-year-old Caucasian man with well-differentiated pNET and involvement of the bone, liver, and lymph nodes entered RADIANT-3 on July 7, 2008, and was assigned to the placebo arm. He had a WHO PS of 0 at baseline. The patient crossed over to open-label treatment after disease progression at 86 days on October 10, 2008 and received everolimus 10 mg/day. Grade 1/2 AEs suspected to be related to treatment included cachexia, stomatitis, dysgeusia, fatigue, weight loss, rash, noncardiac chest pain, jaw pain, esophageal pain and asthenia. Mucositis, rash, jaw pain and esophageal pain were medically treated. After 4.6 months on everolimus, grade 2 esophageal ulcers developed that necessitated a treatment interruption for 12 days. Subsequently, the study medication was resumed at 5 mg/day for the remaining treatment duration. The patient experienced grade 3 asthenia for 30 days, which resolved spontaneously. He was removed from the study on September 1, 2009, 11 months after initiating everolimus treatment, for cancer progression in the liver, pancreas and bone. He was treated with PRRT and subsequently died on April 4, 2012, of progressive cancer. Patient 15 An 81-year-old Caucasian man with well-differentiated pNET and involvement of the lung, liver and kidneys entered RADIANT-3 on April 1, 2009, and was randomly assigned to the everolimus arm. He had a WHO PS of 0 at baseline. On April 6, 2009, he was admitted to the hospital for an acute pulmonary embolus and was treated with anticoagulant therapy. He subsequently developed respiratory failure thought to be associated with his chronic obstructive pulmonary disease and went off the study on July 29, 2009. An episode of grade 1 stomatitis that resolved without intervention after 81 days was the only observed AE suspected to be related to treatment. The patient received everolimus for a total of 85 days. He died on August 4, 2009, of cardiopulmonary arrest unrelated to his malignancy. Wolin
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more days after dose interruption until the patient left the study on January 6, 2010, due to disease progression. She was subsequently treated with hepatic artery chemoembolization, followed by interferon-alpha-2b in combination with octreotide. On October 22, 2012, she started treatment with sunitinib 37.5 mg/day by mouth for progressive metastatic disease and was subsequently lost to follow-up.
We present a case series of 15 patients with advanced, progressive, low- or intermediate-grade pNET who received everolimus during their participation in RADIANT-3 at our study center. The duration of exposure to everolimus for these patients ranged from 76 months. Six patients had stable disease for 2–11 months (range 76–326 days) after the initiation of everolimus therapy, but they subsequently developed progressive disease. Eight patients treated with everolimus experienced stable disease for approximately 19 to >76 months. Five of the 15 patients were alive as of August 2014, including 3 who continued to receive everolimus; these patients had experienced stable disease for 43–76 months on everolimus treatment. At the time of publication of RADIANT-3, an estimated 34% of the patients receiving everolimus were alive and progression-free at 18 months, suggesting that everolimus may provide a prolonged benefit for a considerable proportion of patients [6]. Our observations confirmed such a benefit and, in addition, showed that in a subset of 5 of 15 patients, treatment with everolimus can yield PFS periods of longer than 3–6 years, both in patients receiving the standard dosage of 10 mg/day and in those on a reduced dosage of 5 mg/day. AEs associated with everolimus in RADIANT-3 included stomatitis, rash, fatigue and infections. Infections, pneumonitis and interstitial lung disease represented some of the most important clinical concerns and were primarily grade 1 or 2 [6]. Importantly, AEs associated with everolimus are generally manageable, as demonstrated by the low rate of discontinuation in the RADIANT-3 study [6]. Moreover, everolimus can usually be maintained while the AEs are being appropriately managed [8]. AEs experienced by patients at this site receiving everolimus long-term after completion of the RADIANT-3 study remained similar to those reported during the study and were manageable with concomitant medications and dose adjustments [6]. Only 1 patient, who responded to everolimus with stable disease for almost 22 months, discontinued treatment because of a perceived reduction in quality of life associated with grade 2 weakness and fatigue. Patients with both grade 1 and grade 2 well-differentiated disease responded well to everolimus, including 1 patient with bone involvement. However, 2 patients with bone metastases did not have prolonged response with everolimus. This observation is consistent with the outcomes of a multivariate analysis of patients receiving Long-Term Everolimus in pNET
