V O L U M E 3 0 䡠 N U M B E R 2 4 䡠 A U G U S T 2 0 2 0 1 2
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`O R I G I N A L R E P O R T
`
`Jennifer A. Chan, Craig C. Earle, Pankaj
`Bhargava, Peter C. Enzinger, Jeffrey A.
`Meyerhardt, Charles S. Fuchs, and
`Matthew H. Kulke, Dana-Farber Cancer
`Institute; Jennifer A. Chan, Craig C.
`Earle, Pankaj Bhargava, Peter C.
`Enzinger, Jeffrey A. Meyerhardt,
`Charles S. Fuchs, and Matthew H.
`Kulke, Brigham and Women’s Hospital;
`Keith Stuart and Rebecca Miksad, Beth
`Israel Deaconess Medical Center;
`Jeffrey W. Clark and Lawrence
`Blaszkowsky, Massachusetts General
`Hospital; Hui Zheng, Biostatistics
`Center, Massachusetts General Hospi-
`tal; and Jennifer A. Chan, Keith Stuart,
`Craig C. Earle, Jeffrey W. Clark, Pankaj
`Bhargava, Rebecca Miksad, Lawrence
`Blaszkowsky, Peter C. Enzinger, Jeffrey
`A. Meyerhardt, Charles S. Fuchs, and
`Matthew H. Kulke, Harvard Medical
`School, Boston, MA.
`
`Submitted November 1, 2011; accepted
`May 8, 2012; published online ahead of
`print at www.jco.org on July 9, 2012.
`
`Supported by Genentech and Schering-
`Plough/Merck.
`
`Authors’ disclosures of potential con-
`flicts of interest and author contribu-
`tions are found at the end of this
`article.
`
`Clinical Trials repository link available on
`JCO.org.
`
`Corresponding author: Jennifer A.
`Chan, MD, MPH, Department of Medi-
`cal Oncology, Dana-Farber Cancer Insti-
`tute, 450 Brookline Ave, Boston, MA
`02215; e-mail: jang@partners.org.
`
`© 2012 by American Society of Clinical
`Oncology
`
`0732-183X/12/3024-2963/$20.00
`
`DOI: 10.1200/JCO.2011.40.3147
`
`Prospective Study of Bevacizumab Plus Temozolomide in
`Patients With Advanced Neuroendocrine Tumors
`Jennifer A. Chan, Keith Stuart, Craig C. Earle, Jeffrey W. Clark, Pankaj Bhargava, Rebecca Miksad,
`Lawrence Blaszkowsky, Peter C. Enzinger, Jeffrey A. Meyerhardt, Hui Zheng, Charles S. Fuchs,
`and Matthew H. Kulke
`
`A
`
`B
`
`S
`
`T
`
`R
`
`A
`
`C
`
`T
`
`Purpose
`Both tyrosine kinase inhibitors targeting the vascular endothelial growth factor (VEGF) receptor
`and bevacizumab, a monoclonal antibody targeting VEGF, have antitumor activity in neuroendo-
`crine tumors (NETs). Temozolomide, an oral analog of dacarbazine, also has activity against NETs
`when administered alone or in combination with other agents. We performed a phase II study to
`evaluate the efficacy of temozolomide in combination with bevacizumab in patients with locally
`advanced or metastatic NETs.
`Patients and Methods
`Thirty-four patients (56% with carcinoid, 44% with pancreatic NETs) were treated with temozolomide 150
`mg/m2 orally per day on days 1 through 7 and days 15 through 21, together with bevacizumab at a dose of
`5 mg/kg per day intravenously on days 1 and 15 of each 28-day cycle. All patients received prophylaxis
`against Pneumocystis carinii and varicella zoster. Patients were followed for toxicity, biochemical and
`radiologic response, and survival.
`Results
`The combination of temozolomide and bevacizumab was associated with anticipated grade 3 to 4
`toxicities,
`including lymphopenia (53%) and thrombocytopenia (18%). Although the overall
`radiographic response rate was 15% (five of 34), response rates differed between patients with
`pancreatic NETs (33%; five of 15) and those with carcinoid tumors (zero of 19). The median
`progression-free survival was 11.0 months (14.3 months for pancreatic NETs v 7.3 months for
`carcinoid tumors). The median overall survival was 33.3 months (41.7 months for pancreatic NETs
`v 18.8 months for carcinoid tumors).
