esmo preceptorship programmeoncologypro.esmo.org/content/download/130960/2456023/file/2018... ·...

Treatment of GEP NEN: Route evidence

European Institute of Oncology

Nicola Fazio, M.D., Ph. D.

Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors

European Institute of Oncology Milan, Italy

ESMO PRECEPTORSHIP PROGRAMME

Multidisciplinary management, standards of care and future perspectives

Lugano, Switzerland 13-14 April 2018

CHAIR: Nicola Fazio, Italy SPEAKERS: Pier Luigi Filosso, Italy

George Pentheroudakis, Greece Andrea Frilling, United Kingdom

Rocio Garcia-Carbonero, Spain

Massimo Milione, Italy

Marianne Pavel, Germany

Aviral Singh, Germany

Anders Sundin, Sweden

Christos Toumpanakis, United Kingdom

LEARNING OBJECTIVES

• To learn about best clinical practice in the multidisciplinary management of gastroenteropancreatic (GEP) and thoracic neuroendocrine neoplasms (NEN) patients

• To learn about the biological and clinical principles of diagnostic and therapeutic strategy

• To understand the importance of terminology, pathological and clinical classification, morphological and functional characterization of disease

• To learn how to manage the integration of several different therapies in patients with advanced disease

• To learn how to apply into clinical practice information coming from medical literature, guidelines and recommendations

ACCREDITATION

The programme of this event has been accredited with 10 ESMO-MORA category 1 points. Recertification is necessary for medical oncologists to remain professionally certified by ESMO. Recertification guarantees that a certified medical oncologist has continued to update her/his knowledge and continues to possess the necessary skills and standards for the practice of medical oncology. For further details, please refer to esmo.org.

ACKNOWLEDGEMENTS

This event is supported by an unrestricted educational grant from

ORGANISATION AND CONTACTS

ESMO Head Office Education Department Via Luigi Taddei 4 6962 Lugano - Viganello Switzerland Email: [email protected] www.esmo.org

Disclosure!

Novartis, Ipsen, Pfizer, AAA, Merck Serono: consulting and advisory services!

Novartis, Merck Serono: Research funds (to the institution) !

v  Female 52 y.o. v  Performance status = 0 (ECOG) v  Asymptoma>c v  No comorbidity v  No familial history

Rou>ne abdominal US à liver focal lesions

PanNET clinical case

!

US-‐guided liver biopsy: “well-‐diff. NET”

Ki-‐67 = 8%

Abdominal CT-‐scan

Primary tumor: pancreatic body/tail

High SSTR-‐2 uptake at 68Ga-‐PET-‐CT-‐DOTATOC

Non func(oning G2 panNET

What 1°-‐line systemic therapy? 1.  SSA 2.  Everolimus 3.  Suni(nib 4.  Chemotherapy 5.  PRRT 6.  Other

p=0.0002 HR=0.47 [95% CI: 0.30, 0.73]

CLARINET trial

Lanreotide Autogel 120 mg 32 events / 101 patients

median, not reached

Placebo 60 events / 103 patients

median, 18.0 months [95% CI: 12.1, 24.0]

0 3 6 9 12 18 24 27 0

10

20

30

40

50

60

70

80

90

100

Pat

ient

s al

ive

and

with

no

prog

ress

ion

(%)

Time (months)

62%

22%

Lanreotide autogel vs. placebo 204 enteropancreatic NET pts

Caplin et al., NEJM 2014!

PFS Lanreotide not reached Placebo 18 m

Yao, NEJM 2011!

Raymond, NEJM 2011!

Everolimus 11.4 m Placebo 5.4 m

Sunitinib 11.4 m Placebo 5.5 m

340 pts planned 171 enrolled

Early stop due to significant

difference in deaths, SAEs, and PFS

Figure. 2. Kaplan-Meier estimates of overall survival in the intent-to-treat (ITT) population (A) without adjustment for crossover and (B) both with and without adjustment for crossover in the placebo arm. CI, confidence interval; HR, hazard ratio; mOS, median overall survival; RPSFT, rank-preserving structural

failure time. Figure 2

116x160mm (300 x 300 DPI)