everolimus in combination with octreotide (RADIANT-2 study), which suggested bone involvement as a predictor of worse PFS in patients with NET [9]. Four of 7 patients with a response to everolimus lasting ≤11 months had involvement of ≥3 organs whereas in most patients with a good response to everolimus, only 1 or 2 organs were affected. The exception was patient 8, in whom 4 organs, including the bone, were affected. We observed responses to everolimus, including long-term survival, in patients originally randomly assigned to receive the study drug and in patients who crossed over to open-label everolimus after a progression-free period on placebo of >5 months. In 4 patients who crossed over with more rapid disease progression on placebo (≤90 days), everolimus yielded a shorter duration of PFS (31 months on long-term everolimus treatment had initiated the treatment 27–64 months after diagnosis. Two of 3 patients who entered the study within a short time after diagnosis (≤4 months) responded well to everolimus, and 1 (patient 15) did not; this patient was the oldest of the 15 patients. He had a relatively large number of comorbidities and had the highest frequency of AEs that were not related to treatment during the treatment period (8.8 AEs/month, 9.2 AEs/month total). In conclusion, long-term treatment with everolimus in certain patients was found to be safe and effective, providing cancer control exceeding 3.5 years in 5 of 15 patients. Although some patients required a reduction in everolimus dosage from 10 to 5 mg/day early in the course of treatment, the drug proved to be well tolerated, with only 1 patient discontinuing because of a reduced
quality of life. Although this case series was too small to prove specific patient characteristics associated with successful long-term administration of everolimus, prompt management of AEs, appropriate patient education, medical management and an appropriate dose reduction appeared to be the most important factors. The efficacy of everolimus is being further explored in the phase III RADIANT-4 study (ClinicalTrials.gov ID, NCT01524783), which is investigating the effect of everolimus plus best supportive care versus placebo plus best supportive care in patients with advanced NET of gastrointestinal or lung origin. This study will include quality-of-life analyses as secondary end points.
Acknowledgments The author thanks Jennifer Kulak, PhD and David Gibson, PhD, CMPP for writing assistance funded by Novartis Pharmaceuticals Corporation.
Disclosure Statement Dr. Wolin serves on an advisory board for Novartis Pharmaceuticals Corporation. The RADIANT-3 study was funded by Novartis Pharmaceuticals Corporation.
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Wolin
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1 Yao JC, Eisner MP, Leary C, Dagohoy C, Phan A, Rashid A, Hassan M, Evans DB: Population-based study of islet cell carcinoma. Ann Surg Oncol 2007;14:3492–3500. 2 Yao JC, Hassan M, Phan A, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN, Rashid A, Evans DB: One hundred years after ‘carcinoid’: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008;26:3063– 3072. 3 Afinitor (everolimus) tablets for oral administration prescribing information (2012). http:// www.afinitor.com/index.jsp?site=PC004860& source=01030 (accessed 26 March 2014). 4 Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O’Dorisio TM, Shah MH, Cadiot G, Luppi G, Posey JA, Wiedenmann B: Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors
Received: April 3, 2014 Accepted after revision: November 7, 2014 Published online: March 7, 2015
Long-Term Everolimus Treatment of Patients with Pancreatic Neuroendocrine Tumors Edward M. Wolin Markey Cancer Center/University of Kentucky, Lexington, Ky., USA
Abstract Background/Aims: Based on the significant prolongation of progression-free survival in a randomized phase III trial, RADIANT-3 (RAD001 in Advanced Neuroendocrine Tumors, Third Trial), everolimus has been approved for the management of advanced, progressive pancreatic neuroendocrine tumors (pNET). Here, we describe 15 participants in RADIANT-3 who were treated with everolimus at our study center. We report the long-term survival of a subset of patients. Methods: Patients with advanced, progressive pNET were randomly assigned to the everolimus arm of RADIANT-3 or received everolimus as open-label treatment after experiencing progression on placebo or during the unblinded phase. Results: Five patients on everolimus (5–10 mg/day) had stable disease for >43 to >76 months after initiating treatment. Three patients achieved stable disease for 19–25 months, but died of progressive malignancy thereafter. Seven patients had stable disease for ≤11 months after initiating everolimus therapy. Conclusion: Patients with advanced, progressive pNET can obtain long-term benefit from daily © 2015 S. Karger AG, Basel oral treatment with everolimus.