`Conclusion
`Temozolomide and bevacizumab can be safely administered together in patients with advanced NETs, and
`the combination regimen appears promising for patients with pancreatic NETs. Studies evaluating the
`relative contributions of these two agents to the observed antitumor activity are warranted.
`
`J Clin Oncol 30:2963-2968. © 2012 by American Society of Clinical Oncology
`
`INTRODUCTION
`
`Recent randomized studies1,2 have demonstrated
`improvements in progression-free survival (PFS)
`in patients with advanced pancreatic neuroendo-
`crine tumors (NETs) treated with everolimus or
`sunitinib. Response rates associated with both of
`these agents, however, are relatively modest. In ad-
`dition, there remains no standard treatment for pa-
`tients with advanced carcinoid tumors.
`Although cytotoxic chemotherapy regimens that
`use streptozocin and dacarbazine are associated with
`modest antitumor activity in patients with advanced
`carcinoid tumors and pancreatic NETs, their use has
`been limited because of toxicity concerns.3-7 Temo-
`zolomide was developed as a less toxic alternative to
`
`dacarbazine and has demonstrated activity in NETs
`in both retrospective and prospective studies.8-10
`Overall response rates associated with temozolo-
`mide, administered alone or in combination with
`other agents, range from 8% to 70% in patients with
`pancreatic NETs; response rates in carcinoid tumors
`have generally been lower.
`Bevacizumab, a monoclonal antibody target-
`ing vascular endothelial growth factor, has been
`evaluated in advanced carcinoid tumors in two
`phase II studies. In a randomized phase II study of
`patients with advanced carcinoid tumors,11 treat-
`ment with bevacizumab was associated with an ob-
`jective response rate of 18% and a trend toward
`improved PFS compared with interferon alfa. A sub-
`sequent phase II study12 combined bevacizumab
`
`© 2012 by American Society of Clinical Oncology
`
`2963
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`Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
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`Ex. 1068-0001
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`

`

`Chan et al
`
`with 2-methoxyestradiol, a putative angiogenesis inhibitor, in patients
`with advanced carcinoid tumors. Although no confirmed radiologic
`responses by Response Evaluation Criteria in Solid Tumors (RECIST)
`were observed, 68% of evaluable patients experienced some degree of
`tumor reduction with a promising median PFS duration of
`11.3 months.
`Given the reported activity of both agents in carcinoid tumors
`and pancreatic NETs, we conducted a multi-institutional phase II
`study to assess the safety and efficacy of temozolomide given with
`bevacizumab in patients with advanced NETs.
`
`PATIENTS AND METHODS
`
`The study population consisted of patients with histologically confirmed,
`metastatic or locally unresectable NETs, excluding small-cell carcinoma. Pa-
`tients were required to have measurable disease by RECIST; Eastern Cooper-
`ative Oncology Group (ECOG) performance status of 2 or better; life
`expectancy of at least 12 weeks; and adequate hepatic, renal, and bone mar-
`row function.
`Prior systemic treatment (excluding temozolomide, dacarbazine, bev-
`acizumab) and prior local therapy (chemoembolization, radiation, cryother-
`apy) were permitted if completed 4 or more weeks before initiation of the trial.
`Prior therapy with anti–vascular endothelial growth factor pathway inhibitors
`was permitted. Lesions previously treated with radiation, cryotherapy, or che-
`moembolization were not considered measurable disease; concurrent treat-
`ment with these modalities was not permitted. Exclusion criteria were
`proteinuria ⱖ 2 g/24 hours, clinically significant cardiovascular disease,
`major surgery within 28 days before study initiation, clinically apparent
`CNS metastases, or other severe or uncontrolled medical or psychiatric
`illness. All patients provided signed, informed consent as required by the
`institutional review boards of their institutions. Participating centers were
`Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital,
`Dana-Farber Cancer Institute, and Massachusetts General Hospital (all
`tertiary care centers in Boston, MA).
`Treatment Program
`Temozolomide was administered orally at a starting dose of 150 mg/m2
`per day on days 1 through 7 and days 15 through 21. Bevacizumab was
`administered intravenously at a dose of 5 mg/kg per day on days 1 and 15. This
`cycle was repeated every 28 days. Dose adjustments for temozolomide were
`made for hematologic toxicity. Temozolomide was held if patients developed
`an absolute neutrophil count less than 1,000/␮L or a platelet count less than
`50,000/␮L. On recovery above these parameters, temozolomide was resumed
`with dose reduction by 50 mg/m2. Continued treatment with bevacizumab
`was permitted if temozolomide was delayed for hematologic toxicity.