at ESMO

on Novem

ber 19, 2016http://annonc.oxfordjournals.org/

Dow

nloaded from

Faivre S et al., Ann Oncol 2016

Non significant

Figure. 2. Kaplan-Meier estimates of overall survival in the intent-to-treat (ITT) population (A) without adjustment for crossover and (B) both with and without adjustment for crossover in the placebo arm. CI, confidence interval; HR, hazard ratio; mOS, median overall survival; RPSFT, rank-preserving structural

failure time. Figure 2

116x160mm (300 x 300 DPI)

at ESM

O on N

ovember 19, 2016

http://annonc.oxfordjournals.org/D

ownloaded from

Final OS data from the Phase III Sunitinib trial in pNET

Taking cross-over into account

95% CI, 0.7 to 1.2). This difference did not achieve statisticalsignificance (P = .30; Fig 2).

Survival rates and duration at the 25th percentile are presentedin the Appendix Table A2 (online only).

Using the RPSFTmethod to correct for crossover of patientsfrom placebo to everolimus, 12- and 24-month survival rates were82.6% and 67.7%, respectively, in the everolimus arm and 74.9%and # 55.6%, respectively, in the RPSFT-corrected placebo arm(HR, 0.60; 95% CI, 0.09 to 3.95; Fig 3).

A total of 256 patients (62.4%) had died by the cutoff date of finalsurvival analysis: 126 patients (60.9%) initially randomly assigned to theeverolimus arm and 130 patients (64.0%) initially randomly assigned tothe placebo arm. On the basis of investigator assessment, advanced ormetastatic pancreatic NETwas the primary cause of most of the deathsreported in this study (everolimus arm, 104 of 126 deaths [82.5%];placebo arm, 111 of 130 deaths [85.4%]). Twenty-three of the 130deaths in the placebo arm occurred before crossover of the treatment.

Overall, 154 patients were censored (including 109 patientslost to follow-up) from the OS analysis; of these, 81 were from theeverolimus arm and 73 were from the placebo arm.

BiomarkersEvaluable baseline levels of seven soluble biomarkers were

available from at least 95% of the intent-to-treat population (AppendixTable A3, online only). A prognostic effect was observed with baselineCgA,NSE, PIGF, and sVEGFR1 levels (HR, 0.54 for CgA, 0.36 forNSE,0.53 for PIGF, and 0.71 for sVEGFR1; Fig 4). A multivariate analysisshowed that the association of baseline levels of NSE and PIGF withsurvival holds when adjusting for the effect of other biomarkers(Table 1). The median OS rates of the biomarker subpopulations aregiven in the Appendix Table A4 (online only). No prognostic signalwasdetected for the rest of the angiogenic biomarkers.

SafetyThe safety findings were consistent with the previously re-

ported safety profile of everolimus.6 No unexpected new safetyfindings were identified. In both the double-blind and the open-label

phase, the most commonly reported AEs ($ 20%) suspected to bedrug related in the everolimus group were stomatitis, rash, diarrhea,fatigue, peripheral edema, nausea, and decreased appetite (Table 2).AEs reported in patients who received open-label everolimus wereconsistent with those observed during the double-blind phase.

On-treatment deaths (ie, those occurring during receipt ofstudy medication or within the initial 28 days of discontinuingtherapy) were recorded for 16 patients in the double-blind phase;of these, 12 patients (5.9%) were in the everolimus arm and four(2.0%) were in the placebo arm. Of the 16 on-treatment deaths, eight(five everolimus and three placebo) were attributed to the underlyingmalignancy or progression thereof, and the remaining eight wereattributed to other comorbidities. In the open-label phase, 15 on-treatment deaths occurred, of which 11 (4.9%) were attributed to theunderlying malignancy (Appendix Table A5, online only). None ofthe on-treatment deaths in the double-blind and the open-labelphase, with the exception of one in the everolimus arm caused byacute respiratory distress syndrome, were deemed to be related to thestudy drug, according to the investigators.