© 2015 S. Karger AG, Basel 0009–3157/15/0603–0143$39.50/0 E-Mail [email protected] www.karger.com/che
Introduction
Pancreatic neuroendocrine tumors (pNET), a heterogeneous group of neoplasms of the pancreas, account for approximately 1% of all cases of pancreatic cancer by incidence and 9% of cases by prevalence in the USA, reflecting an increase in incidence and prevalence in the past 30 years [1]. Approximately 65% of pNET are diagnosed at an advanced stage, when the disease has become unresectable or metastatic; this is associated with a poor prognosis [2]. The median survival time is 77 months for patients with regional disease but only 24 months for patients with distant disease [2]. Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), is approved for the treatment of adults with progressive pNET that is unresectable, locally advanced or metastatic [3]. Everolimus has demonstrated efficacy and acceptable tolerability in patients with lowgrade/intermediate-grade advanced pNET in phase II trials [4, 5]. A prospective, randomized, phase III trial, RADIANT-3 (RAD001 in Advanced Neuroendocrine Tumors, Third Trial) evaluated the efficacy and safety of everolimus (10 mg) compared with placebo, both with best supportive care, in patients with advanced, low-grade or intermediate-grade pNET and radiologic progression Edward M. Wolin, MD Markey Cancer Center University of Kentucky, 800 Rose Street Lexington, KY 40536-0093 (USA) E-Mail edward.wolin @ uky.edu
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Key Words Pancreatic cancer · Neuroendocrine tumors · Everolimus
Patients and Methods The methodology of RADIANT-3 has been published in detail [6]. Patients with advanced pNET and radiologic progression within the previous 12 months were randomly assigned to receive everolimus (10 mg once daily) or placebo, both with best supportive care. The primary end point was PFS. All patients enrolled in RADIANT3 signed written informed consent, and the RADIANT-3 protocol was approved by the institutional review board [6].
Results
At our institution, patients with advanced, progressive pNET enrolled in RADIANT-3 were randomly assigned to the everolimus arm (n = 7) or received everolimus as open-label treatment after experiencing progression on 1
At the time of the final overall survival (OS) analysis of the RADIANT-3 trial (after 256 events), everolimus demonstrated a median OS of 44 months, the longest reported for patients with advanced pNET in a phase III study. A clinically relevant improvement in median OS of 6.3 months was observed compared with placebo (37.7 months; HR 0.94 (95% CI, 0.73–1.20); p = 0.30; significance boundary 0.0249). AEs occurring during the extension phase were consistent with those occurring during the blinded phase, most commonly stomatitis (47%), diarrhea (44%), and rash (40%) [7].
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placebo (n = 7) or after unblinding (n = 1). Of the 15 patients, 8 demonstrated responses to everolimus of ≥19 months and 7 demonstrated responses of ≤11 months. The baseline characteristics of patients who responded to everolimus for ≥19 months are presented in table 1 (patients 1–8). The baseline characteristics of patients who responded to everolimus for ≤11 months are presented in table 2 (patients 9–15). All 15 patients had previously received therapy with somatostatin analogs. Patients Who Responded to Everolimus for Approximately 19 to >76 Months Patient 1 A 36-year-old Caucasian woman with well-differentiated pNET and involvement of the liver, diagnosed on June 4, 2008, entered RADIANT-3 and was assigned to the everolimus arm on August 15, 2008. She had a World Health Organization (WHO) performance status (PS) of 1 at baseline and received an everolimus dose of 10 mg/ day. AEs possibly related to treatment were of grade 1/2 and included chills, night sweats, rash, epistaxis, stomatitis, hair and weight loss, hyperglycemia and peripheral edema. Concomitant medications were administered for hyperglycemia, rash and stomatitis. The patient experienced grade 3 pneumonitis requiring a temporary dose interruption for 10 days; subsequently, the study medication was resumed at the previous dose. She received everolimus for 19 months, from August 2008 until disease progression in March 2010. She was subsequently treated with temozolomide and capecitabine, and with etoposide and carboplatin. The patient died on June 1, 2011, of progressive disease. Patient 2 A 40-year-old