`Treatment with temozolomide and bevacizumab was held for all nonhe-
`matologic treatment-related toxicities grade ⱖ 3 according to the National
`Cancer Institute Common Toxicity Criteria, version 3. Treatment with
`both agents resumed with dose reduction if nonhematologic toxicities
`recovered to grade ⱕ 1 within 3 weeks. If nonhematologic toxicity did not
`recover within 3 weeks or if the patient experienced an unacceptable
`toxicity, study treatment was discontinued.
`To protect against temozolomide-related selective lymphopenia and risk
`of opportunistic infection, patients received prophylaxis against Pneumocystis
`carinii (PCP) with double-strength trimethoprim-sulfamethoxazole, one tab-
`let orally every Monday, Wednesday, and Friday. Patients with allergies to
`trimethoprim-sulfamethoxazole received an alternate prophylaxis regimen.
`Patients also received prophylaxis against varicella zoster with acyclovir 400
`mg orally three times per day while receiving protocol therapy.
`Radiologic tumor assessments with computed tomography scan and
`biochemical assessments with plasma chromogranin A levels were performed
`at baseline and every two cycles after initiation of treatment. Radiologic re-
`sponse was classified according to RECIST. Biochemical response for patients
`with an increased baseline chromogranin A was defined as a decrease in
`chromogranin A by 50% or more from baseline.
`
`Statistical Methods
`The primary objective of this study was to determine the radiographic
`response rate for the combination of temozolomide and bevacizumab in
`patients with NETs. Secondary objectives included assessment of PFS, bio-
`chemical response, toxicity, and overall survival (OS).
`Patients who underwent restaging scans after completing two cycles of
`therapy were evaluated for radiologic response. Patients with increased chro-
`mogranin A levels at baseline who had follow-up assessment of chromogranin
`A were evaluated for biochemical response. PFS was defined as the time
`between study enrollment and progression of disease by RECIST or death
`while on protocol; patients who withdrew from the study for reasons other
`than progression or death were censored at the time of discontinuation of
`study therapy. Patients were followed for survival through July 2010. OS was
`defined as the time between study enrollment and death. Both PFS and OS
`were estimated by the Kaplan-Meier method with intention-to-treat analysis.
`Toxicity assessments were based on reports of adverse events, physical exam-
`inations, and laboratory assessments.
`Power calculations were based on a phase II two-stage design. A total of
`34 eligible patients (defined as receiving at least one dose of therapy) were
`entered onto the study in a two-stage design. Seventeen patients were entered
`in the first stage; one response was required to enroll an additional 17 patients
`onto the second stage of the study. With this design, the probability of termi-
`nating the study after 17 patients were recruited was 0.42 if the true but
`unknown response rate was 5% but 0.06 if the true but unknown response rate
`was 15%. The study had an overall power of 0.87 and overall type I error of
`0.22. The trial was designed for a combined analysis of patients with carcinoid
`tumors and pancreatic NETs on the basis of standard study design at the time
`the trial was initiated. Response rates and survival durations were analyzed for
`the entire cohort and separately in patients with carcinoid tumors and pancre-
`atic NETs. However, the study was not powered for separate analysis of each
`group. Statistical analyses were conducted by using SAS version 9.2 (SAS
`Institute, Cary, NC). Statistical significance was determined by a P value less
`than .05.
`
`RESULTS
`
`Patient Characteristics
`Between November 2004 and July 2005, a total of 34 patients
`enrolled onto the study. Baseline characteristics of the patients are
`listed in Table 1. The median age of the patient population was 60
`years, and 56% were male. The majority of patients had an ECOG
`performance status of 0 or 1 (94%). Nineteen patients had carcinoid
`tumors (56%), and 15 (44%) had pancreatic NETs. Although patients
`with small-cell neuroendocrine carcinoma were excluded, three pa-
`tients with pancreatic NETs had poorly differentiated or high-grade
`histology. All but seven patients had evidence of radiographic disease
`progression before initiation of therapy. Seven patients (21%) had
`received prior cytotoxic chemotherapy. Twenty patients (59%) had
`received prior therapy with octreotide, and 12 patients (35%) received
`octreotide concurrent with study therapy. Twenty patients (nine with
`pancreatic NETs and 11 with carcinoid tumors) had increased chro-
`mogranin A levels (⬎ 39 ng/mL) at baseline. The median chromo-
`granin A level at baseline was 175 ng/mL, with a range of 5 to 26,800
`ng/mL. Nine patients with carcinoid tumors had increased 24-hour
`urinary 5-hydroxyindoleacetic acid levels at baseline (⬎ 6 mg/24
`hours); the median 5-hydroxyindoleacetic acid level of these nine
`patients was 122.3 mg/24 hours (range, 8.5 to 352.1 mg/24 hours).