In the double-blind phase, serious AEs (SAEs) were re-ported more often in the everolimus arm (84 patients [41.2%] v 52patients [25.6%] in the placebo arm). In the everolimus arm, 44patients (21.6%) experienced SAEs that were suspected by the in-vestigator to be drug related. The most commonly reported SAEs($ 2% incidence, irrespective of study drug relationship) in theeverolimus arm were pyrexia, pneumonitis, anemia, abdominalpain, dyspnea, diarrhea, pulmonary embolism, asthenia, and de-hydration. A total of 108 patients (48%) experienced SAEs duringthe open-label phase. Of these, 40 patients (17.8%) had SAEs thatwere suspected by the investigator to be drug related. Abdominalpain, vomiting, pneumonia, pyrexia, nausea, asthenia, GI hemor-rhage, and cholangitis were the most frequently reported SAEs ($ 2%incidence) in the open-label period (irrespective of causality).

The frequency of AEs leading to study drug discontinuationwas more noticeable in the everolimus arm (21.1%) versus theplacebo arm (5.9%) in the double-blind phase. The most frequentAEs leading to discontinuation in the everolimus group werepneumonitis (seven patients [3.4%]) and pyrexia (three patients

100

80

60

40

Perc

enta

ge o

f Ove

rall

Surv

ival

20

0 4

Censoring timesEverolimus (n of N = 126 of 207)

Kaplan-Meier medians (95% CI), monthsEverolimus: 44.02 (35.61 to 51.57)Placebo: 37.68 (29.14 to 45.77)

8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80

207Everolimus

No. of patientsstill at risk Time (months)

Placebo194 181 163 152 142 130 122 112 105 97 93 87 77 67 39 22 10 2 0 0

203 195 175 162 150 140 123 113 104 96 91 81 77 68 64 45 25 10 6 1 0

Placebo (n of N = 130 of 203)

Fig 2. Kaplan-Meier plot of overall survival(full analysis set).

4 © 2016 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

Yao et al

Downloaded from jco.ascopubs.org by Nicola Fazio on September 18, 2016 from 2.233.251.44Copyright © 2016 American Society of Clinical Oncology. All rights reserved.

Final OS data from the RADIANT-3 trial

Non significant Taking cross-over into account

Yao J et al., JCO 2016

Non functioning advanced panNET: first-line therapy

Treatment arm Control arm Tumours Pa>ents 1° line Prior

SSA Concomitant

SSA Author

CLARINET Lanreo>de autogel placebo

Non-‐func(oning enteropancrea(

c 204 80 % no /

Caplin NEJM 2014

RADIANT-‐3

Everolimus +/-‐

octreo>de LAR

Placebo +/-‐ octreo(de

LAR PNET 410 ? 50 % 40 %

Yao NEJM 2011

A6181111 Suni>nib placebo PNET 171 ? 40% 28 % Raymond NEJM 2011

trial Presented/published therapy PFS exp. arm PFS PLB arm setting

CLARINET Caplin, NEJM

2014 Phan, ASCO

2015

LAN A vs. PLB Not reached 12 mo

Well-diff enteropancreatic <10% Ki-67

RADIANT-3 Yao, NEJM 2011 EVE vs. PLB 11.4 mo 5.4 mo Well-diff

pancreatic

NCT00510068 ! Raymond, NEJM 2011 SUN vs. PLB 11 .4 mo 5.5 mo Well-diff

pancreatic

Phase III trial-related evidence in panNET

Different populations

CLARINET trial: pancreatic NET subgroup

•  Ki-67 < 10% •  1st line = 80% •  Prior chemo = 20%

Phan, ASCO GI 2015!

Lanreotide depot

18 events/42 patients

Median, not reached

49 48 38 33 23 17 8 0

0 42 39 32 29 24 20 13

Placebo

31 events/49 patients

Median, 12.1 months [95% CI: 9.4, 18.3]

Time from randomization to death/PD (months)

0 3 6 9 12 18 24 27

100

90

80

70

60

50

40

30

20

10

0

Pat

ient

s w

ith P

FS (%

)

Patients at risk!of PD/death!

Lanreotide 120 mg vs. placebo HR: 0.58 [95% CI: 0.32, 1.04]

PFS Lanreotide not reached Placebo 12 m

CLARINET trial: panNET subgroup characteristics

Lanreotide depot (n=42)! Placebo (n=49)!Age, mean (SD) in years! 63.8 (9.1)! 63.7 (9.2)!

Male! 26 (62)! 29 (59)!Time since diagnosis, mean (SD) in months! 30.4 (36.7)! 42.1 (50.1)!