Caucasian woman with well-differentiated pNET and involvement of the liver and abdominal lymph nodes enrolled in RADIANT-3 on March 6, 2008, and was assigned to placebo. She had a WHO PS of 1 at baseline. In October 2008, because of disease progression at day 169 of the study, she received open-label everolimus (10 mg/day). AEs possibly related to treatment were grade 1/2 and included fatigue, asthenia, erythema, rash, peripheral edema, pruritus and anemia. The patient received everolimus for 25 months without dose modification but died of progressive disease on November 11, 2010. Patient 3 A 71-year-old Caucasian woman with well-differentiated pNET and involvement of the liver, lymph nodes and abdomen entered RADIANT-3 on March 12, 2008, Wolin
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within the previous 12 months [6]. Median progressionfree survival (PFS) was 11.0 months with everolimus and 4.6 months with placebo [hazard ratio (HR) 0.35; 95% confidence interval (CI) 0.27–0.45; p < 0.001] based on assessments by the local investigators. The estimated proportion of patients who were alive and progression-free at 18 months was 34% (95% CI 26–43) with everolimus compared with 9% (95% CI 4–16) with placebo.1 Confirmed objective tumor responses (all partial responses) as assessed by local investigators were observed in 10 patients receiving everolimus (5%) compared with 4 patients receiving placebo (2%). Stable disease was achieved in 73% of the patients who received everolimus compared with 51% of the patients who received placebo. Tumor shrinkage was observed in 64% of the patients who received everolimus compared with 21% of the patients who received placebo. The safety profile of everolimus was consistent with that of previous reports from other trials, and most adverse events (AEs) were grade 1 or 2, allowing for potential long-term daily use [4–6]. At the time of publication of RADIANT-3 results, treatment was ongoing for 32% and 13% of patients in the everolimus and placebo groups, respectively. Here, we describe the outcomes of everolimus treatment including long-term survival for 15 patients with pNET enrolled in RADIANT-3 at our study center.
Table 1. Baseline characteristics of patients who responded to treatment with everolimus for ≥19 months Patient
WHO PSa
Clinical presentation
Previous surgery
Treatment
No.
age, years
sex
race
arm
period on everolimus, months
1
36
F
C
1
Well-differentiated pNET with involvement of the liver
–
E
19
2
40
F
C
1
Well-differentiated pNET with involvement of the liver and lymph nodes, including those in the abdomen
Excision of left portal lymph node; whipple procedure; pancreatic duodenectomy
P
25
3
71
F
C
0
Well-differentiated pNET with involvement of the liver, lymph nodes and abdomen
Radical resection distal tail pancreas; splenectomy; radical left nephrectomy; removal of intraportal tumor and repair of portal vein; partial gastrectomy; hepatic lymph node excision; adrenalectomy, left; resection of small cell carcinoma, upper lip
P
>50
4
58
F
A
0
Well-differentiated pNET with involvement of the liver
Hepatic left lateral segmentectomy; subtotal pancreatectomy; splenectomy; cholecystectomy
P
>56b
5
51
M
C
1
Well-differentiated grade 2 pNET with involvement of the retroperitoneum
Distal pancreatectomy; splenectomy
E
>72c
6
54
M
C
0
Well-differentiated grade 2 pNET with involvement of the liver and paraaortic lymph node
Splenectomy; distal pancreatectomy; orchiectomy; left upper lobectomy; retroperitoneal mass/lymph node
E
>76c
7
54
M
C
1
Well-differentiated pNET with involvement of the liver and paraaortic lymph node
–
E
>43c, d
8
65
M
C
0
Well-differentiated pNET with involvement of the bone, liver, pancreas, lymph nodes and peritoneum
–
P
22
A = Asian; C = Caucasian; E = everolimus; F = female; M = male; P = placebo. a WHO PS at baseline. b The patient received everolimus for approximately 10 months and then discontinued it because of grade 4 hyponatremia. She has subsequently received octreotide (long-acting repeatable, 30 mg i.m. every 4 weeks) for approximately 3 years and, as of August 2014, has had stable disease for >46 months. c As of August 2014, these patients were receiving ongoing everolimus treatment. d The patient voluntarily interrupted everolimus treatment after experiencing 20.7 months of stable disease; 43 months reflects the duration of treatment/ stable disease since the patient resumed everolimus after treatment interruption and disease progression.