`
`Duration of Therapy
`Patients received a median of five 4-week treatment cycles (range,
`1 to 39 cycles). Disease progression was the most common reason for
`
`2964
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`© 2012 by American Society of Clinical Oncology
`
`JOURNAL OF CLINICAL ONCOLOGY
`
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`Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
`
`Ex. 1068-0002
`
`

`

`Bevacizumab and Temozolomide for Advanced Neuroendocrine Tumors
`
`Table 1. Baseline Patient Characteristics
`
`Table 2. Treatment-Related Toxicity
`
`Characteristic
`
`No. of Patients
`(N ⫽ 34)
`
`%
`
`Age, years
`Median
`Range
`Sex
`Male
`Female
`ECOG performance status
`0
`1
`2
`Type of tumor
`Carcinoid
`Appendix
`Small bowel/likely midgut
`Bronchial
`Unknown primary
`Pancreatic neuroendocrine tumor
`Concurrent octreotide use
`Evidence of radiographic disease progression prior
`to treatment initiation
`Prior treatmentⴱ
`Octreotide
`Embolization
`Chemotherapy†
`Sunitinib
`Radiofrequency ablation
`Interferon
`Radiation
`No. of prior systemic therapy regimens‡
`0
`1
`2 or more
`Patients with increased baseline
`chromogranin A (⬎ 39 ng/mL)
`Baseline chromogranin A, ng/mL
`Median
`Range
`
`60
`36-74
`
`19
`15
`
`12
`20
`2
`
`19
`1
`7
`4
`7
`15
`12
`
`27
`
`20
`11
`7
`6
`3
`3
`4
`
`19
`13
`2
`
`20
`
`175
`5-26,800
`
`56
`44
`
`35
`59
`6
`
`56
`3
`21
`12
`21
`44
`35
`
`79
`
`59
`32
`21
`18
`9
`9
`12
`
`56
`38
`6
`
`59
`
`Abbreviation: ECOG, Eastern Cooperative Oncology Group.
`ⴱSome patients received more than one prior therapy; therefore, percent-
`ages do not add to 100%.
`†Prior chemotherapy regimens: platinum-etoposide (n ⫽ 3), docetaxel (n ⫽
`2), capecitabine (n ⫽ 1), streptozocin-doxorubicin (n ⫽ 1), cisplatin-irinotecan
`(n ⫽ 1), carboplatin-etoposide-paclitaxel (n ⫽ 1).
`‡Not including octreotide.
`
`treatment discontinuation; of the 16 patients who discontinued ther-
`apy because of progression, one died because of progressive disease, 10
`had documented radiologic progression by RECIST, and five discon-
`tinued treatment because of clinical progression. An additional 10
`patients discontinued treatment because of treatment-related toxicity:
`grade 3 thrombocytopenia (five patients), grade 3 neutropenia (two
`patients), infection (one patient), and fatigue (two patients). Treat-
`ment discontinuation for toxicity occurred after at least 3.4 months of
`therapy, with a median time to discontinuation for these patients of
`6.5 months (range, 3.4 to 14.7 months). Eight patients discontinued
`treatment after withdrawing consent, including one patient who
`wished to continue treatment elsewhere and three who withdrew
`consent despite prolonged stable disease while on study.