Previous therapy! 9 (21)! 12 (24)!Previous chemotherapy! 8 (19)! 11 (22)!

Previous surgery! 18 (43)! 17 (35)!Tumor progression! 3 (7)! 2 (4)!Tumor grade:* G1/G2! 25 (60)/17 (40)! 32 (65)/16 (33)!HTL: >25% ! 19 (45)! 15 (31)!

Mostly stable according to RECIST, 40% G2 and over one third with tumor liver load >25%

Data are number (%), unless otherwise stated. *Ki-‐67 thresholds stated as per World Health Organiza(on 2010 classifica(on, with pa(ents with Ki-‐67 values >2% and ≤10% in the present study assigned to grade 2.

HTL, hepa(c tumor load.

Phan, ASCO GI 2015

CLARINET trial: any tumor shrinkage in the panNET subgroup

Data are sum of longest diameters for target tumor lesions.!*Centrally assessed and using % thresholds defined in RECIST. !!

Phan, ASCO GI 2015

More tumor response in lanreotide arm

Author! Jann, Neuroendocrinology 2013!

n. pts! 43!

Type! retrospective!

tumor! panNET!

Ki67 < 2%! 18%!

Ki67 3-20%! 70%!

Baseline PD! 53%!

SRS +! 86 %!

Pre-treated! no!

Drug! Octreotide LAR 20-30 mg q4w!

TTP/PFS! 13 m!

Non functioning advanced panNET: first-line therapy Everolimus + OCT LAR and Sunitinib

Author Treatment Type of trial Patients Tumor

population

Biology Syndrome y/n

Median TTP / PFS

(Mo)

Bajetta et al, Cancer

2014

Everolimus + octreotide

LAR Phase II 14 / 50 GEP/

Lung Well diff. both Not

reached

Raymond et al.,

ENETS 2017

Sunitinib Phase IV 61 / 102 Pancreas only

Well/mod. diff.

both 15

1

EVE or SUN

2 4 5 3

Advanced non functioning well differentiated panNET: First-line treatment according to the best evidence

LAN

OCT SUN EVE

Non functioning, low-grade advanced panNET

Lanreotide

1

CLARINET trial

2

orOctreotide

Non func(oning G2 panNET progressing on SSA

What 2°-‐line systemic therapy? 1.  Everolimus 2.  Suni(nib 3.  Chemotherapy 4.  PRRT 5.  Other

SSA

Advanced pancreatic well-differentiated NET

1 2

Everolimus+/- SSA

or

Sunitinib +/- SSA

or

Chemotherapy orPRRT orother MTAs

Sunitinib or Everolimus +/- SSA

3

Chemotherapy orPRRT orother MTAs

CLARINET trial

RADIANT-3 trial

A6181111 trial

Everolimus +/- SSA

“real world” data

Sunitinib +/- SSA

“compassionate use” data

Everolimus orsunitinib +/- SSA

A6181111 trial

RADIANT-3 trial

Advanced panNET Everolimus / Chemotherapy: which sequence?

Prior therapy EVE PBO

Surgery n.r. n.r.

Radiotherapy 23 % 20 %

Chemotherapy 50 % 50 %

SSA 49 % 50 %

Yao et al., NEJM 2011

original article

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 364;6 nejm.org february 10, 2011514

Everolimus for Advanced Pancreatic Neuroendocrine Tumors

James C. Yao, M.D., Manisha H. Shah, M.D., Tetsuhide Ito, M.D., Ph.D., Catherine Lombard Bohas, M.D., Edward M. Wolin, M.D.,

Eric Van Cutsem, M.D., Ph.D., Timothy J. Hobday, M.D., Takuji Okusaka, M.D., Jaume Capdevila, M.D., Elisabeth G.E. de Vries, M.D., Ph.D.,

Paola Tomassetti, M.D., Marianne E. Pavel, M.D., Sakina Hoosen, M.D., Tomas Haas, Ph.D., Jeremie Lincy, M.Sc., David Lebwohl, M.D.,

and Kjell Öberg, M.D., Ph.D., for the RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group