Long-Term Everolimus in pNET
off the study because of disease progression, after having received everolimus 5 mg/day for >50 months with stable disease since the initiation of everolimus treatment in September 2008. Patient 4 A 58-year-old Asian woman had well-differentiated pNET and involvement of the liver. She entered RADIANT-3 on April 7, 2009, and was assigned to the placebo arm. She had a WHO PS of 0 at baseline. At disease progression after 228 days (December 2009), she received open-label everolimus 10 mg/day. After 6 days on Chemotherapy 2014;60:143–150 DOI: 10.1159/000369780
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and was assigned to the placebo arm. She had a WHO PS of 0 at baseline. Due to disease progression at day 169 of the study, she began treatment with open-label everolimus 10 mg/day on September 15, 2008. AEs possibly related to treatment were grade 1/2 rash, alopecia, nail disorder, hyperglycemia, hypertension and pruritus. The alopecia resolved spontaneously. Hypertension and hyperglycemia, thought to be related to the study drug, developed 160 and 491 days after the start of the everolimus treatment, respectively. Pneumonitis in March 2012 necessitated a dose reduction to 5 mg/day. On December 5, 2012, the patient went
Table 2. Baseline characteristics of patients who responded to treatment with everolimus for ≤11 months Patient No.
WHO PSa
age, years
sex
race
9
49
F
C
0
10
47
F
C
11
64
F
12
59
13
Clinical presentation
Previous surgery
Treatment arm
period on everolimus
Well-differentiated pNET with involvement Peripancreatic and mediastinal lymph node of the liver and abdominal lymph nodes (fine-needle aspiration)
E
11 months
1
Well-differentiated pNET with involvement Omentum nodule excision; celiac and portal of the liver lymph node excision; peripancreatic and bile duct lymph node excision; portal lymph node excision
E
84 days
C
0
Well-differentiated pNET with involvement Peripancreatic neuroendocrine mass resection of the liver and lung
P
5 months
M
C
0
Well-differentiated pNET with involvement Cholecystectomy of the liver, lymph nodes and mediastinum
P
8 months
71
M
C
1
Well-differentiated pNET with involvement – of the bone, liver and lymph nodes
P
76 days
14
73
M
C
0
Well-differentiated pNET with involvement Thoracotomy; mediastinal lymph node of the bone, liver and lymph nodes dissection; right pneumonectomy
P
11 months
15
81
M
C
0
Well-differentiated pNET with involvement – of the lung, liver and kidneys
E
85 days
C = Caucasian; F = female; M = male; E = everolimus; P = placebo. baseline.
a At
Patient 5 A 51-year-old Caucasian man with a well-differentiated, grade 2 pNET and involvement of the retroperitoneum entered RADIANT-3 on August 8, 2008, and was assigned to the everolimus arm. He had a WHO PS of 1 at baseline. Grade 1/2 AEs in the course of his everolimus therapy suspected to be related to treatment were headache, dysgeusia, stomatitis, rash, palpitations, viral infec146
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tion, peripheral edema, peripheral neuropathy, eczema and stomatitis. The stomatitis was controlled with topical therapy. The eczema resolved spontaneously, and the edema responded to diuretics. He experienced a grade 3 pulmonary embolism for 6 days that necessitated hospitalization, anticoagulant therapy and a 4-day dose interruption. Subsequently, the study drug was resumed at the full dose. As of August 2014, the patient is continuing with everolimus 10 mg/day and has had stable disease for >72 months since treatment initiation in August 2008. Patient 6 A 54-year-old Caucasian man with well-differentiated, grade 2 pNET and involvement of the liver and paraaortic lymph nodes began RADIANT-3 on April 10, 2008, and was randomly assigned to the everolimus arm. He had a WHO PS of 0 at baseline. During the course of the everolimus therapy, he experienced grade 1/2 AEs, including headache, dyspnea, erythematous rash, stomatitis, herpes zoster, upper respiratory tract infection, peripheral edema, hyperglycemia and joint swelling, suspected to be related to treatment. After 72 days on study medication, he experienced grade 3 fatigue and asthenia lasting 154 days; these symptoms improved to grade 1 without intervenWolin
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the study drug, she experienced grade 3 stomatitis and asthenia for 31 and 42 days, respectively, and required a dose interruption for 10 days and a dose reduction to 5 mg/day for 32 days. She then experienced grade 1/2 AEs, including dry skin, rash, increased blood cholesterol, dyspnea, stomatitis, hyperglycemia and hypertension, suspected to be related to the treatment. The hypertension was medically controlled. All other conditions resolved 36–42 days after the dose interruption and reduction. The patient received everolimus for 10 months, but was removed from the study on October 18, 2010, because of grade 4 hyponatremia. She has subsequently received octreotide (long-acting repeatable, 30 mg i.m. every 4 weeks) and, as of August 2014, has had stable disease for >56 months.