`
`Maximum Toxicity Grade
`
`1
`
`2
`
`3
`
`4
`
`Toxicity
`
`No. % No. % No. % No. %
`
`Hematologic
`Hemoglobin
`Leukocytes
`Neutrophils
`Lymphocytes
`Platelets
`Nonhematologic
`Nausea
`Fatigue
`Anorexia
`Vomiting
`Diarrhea
`Increased alkaline phosphatase
`Constipation
`Mucositis
`Dyspnea
`Weight loss
`Headache
`Increased PTT
`Proteinuria
`Pruritis
`Fever
`Epistaxis
`Anxiety
`Hypertension
`Increased AST
`Increased ALT
`Increased INR
`Abdominal pain
`Elevated bilirubin
`Skin rash
`Hyponatremia
`Dehydration
`
`11
`6
`3
`1
`14
`
`17
`14
`10
`11
`9
`8
`7
`5
`5
`5
`5
`5
`4
`4
`4
`4
`3
`3
`3
`2
`3
`2
`1
`1
`1
`
`32
`18
`9
`3
`41
`
`50
`41
`29
`32
`26
`24
`21
`15
`15
`15
`15
`15
`12
`12
`12
`12
`9
`9
`9
`6
`9
`6
`3
`3
`3
`
`4
`7
`5
`2
`3
`
`4
`10
`5
`8
`1
`1
`3
`
`2
`1
`2
`
`1
`1
`
`1
`1
`4
`2
`1
`
`2
`
`2
`
`1
`
`12
`21
`15
`6
`9
`
`12
`29
`15
`24
`3
`3
`9
`
`6
`3
`6
`
`3
`3
`
`3
`3
`12
`6
`3
`
`6
`
`6
`
`3
`
`3
`1
`14
`6
`
`9
`3
`41
`18
`
`1
`4
`
`3
`12
`
`2
`2
`
`3
`
`1
`
`6
`6
`
`9
`
`3
`
`1
`
`3
`
`1
`
`1
`
`1
`1
`
`3
`
`3
`
`3
`3
`
`Abbreviations: INR, international normalized ratio; PTT, partial thromboplastin time.
`
`Toxicity
`All thirty-four treated patients were assessable for toxicity, as
`summarized in Table 2. The most common grade 3 or 4 toxicities
`were lymphopenia (53%) and thrombocytopenia (18%). Lym-
`phopenia generally developed in the absence of significant leuko-
`penia or neutropenia.
`A total of five patients developed infections while receiving study
`treatment. One patient who received concurrent steroids developed a
`Mycobacterium avium intracellulare complex opportunistic infection
`that was successfully treated. Four patients developed upper respira-
`tory infections. However, no documented cases of PCP or varicella
`zoster were reported.
`The most common nonhematologic adverse events were fatigue
`(76%), nausea (68%), vomiting (65%), anorexia (44%), constipation
`(32%), and diarrhea (29%). Most toxicities were relatively mild.
`Grade 3 or higher toxicities occurring in more than one patient were
`vomiting (three patients), nausea (two patients), and fatigue (two
`patients). Treatment-related hypertension developed in eight patients
`(24%). Proteinuria developed in six patients (18%), including one
`with grade 3 proteinuria.
`
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`© 2012 by American Society of Clinical Oncology
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`

`Chan et al
`
`Table 3. Radiographic Tumor Response (RECIST)
`
`Disease Response
`
`Partial response
`Stable disease
`Progressive disease
`Not evaluableⴱ
`
`No. of Patients
`(N ⫽ 34)
`
`5
`22
`4
`3
`
`%
`
`15
`65
`12
`
`95% CI
`
`7 to 30
`48 to 79
`5 to 27
`
`No. Among Patients With
`Pancreatic NETs (n ⫽ 15)
`
`5
`8
`2
`0
`
`%
`
`33
`53
`13
`
`95% CI
`
`15 to 59
`30 to 75
`4 to 38
`
`No. Among Patients With
`Carcinoid Tumors (n ⫽ 19)
`
`0
`14
`2
`3
`
`%
`
`0
`74
`11
`
`95% CI
`
`51 to 88
`3 to 32
`
`Abbreviations: NET, neuroendocrine tumor; RECIST, Response Evaluation Criteria in Solid Tumors.
`ⴱThree patients with carcinoid tumor were not evaluable for response: one patient withdrew consent before restaging scans, one patient discontinued treatment
`to undergo surgery, and one patient died as a result of disease before restaging scans.
`
`Efficacy
`Of the 34 patients treated on the study, 31 were radiographically
`assessable for treatment response (Table 3). Using RECIST, five pa-
`tients (15%; 95% CI, 7% to 30%) experienced partial radiographic
`responses as the best response to treatment, including one patient with
`a near complete response. All five of these patients had pancreatic
`NETs. Twenty-two patients (65%; 95% CI, 48% to 79%) experienced
`stable disease, and four (12%; 95% CI, 5% to 27%) experienced
`progressive disease as the best response (Fig 1). By using a waterfall
`plot analysis, 24 patients experienced some degree of tumor shrinkage
`as the best response to treatment, including 12 patients with pancre-
`atic NETs (80%; 95% CI, 54% to 93%) and 12 patients with carcinoid
`tumors (63%; 95% CI, 41% to 81%).