From the University of Texas M.D. Ander-son Cancer Center, Houston (J.C.Y.); Ohio State University Comprehensive Cancer Center, Columbus (M.H.S.); Graduate School of Medical Sciences, Ky-ushu University, Fukuoka, Japan (T.I.); Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France (C.L.B.); Cedars–Sinai Medical Center, Los Angeles (E.M.W.); University Hospital Gasthuis-berg, Leuven, Belgium (E.V.C.); Mayo Clinic, Rochester, MN (T.J.H.); National Cancer Center Hospital, Tokyo (T.O.); Vall d’Hebron University Hospital, Barce-lona (J.C.); University Medical Center, Groningen, the Netherlands (E.G.E.V.); University Hospital St. Orsola, Bologna, Italy (P.T.); Charité University Medicine, Berlin (M.E.P.); Novartis Oncology, Flor-ham Park, NJ (S.H., T.H., J.L., D.L.); and University Hospital, Uppsala, Sweden (K.Ö.). Address reprint requests to Dr. Yao at the University of Texas M.D. An-derson Cancer Center, 1515 Holcombe Blvd., Box 426, Houston, TX 77030, or at [email protected].

N Engl J Med 2011;364:514-23.Copyright © 2011 Massachusetts Medical Society.

A BS TR AC T

BACKGROUNDEverolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study.

METHODSWe randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the pre-vious 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treat-ment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus.

ResultsThe median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stoma-titis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyper-glycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks).

ConclusionsEverolimus, as compared with placebo, significantly prolonged progression-free sur-vival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncol-ogy; RADIANT-3 ClinicalTrials.gov number, NCT00510068.)

The New England Journal of Medicine Downloaded from nejm.org at CILEA BIBLIOSAN on February 11, 2011. For personal use only. No other uses without permission.

Copyright © 2011 Massachusetts Medical Society. All rights reserved.

original article

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 364;6 nejm.org february 10, 2011514

Everolimus for Advanced Pancreatic Neuroendocrine Tumors

James C. Yao, M.D., Manisha H. Shah, M.D., Tetsuhide Ito, M.D., Ph.D., Catherine Lombard Bohas, M.D., Edward M. Wolin, M.D.,

Eric Van Cutsem, M.D., Ph.D., Timothy J. Hobday, M.D., Takuji Okusaka, M.D., Jaume Capdevila, M.D., Elisabeth G.E. de Vries, M.D., Ph.D.,

Paola Tomassetti, M.D., Marianne E. Pavel, M.D., Sakina Hoosen, M.D., Tomas Haas, Ph.D., Jeremie Lincy, M.Sc., David Lebwohl, M.D.,

and Kjell Öberg, M.D., Ph.D., for the RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group

From the University of Texas M.D. Ander-son Cancer Center, Houston (J.C.Y.); Ohio State University Comprehensive Cancer Center, Columbus (M.H.S.); Graduate School of Medical Sciences, Ky-ushu University, Fukuoka, Japan (T.I.); Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France (C.L.B.); Cedars–Sinai Medical Center, Los Angeles (E.M.W.); University Hospital Gasthuis-berg, Leuven, Belgium (E.V.C.); Mayo Clinic, Rochester, MN (T.J.H.); National Cancer Center Hospital, Tokyo (T.O.); Vall d’Hebron University Hospital, Barce-lona (J.C.); University Medical Center, Groningen, the Netherlands (E.G.E.V.); University Hospital St. Orsola, Bologna, Italy (P.T.); Charité University Medicine, Berlin (M.E.P.); Novartis Oncology, Flor-ham Park, NJ (S.H., T.H., J.L., D.L.); and University Hospital, Uppsala, Sweden (K.Ö.). Address reprint requests to Dr. Yao at the University of Texas M.D. An-derson Cancer Center, 1515 Holcombe Blvd., Box 426, Houston, TX 77030, or at [email protected].


A BS TR AC T

BACKGROUNDEverolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study.

METHODSWe randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the pre-vious 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treat-ment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus.

ResultsThe median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stoma-titis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyper-glycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks).

ConclusionsEverolimus, as compared with placebo, significantly prolonged progression-free sur-vival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncol-ogy; RADIANT-3 ClinicalTrials.gov number, NCT00510068.)