Patient 7 A 54-year-old Caucasian man with well-differentiated pNET and involvement of the liver and paraaortic lymph nodes entered RADIANT-3 on January 7, 2009, and was assigned to the everolimus arm. He had a WHO PS of 1 at baseline. Grade 1/2 AEs suspected to be related to treatment, and beginning in the first month of therapy, were stomatitis, rash and dermatitis. These did not require a dose adjustment, but medical treatment was needed for the rash and the dermatitis. After experiencing stable disease for 21 months since the initiation of everolimus in January 2009, he withdrew from the study on October 6, 2010, to use somatostatin analog therapy only. However, on January 24, 2011, he resumed the everolimus treatment, off trial, because of disease progression. As of August 2014, >43 months since resuming everolimus 10 mg/day plus octreotide, the patient has had stable disease. Patient 8 A 65-year-old Caucasian man with well-differentiated pNET and involvement of bone, liver, pancreas, lymph nodes and peritoneum entered RADIANT-3 on December 4, 2008, and was assigned to the placebo arm. He had a WHO PS of 0 at baseline and did not experience disease progression for >14 months on placebo. He then began open-label everolimus 10 mg/day after discontinuing placebo therapy on June 28, 2010. After experiencing stable disease on everolimus for almost 22 months, he voluntarily withdrew from the study on December 14, 2011, because of grade 2 weakness and fatigue, which he felt were interfering with the quality of his life. The patient died on May 10, 2012, of progressive cancer. Patients Who Responded to Everolimus for ≤11 Months Patient 9 A 49-year-old Caucasian woman with well-differentiated pNET and involvement of the liver and abdominal Long-Term Everolimus in pNET
lymph nodes began RADIANT-3 on January 6, 2009, and was randomly assigned to everolimus. She had a WHO PS of 0 at baseline. While taking everolimus 10 mg/day, starting in the first month of therapy, the patient experienced grade 1/2 AEs, probably related to treatment, including rash, stomatitis, dyspepsia, pruritus and anemia. Intravenous iron was administered for the anemia. Two brief episodes of facial rash resolved spontaneously, the first after 22 days and the second after 13 days. An episode of dyspepsia also resolved spontaneously after 15 days. Short episodes of oral mucositis and pruritus resolved without medical treatment. The patient continued to receive everolimus 10 mg/day for 11 months before leaving the study on December 13, 2009, because of disease progression. She was subsequently treated with octreotide (long-acting repeatable) and peptide receptor radionuclide therapy (PRRT). The patient died on April 18, 2012, of biliary sepsis after PRRT. Patient 10 A 47-year-old Caucasian woman with well-differentiated pNET and involvement of the liver entered RADIANT-3 on August 5, 2008, and was randomly assigned to the everolimus arm. She had a WHO PS of 1 at baseline. Grade 1/2 AEs suspected to be related to treatment included headache, nausea, urinary tract infection, stomatitis, diarrhea, peripheral edema and paronychia. The headache, rash, diarrhea and urinary tract infections required medical therapy. She received everolimus treatment for 84 days before discontinuation on October 30, 2008, due to progressive disease. She was subsequently treated with PRRT but died of progressive cancer on March 18, 2011. Patient 11 A 64-year-old Caucasian woman with well-differentiated pNET and involvement of the liver and lung entered RADIANT-3 on April 3, 2009, and was assigned to the placebo arm. She had a WHO PS of 0 at baseline. Because of disease progression after 85 days, she crossed over to treatment with open-label everolimus 10 mg/day. AEs after the cross-over suspected to be related to treatment were grade 1/2 rash, stomatitis and cachexia. After 4.6 months of everolimus therapy, grade 3 aspiration pneumonia developed that was unrelated to the study drug, lasted 12 days and resolved with antibiotic therapy, necessitating a dose interruption of 18 days. There was no indication of everolimus pneumonitis. Concomitantly and not related to the study drug, a pulmonary embolus developed for 37 days, resulting in a dose of 5 mg/day for 15 Chemotherapy 2014;60:143–150 DOI: 10.1159/000369780
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tion. The patient responded to medical treatment for herpes zoster, peripheral edema and joint swelling. No dose reduction was necessary. The patient developed hyperglycemia, probably related to the study drug, after 317 days of everolimus and required medical treatment with oral hypoglycemic agents. He withdrew from the study on May 9, 2012, because of the inconvenience of the longdistance travel (>1,000 miles to our center) but continued to receive everolimus 10 mg/day. As of August 2014, he has had stable disease for >76 months since the initiation of everolimus treatment in April 2008.