`Seven patients with pancreatic NETs had increased baseline
`chromogranin A levels and were assessable for chromogranin A re-
`sponse (Table 4). Of these patients, the best biochemical response for
`four (57%) was a chromogranin A decrease of more than 50%; for two
`(29%), it was a stable chromogranin A level (⬍ 50% decrease or
`⬍ 25% increase); and for one (14%), it was progressive chromogranin
`A level. Three of the four patients with chromogranin A response had
`partial radiographic responses, including one patient with an insulin-
`producing tumor whose glucose levels improved after starting ther-
`apy. However, the patient was also receiving concurrent diazoxide and
`octreotide. The other patients with biochemical response did not have
`functional tumors. Nine patients with carcinoid tumors had increased
`baseline chromogranin A levels and were evaluable for chromogranin
`A response. None experienced more than 50% decrease in chromo-
`
`granin A, seven (78%) experienced stable chromogranin A levels, and
`two (22%) experienced progressive chromogranin A levels as their
`best response to treatment.
`The median follow-up time for the patient cohort was 28.7
`months (range, 1 to 65 months). Eleven patients (32%) developed
`progressive disease while receiving study therapy. The median PFS for
`the entire cohort was 11.0 months (95% CI, 7.3 months to not estima-
`ble [NE] upper limit). As we observed with tumor responses, we also
`observed a difference in PFS according to tumor type. The median PFS
`was 14.3 months (95% CI, 8.5 months to NE) for patients with pan-
`creatic NETs and 7.3 months (95% CI, 3.9 months to NE) for patients
`with carcinoid tumors (P ⫽ .23; Fig 2A). The proportion of patients
`without progression at 6 months was 76% (95% CI, 67% to 84%) for
`the entire cohort; for pancreatic NETs, 6-month PFS was 87% (95%
`CI, 78% to 95%) compared with 66% (95% CI, 53% to 79%) for
`carcinoid tumors. The median OS was 33.3 months (95% CI, 13.4 to
`41.7 months). The median OS also differed by subtype: 41.7 months
`for pancreatic NETs (95% CI, 23.6 months to NE) and 18.8 months
`for carcinoid tumors (95% CI, 8.5 to 36.1 months; P ⫽ .07; Fig
`2B).There was no significant association between PFS and concurrent
`octreotide use. The median PFS for patients receiving concurrent
`octreotide was 25.3 months compared with 39.9 months for patients
`not receiving octreotide (P ⫽ .18). Similarly, there was no correlation
`between OS and concurrent octreotide use. We also found no signif-
`icant difference in median PFS between patients who had and who had
`not experienced evidence of prior progression (14.3 months v 8.5
`months, respectively; P ⫽ .51).
`
`Table 4. Biochemical Response
`
`No. Among
`Patients
`With
`Pancreatic
`NETs
`(n ⫽ 7)
`
`No. Among
`Patients
`With
`Carcinoid
`Tumors
`(n ⫽ 9)
`
`No. of
`Evaluable
`Patientsⴱ
`(n ⫽ 16)
`
`Disease Response
`⬎ 50% decline in chromogranin A
`⬍ 50% decline to ⬍ 25% increase
`in chromogranin A
`⬎ 25% increase in chromogranin A
`
`No. % No. % No. %
`
`4
`
`9
`3
`
`25
`
`56
`19
`
`4
`
`2
`1
`
`57
`
`29
`14
`
`0
`
`7
`2
`
`78
`22
`
`Abbreviation: NET, neuroendocrine tumor.
`ⴱTwenty patients had elevated baseline chromogranin A levels. Four of these
`patients did not have follow-up assessment of chromogranin A. The 16
`evaluable patients consisted of those with baseline increase in chromogranin
`A who were subsequently evaluable for biochemical response.
`
`*
`
`*
`
`Pancreatic NET
`Carcinoid
`
`60
`
`40
`
`20
`
`0
`
`-20
`
`-40
`
`-60
`
`-80
`
`-100
`
`Best Response (%)
`
`Patients (n = 31)
`
`Fig 1. Best objective radiographic tumor response. (*) Patients who experi-
`enced progressive disease on the basis of new lesions. NET, neuroen-
`docrine tumor.
`
`2966
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`JOURNAL OF CLINICAL ONCOLOGY
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`Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
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`Ex. 1068-0004
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`

`

`Bevacizumab and Temozolomide for Advanced Neuroendocrine Tumors
`
`associated with radiographic response in 21 (70%) of 30 patients.10
`Although the response rate reported in this study is higher than what
`we observed and what has been reported in other studies of
`temozolomide-based therapy in NETs,8,9 the findings warrant further
`evaluation in a prospective, randomized trial.