Everolimus in panNETs: prior chemotherapy

Type of study

Treatment arms

Primary site sebng status

RADIANT-‐1 Strat. Phase II

Everolimus +/-‐

octreo>de LAR

pancreas PD on

chemotherapy

Yao, JCO 2010

Everolimus after chemotherapy in pan NET

Advanced panNET Sunitinib / Chemotherapy: which sequence?

Sunitinib for Pancreatic Neuroendocrine Tumors

n engl j med 364;6 nejm.org february 10, 2011 505

Study Treatment

Patients received sunitinib for a median duration of 4.6 months (range, 0.4 to 17.5), and patients received placebo for a median duration of 3.7 months (range, 0.03 to 20.2). Nineteen patients

(22%) who were randomly assigned to sunitinib remained in the study for more than 1 year, as compared with four patients who were randomly assigned to placebo (5%).

The most common reasons for study discon-

Table 1. (Continued.)

VariableSunitinib(N = 86)

Placebo(N = 85)

Ki-67 index

No. of patients with data that could be evaluated 36 36

Index — no. (%)

≤2% 7 (19) 6 (17)

>2%–5% 16 (44) 14 (39)

>5%–10% 5 (14) 10 (28)

>10% 8 (22) 6 (17)

No. of sites of disease — no. (%)§

1 30 (35) 23 (27)

2 31 (36) 26 (31)

≥3 24 (28) 35 (41)

Not reported 1 (1) 1 (1)

Presence of distant metastases — no. (%)

Any, including hepatic 82 (95) 80 (94)

Extrahepatic 21 (24) 34 (40)

Previous treatment — no. (%)§

Surgery 76 (88) 77 (91)

Radiation therapy 9 (10) 12 (14)

Chemoembolization 7 (8) 14 (16)

Radiofrequency ablation 3 (3) 6 (7)

Percutaneous ethanol injection 1 (1) 2 (2)

Somatostatin analogues†† 30 (35) 32 (38)

Previous systemic chemotherapy — no. (%)

Any 57 (66) 61 (72)

Streptozocin 24 (28) 28 (33)

Anthracyclines 27 (31) 35 (41)

Fluoropyrimidines 20 (23) 25 (29)

* Race was self-reported.† In accordance with local regulations, data on race were not routinely collected in one participating country.‡ The Eastern Cooperative Oncology Group (ECOG) performance status is based on an assessment of activities of daily

living, on a scale from 0 (fully active) to 5 (dead).§ The study groups did not differ significantly (P>0.05 by Fisher’s exact test) with respect to ECOG performance status

(0 vs. 1 or 2), tumor functional status (nonfunctioning vs. other), the number of involved disease sites (<3 vs. ≥3), and the number of previous systemic regimens (<2 vs. ≥2).

¶ Enrollment of this patient was a protocol deviation.�∥ Data were available for 85 patients in each group.** Tumor functionality was reported by investigators. On the basis of the investigators’ assessment, patients included in

the “unknown” category had clinical symptoms but no identified corresponding neuropeptide secretion.†† This category includes patients who received somatostatin analogues (predominantly octreotide, octreotide acetate,

and lanreotide) before the first dose of study drug, regardless of whether they continued receiving somatostatin ana-logues concomitantly with the study drug.




The new england journal of medicineestablished in 1812 february 10, 2011 vol. 364 no. 6

Sunitinib Malate for the Treatment of Pancreatic Neuroendocrine Tumors

Eric Raymond, M.D., Ph.D., Laetitia Dahan, M.D., Ph.D., Jean-Luc Raoul, M.D., Ph.D., Yung-Jue Bang, M.D., Ivan Borbath, M.D., Ph.D., Catherine Lombard-Bohas, M.D., Juan Valle, M.D., Peter Metrakos, M.D., C.M.,

Denis Smith, M.D., Aaron Vinik, M.D., Ph.D., Jen-Shi Chen, M.D., Dieter Hörsch, M.D., Pascal Hammel, M.D., Ph.D., Bertram Wiedenmann, M.D., Ph.D., Eric Van Cutsem, M.D., Ph.D., Shem Patyna, Ph.D., Dongrui Ray Lu, M.Sc., Carolyn Blanckmeister, Ph.D., Richard Chao, M.D.,

and Philippe Ruszniewski, M.D.