Patient 12 A 59-year-old Caucasian man with well-differentiated pNET and involvement of the liver, lymph nodes and mediastinum entered RADIANT-3 on January 22, 2009, and was assigned to the placebo arm. He had a WHO PS of 0 at baseline. He experienced disease progression after 85 days in the study and switched to open-label everolimus 10 mg/day on May 1, 2009. AEs possibly related to treatment were grade 1/2 and included upper abdominal pain, weight loss, decreased appetite, gastrointestinal reflux disease, dermatitis, hyperglycemia, pruritus and stomatitis. On study day 245, he experienced acute, grade 3 cholangitis with biliary stent occlusion, lasting 5 and 2 days, respectively, and was admitted to the hospital and administered concomitant medications. The patient continued to take everolimus 10 mg/day for 90 additional days. Overall, he received everolimus treatment for 8 months, but left the study on December 30, 2009, because of disease progression. He received no further therapy and died on June 30, 2010, of progressive malignancy complicated by acute renal failure. Patient 13 A 71-year-old Caucasian man with well-differentiated pNET and involvement of the bone, liver and lymph nodes entered RADIANT-3 on May 1, 2008, and was randomly assigned to the placebo arm. He had a WHO PS of 1 at baseline. Due to disease progression on day 90, he crossed over to open-label treatment with everolimus on September 4, 2008, at a dose of 10 mg/day. Grade 1/2 AEs suspected to be related to treatment started in the first month of therapy and included nausea, diarrhea, headache and cachexia. The diarrhea and cachexia responded to medical management. While in the study, the patient was admitted to the hospital for 3 days for anemia, not suspected to be related to everolimus treatment. After 72 days on the study drug, grade 2 pneumonitis developed that was suspected to be related to treatment. Everolimus treatment was interrupted 4 days later, on November 18, 2008, and was not resumed because the patient was again 148
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in hospital, this time for hypercalcemia, metabolic encephalopathy and cerebrovascular accident. He was taken off the study on November 25, 2008, for progressive metastatic disease in the liver, periportal lymph nodes and retroperitoneal lymph nodes. He had received everolimus for 76 days in total. The patient moved out of state and was then treated with gemcitabine, 5-fluorouracil, irinotecan and platinum. He died of progressive malignancy on May 25, 2010. Patient 14 A 73-year-old Caucasian man with well-differentiated pNET and involvement of the bone, liver, and lymph nodes entered RADIANT-3 on July 7, 2008, and was assigned to the placebo arm. He had a WHO PS of 0 at baseline. The patient crossed over to open-label treatment after disease progression at 86 days on October 10, 2008 and received everolimus 10 mg/day. Grade 1/2 AEs suspected to be related to treatment included cachexia, stomatitis, dysgeusia, fatigue, weight loss, rash, noncardiac chest pain, jaw pain, esophageal pain and asthenia. Mucositis, rash, jaw pain and esophageal pain were medically treated. After 4.6 months on everolimus, grade 2 esophageal ulcers developed that necessitated a treatment interruption for 12 days. Subsequently, the study medication was resumed at 5 mg/day for the remaining treatment duration. The patient experienced grade 3 asthenia for 30 days, which resolved spontaneously. He was removed from the study on September 1, 2009, 11 months after initiating everolimus treatment, for cancer progression in the liver, pancreas and bone. He was treated with PRRT and subsequently died on April 4, 2012, of progressive cancer. Patient 15 An 81-year-old Caucasian man with well-differentiated pNET and involvement of the lung, liver and kidneys entered RADIANT-3 on April 1, 2009, and was randomly assigned to the everolimus arm. He had a WHO PS of 0 at baseline. On April 6, 2009, he was admitted to the hospital for an acute pulmonary embolus and was treated with anticoagulant therapy. He subsequently developed respiratory failure thought to be associated with his chronic obstructive pulmonary disease and went off the study on July 29, 2009. An episode of grade 1 stomatitis that resolved without intervention after 81 days was the only observed AE suspected to be related to treatment. The patient received everolimus for a total of 85 days. He died on August 4, 2009, of cardiopulmonary arrest unrelated to his malignancy. Wolin
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more days after dose interruption until the patient left the study on January 6, 2010, due to disease progression. She was subsequently treated with hepatic artery chemoembolization, followed by interferon-alpha-2b in combination with octreotide. On October 22, 2012, she started treatment with sunitinib 37.5 mg/day by mouth for progressive metastatic disease and was subsequently lost to follow-up.