`The relative contribution of bevacizumab to the activity observed in
`our study is uncertain. Bevacizumab has not been prospectively evaluated
`previously in pancreatic NETs but has demonstrated preliminary evi-
`dence of activity in carcinoid tumors. A recent study12 of bevacizumab
`and2-methoxyestradiolreportedahighrateoftumorstabilizationandan
`encouraging PFS duration in carcinoid tumors but did not report any
`objective responses as defined by RECIST. Recent randomized studies1,2
`of sunitinib or everolimus in pancreatic NETs showed a similar pattern of
`low radiographic response rates but high rates of disease stabilization
`translating into improved PFS. Although based on relatively small num-
`bers,thePFSdurationof14.3monthsobservedinourstudyforpancreatic
`NETs compares favorably with the PFS observed in the randomized stud-
`ies of everolimus and sunitinib: 11 and 11.4 months, respectively.
`WhethertheencouragingPFSdurationinpancreaticNETsinourstudyis
`attributable to temozolomide alone or to the addition of bevacizumab is
`uncertain; a randomized study investigating this question is warranted.
`Temozolomide has been safely and effectively administered
`with bevacizumab in several different dosing regimens. Glioma
`studies have generally used a 5-day per every 4 weeks temozolo-
`mide dosing regimen,15 whereas a recent melanoma study used a
`dose-intense regimen similar to that in our study.16 There has also
`been variability in temozolomide regimens in trials for NETs. Al-
`though a prior phase II trial of temozolomide and thalidomide used
`the dose-intense regimen of temozolomide,9 a study of temozolomide
`with capecitabine used the 5-day per month regimen.10 Although no
`patients developed PCP or varicella zoster in our study, five patients
`developed other infections, typically after more than 6 months of
`therapy. Therefore, future studies may minimize infectious complica-
`tions by limiting exposure to dose-intense temozolomide to ⱕ 6
`months. Alternatively, the less immunosuppressive nature of the
`monthly dosing regimen of temozolomide may allow therapy without
`interruption. Although 10 patients in this study discontinued therapy
`because of treatment-related adverse events, the toxicities leading to
`discontinuation were primarily reversible hematologic adverse events.
`Trials comparing dose-intense versus standard temozolomide regi-
`mens would help clarify the relative efficacy and safety of these dosing
`schedules for patients with NETs.
`Several limitations of our study deserve comment. First, the
`number of patients limits statistical comparison between patients with
`pancreatic NETs and carcinoid tumors. However, our observations
`are consistent with prior reports demonstrating higher response rates
`to temozolomide-based therapy in pancreatic NETs compared with
`carcinoid tumors. Second, our type I error rate of 22% is somewhat
`higher than the 10% to 20% observed in many randomized phase II
`studies.17 Although this could lead to a relatively high false-positive
`rate, our results are consistent with the results of prior studies showing
`activity of temozolomide-based therapy in NETs. Nonetheless, future
`studies are warranted to extend these findings. Third, there were
`differences among patients in the use of concurrent octreotide. Given
`that objective tumor shrinkage with octreotide is rare, it is unlikely that
`differential octreotide use explains observed differences in radio-
`graphic tumor response rate. Although the antiproliferative effects of
`
`Carcinoid tumor
`Pancreatic NET
`Censored carcinoid tumor
`Censored pancreatic NET
`
`1.00
`
`0.75
`
`0.50
`
`0.25
`
`A
`
`Survival (probability)
`Progression-Free
`
`0
`
`5
`
`10
`
`15
`20
`25
`Time (months)
`
`30
`
`35
`
`40
`
`Carcinoid tumor
`Pancreatic NET
`Censored carcinoid tumor
`Censored pancreatic NET
`
`1.00
`
`0.75
`
`0.50
`
`0.25
`
`B
`
`Overall Survival
`
`(probability)
`
`0
`
`10
`
`20
`
`40
`30
`Time (months)
`
`50
`
`60
`
`70
`
`Fig 2. (A) Progression-free survival, and (B) overall survival. NET, neuroendo-
`crine tumor.
`
`DISCUSSION
`
`This phase II study demonstrates that the combination of temozolo-
`mide and bevacizumab has antitumor activity in advanced NETs.