A BS TR AC T

From the Service Inter-Hospitalier de Cancérologie et Service de Gastroentero-pancréatologie, Hôpital Beaujon, Clichy (E.R., P.H., P.R.); Service d’Oncologie Di-gestive, Hôpital Timone, Marseille, and Réseau National des Tumeurs Endo-crines, Provence Alpes Cote d’Azure (L.D.); Eugène Marquis Centre, University of Rennes, Rennes (J.-L.R.); Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon (C.L.-B.); and Hôpital Saint-André, Bor-deaux (D.S.) — all in France; Seoul Na-tional University Hospital, Seoul, Korea (Y.-J.B.); Cliniques Universitaires Saint-Luc, Brussels (I.B.); Department of Medi-cal Oncology, Christie Hospital National Health Service Foundation Trust, Man-chester, United Kingdom (J.V.); McGill Uni-versity Hospital Centre, Montreal (P.M.); Eastern Virginia Medical School Strelitz Diabetes Center and Neuroendocrine Unit, Norfolk (A.V.); Chang Gung Memo-rial Hospital and Chang Gung University, Kwei-Shan, Taoyuan, Taiwan (J.-S.C.); Clin-ic for Internal Medicine, Gastroenterology and Endocrinology, Center for Neuroendo-crine Tumors, Bad Berka Central Clinic, Bad Berka, Germany (D.H.); the Depart-ment of Hepatology and Gastroenterology, Charité Medical School, Humboldt-Uni-versität zu Berlin, Berlin (B.W.); University Hospital Gasthuisberg Leuven, Leuven, Belgium (E.V.C.); Pfizer Oncology, Devel-opment, La Jolla, CA (S.P., D.R.L., R.C.); and Pfizer Oncology, Emerging Markets, New York (C.B.). Address reprint requests to Dr. Raymond at Service Inter-Hospit-alier de Cancérologie Beaujon–Bichat, Uni-versity Paris 7 Diderot (INSERM Unité 728) and Assistance Publique–Hôpitaux de Par-is, Hôpital Beaujon, 100 Blvd. du Général Leclerc, 92118 Clichy CEDEX, France, or at [email protected].


BackgroundThe multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in preclinical models and phase 1 and 2 trials.

MethodsWe conducted a multinational, randomized, double-blind, placebo-controlled phase 3 trial of sunitinib in patients with advanced, well-differentiated pancreatic neuro-endocrine tumors. All patients had Response Evaluation Criteria in Solid Tumors–defined disease progression documented within 12 months before baseline. A total of 171 patients were randomly assigned (in a 1:1 ratio) to receive best supportive care with either sunitinib at a dose of 37.5 mg per day or placebo. The primary end point was progression-free survival; secondary end points included the objective response rate, overall survival, and safety.

ResultsThe study was discontinued early, after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib. Median pro-gression-free survival was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group (hazard ratio for progression or death, 0.42; 95% confidence interval [CI], 0.26 to 0.66; P<0.001). A Cox proportional-hazards analy-sis of progression-free survival according to baseline characteristics favored suni-tinib in all subgroups studied. The objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group. At the data cutoff point, 9 deaths were re-ported in the sunitinib group (10%) versus 21 deaths in the placebo group (25%) (hazard ratio for death, 0.41; 95% CI, 0.19 to 0.89; P = 0.02). The most frequent ad-verse events in the sunitinib group were diarrhea, nausea, vomiting, asthenia, and fatigue.

ConclusionsContinuous daily administration of sunitinib at a dose of 37.5 mg improved pro-gression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00428597.)



Raymond et al., NEJM 2011

Sunitinib for Pancreatic Neuroendocrine Tumors


Study Treatment

Patients received sunitinib for a median duration of 4.6 months (range, 0.4 to 17.5), and patients received placebo for a median duration of 3.7 months (range, 0.03 to 20.2). Nineteen patients

(22%) who were randomly assigned to sunitinib remained in the study for more than 1 year, as compared with four patients who were randomly assigned to placebo (5%).

The most common reasons for study discon-

Table 1. (Continued.)