We present a case series of 15 patients with advanced, progressive, low- or intermediate-grade pNET who received everolimus during their participation in RADIANT-3 at our study center. The duration of exposure to everolimus for these patients ranged from 76 months. Six patients had stable disease for 2–11 months (range 76–326 days) after the initiation of everolimus therapy, but they subsequently developed progressive disease. Eight patients treated with everolimus experienced stable disease for approximately 19 to >76 months. Five of the 15 patients were alive as of August 2014, including 3 who continued to receive everolimus; these patients had experienced stable disease for 43–76 months on everolimus treatment. At the time of publication of RADIANT-3, an estimated 34% of the patients receiving everolimus were alive and progression-free at 18 months, suggesting that everolimus may provide a prolonged benefit for a considerable proportion of patients [6]. Our observations confirmed such a benefit and, in addition, showed that in a subset of 5 of 15 patients, treatment with everolimus can yield PFS periods of longer than 3–6 years, both in patients receiving the standard dosage of 10 mg/day and in those on a reduced dosage of 5 mg/day. AEs associated with everolimus in RADIANT-3 included stomatitis, rash, fatigue and infections. Infections, pneumonitis and interstitial lung disease represented some of the most important clinical concerns and were primarily grade 1 or 2 [6]. Importantly, AEs associated with everolimus are generally manageable, as demonstrated by the low rate of discontinuation in the RADIANT-3 study [6]. Moreover, everolimus can usually be maintained while the AEs are being appropriately managed [8]. AEs experienced by patients at this site receiving everolimus long-term after completion of the RADIANT-3 study remained similar to those reported during the study and were manageable with concomitant medications and dose adjustments [6]. Only 1 patient, who responded to everolimus with stable disease for almost 22 months, discontinued treatment because of a perceived reduction in quality of life associated with grade 2 weakness and fatigue. Patients with both grade 1 and grade 2 well-differentiated disease responded well to everolimus, including 1 patient with bone involvement. However, 2 patients with bone metastases did not have prolonged response with everolimus. This observation is consistent with the outcomes of a multivariate analysis of patients receiving Long-Term Everolimus in pNET
everolimus in combination with octreotide (RADIANT-2 study), which suggested bone involvement as a predictor of worse PFS in patients with NET [9]. Four of 7 patients with a response to everolimus lasting ≤11 months had involvement of ≥3 organs whereas in most patients with a good response to everolimus, only 1 or 2 organs were affected. The exception was patient 8, in whom 4 organs, including the bone, were affected. We observed responses to everolimus, including long-term survival, in patients originally randomly assigned to receive the study drug and in patients who crossed over to open-label everolimus after a progression-free period on placebo of >5 months. In 4 patients who crossed over with more rapid disease progression on placebo (≤90 days), everolimus yielded a shorter duration of PFS (31 months on long-term everolimus treatment had initiated the treatment 27–64 months after diagnosis. Two of 3 patients who entered the study within a short time after diagnosis (≤4 months) responded well to everolimus, and 1 (patient 15) did not; this patient was the oldest of the 15 patients. He had a relatively large number of comorbidities and had the highest frequency of AEs that were not related to treatment during the treatment period (8.8 AEs/month, 9.2 AEs/month total). In conclusion, long-term treatment with everolimus in certain patients was found to be safe and effective, providing cancer control exceeding 3.5 years in 5 of 15 patients. Although some patients required a reduction in everolimus dosage from 10 to 5 mg/day early in the course of treatment, the drug proved to be well tolerated, with only 1 patient discontinuing because of a reduced
quality of life. Although this case series was too small to prove specific patient characteristics associated with successful long-term administration of everolimus, prompt management of AEs, appropriate patient education, medical management and an appropriate dose reduction appeared to be the most important factors. The efficacy of everolimus is being further explored in the phase III RADIANT-4 study (ClinicalTrials.gov ID, NCT01524783), which is investigating the effect of everolimus plus best supportive care versus placebo plus best supportive care in patients with advanced NET of gastrointestinal or lung origin. This study will include quality-of-life analyses as secondary end points.
Acknowledgments The author thanks Jennifer Kulak, PhD and David Gibson, PhD, CMPP for writing assistance funded by Novartis Pharmaceuticals Corporation.
Disclosure Statement Dr. Wolin serves on an advisory board for Novartis Pharmaceuticals Corporation. The RADIANT-3 study was funded by Novartis Pharmaceuticals Corporation.
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