`Consistent with prior studies, response rates were higher among pa-
`tients with pancreatic NETs (33%) than in those with carcinoid tu-
`mors (0%). Notably, PFS was also longer in patients with pancreatic
`NETs (14.3 months) than in those with carcinoid tumors (7.3
`months). The shorter-than-expected PFS and OS durations in pa-
`tients with carcinoid tumors may reflect a more heavily pretreated
`patient population.
`Our observation of higher response rates in pancreatic NETs
`compared with carcinoid tumors is consistent with other studies of
`alkylating agents in NETs. Streptozocin-based therapy has been asso-
`ciated with responses of 39% to 69% in patients with pancreatic
`NETs.4,5 In contrast, radiographic response rates associated with
`streptozocin-based regimens in patients with carcinoid tumors have
`ranged between 16% and 33%.3,7,13 The combination of temozolo-
`mide and thalidomide was also found to be more active in pancreatic
`NETs than in carcinoid tumors.9 This observation was confirmed in a
`large retrospective series in which the radiographic response rate to
`temozolomide-based regimens was 34% in pancreatic NETs and only
`2% in carcinoid tumors. In that study,14 the activity of temozolomide-
`based therapy in NETs was associated with the absence of the DNA
`repair protein O6-methylguanine methyltransferase.
`In a recent retrospective series of patients with advanced pancre-
`atic NETs, the combination of temozolomide and capecitabine was
`
`www.jco.org
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`© 2012 by American Society of Clinical Oncology
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`Ex. 1068-0005
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`

`Chan et al
`
`octreotide might have affected PFS, we found no statistically signifi-
`cant difference in PFS depending on octreotide use.18 Fourth, al-
`though the majority of patients had well-differentiated tumors, there
`was heterogeneity in tumor histology: three patients with pancre-
`atic NETs had poorly differentiated or high-grade histology. Al-
`though the radiographic response rate was higher in patients with
`pancreatic NETs, all patients with higher-grade histology had ei-
`ther stable disease or progressive disease as the best response to
`therapy. Finally, there was heterogeneity in disease activity before
`study enrollment because 21% did not demonstrate radiographic
`progression of disease before study entry. However, we found no
`significant difference in PFS between patients who had and had not
`experienced evidence of prior progression.
`In summary, the combination of temozolomide and bevaci-
`zumab has activity in patients with advanced pancreatic NETs. Fur-
`ther studies examining the optimal dose regimen for temozolomide
`and the relative contributions of temozolomide and bevacizumab to
`the antitumor activity and PFS are warranted.
`
`AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
`OF INTEREST
`
`Although all authors completed the disclosure declaration, the following
`author(s) and/or an author’s immediate family member(s) indicated a
`financial or other interest that is relevant to the subject matter under
`consideration in this article. Certain relationships marked with a “U” are
`
`those for which no compensation was received; those relationships marked
`with a “C” were compensated. For a detailed description of the disclosure
`categories, or for more information about ASCO’s conflict of interest policy,
`please refer to the Author Disclosure Declaration and the Disclosures of
`Potential Conflicts of Interest section in Information for Contributors.
`Employment or Leadership Position: None Consultant or Advisory
`Role: Peter C. Enzinger, Genentech (C); Charles S. Fuchs, Genentech
`(C), Infinity Pharmaceuticals (C), Pfizer (C), Roche (C), sanofi-aventis
`(C) Stock Ownership: Jennifer A. Chan, Merck Honoraria: Peter C.
`Enzinger, Genentech Research Funding: Jennifer A. Chan, Bayer, Merck,
`Novartis, Onyx Pharmaceuticals Expert Testimony: None Other
`Remuneration: None
`
`AUTHOR CONTRIBUTIONS
`
`Conception and design: Matthew H. Kulke
`Administrative support: Rebecca Miksad
`Provision of study materials or patients: Keith Stuart, Craig C. Earle,
`Jeffrey W. Clark, Pankaj Bhargava, Rebecca Miksad, Lawrence
`Blaszkowsky, Peter C. Enzinger, Jeffrey A. Meyerhardt, Charles S. Fuchs,
`Matthew H. Kulke
`Collection and assembly of data: Jennifer A. Chan, Keith Stuart, Craig
`C. Earle, Jeffrey W. Clark, Pankaj Bhargava, Rebecca Miksad, Lawrence
`Blaszkowsky, Peter C. Enzinger, Jeffrey A. Meyerhardt, Charles S. Fuchs,
`Matthew H. Kulke
`Data analysis and interpretation: Jennifer A. Chan, Rebec