VariableSunitinib(N = 86)

Placebo(N = 85)

Ki-67 index

No. of patients with data that could be evaluated 36 36

Index — no. (%)

≤2% 7 (19) 6 (17)

>2%–5% 16 (44) 14 (39)

>5%–10% 5 (14) 10 (28)

>10% 8 (22) 6 (17)

No. of sites of disease — no. (%)§

1 30 (35) 23 (27)

2 31 (36) 26 (31)

≥3 24 (28) 35 (41)

Not reported 1 (1) 1 (1)

Presence of distant metastases — no. (%)

Any, including hepatic 82 (95) 80 (94)

Extrahepatic 21 (24) 34 (40)

Previous treatment — no. (%)§

Surgery 76 (88) 77 (91)

Radiation therapy 9 (10) 12 (14)

Chemoembolization 7 (8) 14 (16)

Radiofrequency ablation 3 (3) 6 (7)

Percutaneous ethanol injection 1 (1) 2 (2)

Somatostatin analogues†† 30 (35) 32 (38)

Previous systemic chemotherapy — no. (%)

Any 57 (66) 61 (72)

Streptozocin 24 (28) 28 (33)

Anthracyclines 27 (31) 35 (41)

Fluoropyrimidines 20 (23) 25 (29)

* Race was self-reported.† In accordance with local regulations, data on race were not routinely collected in one participating country.‡ The Eastern Cooperative Oncology Group (ECOG) performance status is based on an assessment of activities of daily

living, on a scale from 0 (fully active) to 5 (dead).§ The study groups did not differ significantly (P>0.05 by Fisher’s exact test) with respect to ECOG performance status

(0 vs. 1 or 2), tumor functional status (nonfunctioning vs. other), the number of involved disease sites (<3 vs. ≥3), and the number of previous systemic regimens (<2 vs. ≥2).

¶ Enrollment of this patient was a protocol deviation.�∥ Data were available for 85 patients in each group.** Tumor functionality was reported by investigators. On the basis of the investigators’ assessment, patients included in

the “unknown” category had clinical symptoms but no identified corresponding neuropeptide secretion.†† This category includes patients who received somatostatin analogues (predominantly octreotide, octreotide acetate,

and lanreotide) before the first dose of study drug, regardless of whether they continued receiving somatostatin ana-logues concomitantly with the study drug.



Sunitinib in panNETs: prior chemotherapy

Minimal consensus statement: Everolimus or sunitinib are generally recommended after failure of SSA or chemotherapy in pancreatic NET. Everolimus and sunitinib ………….. can be considered a first line therapy, especially if SSA is not an option, and if systemic chemotherapy is not clinically required, not feasible or not tolerated.

Advanced panNETs 2016 ENETS guidelines

Pavel et al., Neuroendocrinology Jan 2016

SSA

Advanced pancreatic well-differentiated NETAccording to ENETS guidelines

1

Chemotherapy

EverolimusorSunitinib

PRRTSunitinib or Everolimus

2 4 53

SSA

Advanced pancreatic well-differentiated NET according to the best level of evidence

1

Everolimus or Sunitinib

2 3

Chemo or PRRT

within clinical trials

Advanced panNET Everolimus / Sunitinib: which sequence?

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

RADIANT-1

RADIANT-2

RADIANT-3

RADIANT-4

Enrollment periods of the RADIANT trials

EVE+OCT RAMSETE LUNA

Everolimus 10 mg/day continuously

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

RADIANT-1

RADIANT-2

RADIANT-3

Enrollment periods of the RADIANT trials

EVE+OCT

Everolimus 10 mg/day continuously

Everolimus Investigation in NETs RADIANT (RAD001 in Advanced Neuroendocrine

Tumors)

2005! 2006! 2007! 2008! 2009! 2010! 2011! 2012! 2013! 2014!

RADIANT-3

RADIANT-2

RADIANT-1

EVE+OCT RAMSETE LUNA

EVE+OCT 1ST Line ITMO

RADIANT-4

Phase III

Phase II

Post-marketing Phase IV trial of Sunitinib in panNETs: NANETS 2016 poster

Presented at the North American Neuroendocrine Tumor Society (NANETS) Symposium, September 30–October 1, 2016, Jackson Hole, WY

CONCLUSIONS n Median PFS of 13.2 months (95% CI, 10.9–16.7) and ORR of

24.5% (95% CI, 16.7–33.8) observed in this phase IV trial support the outcomes of the pivotal phase III of sunitinib in pNETs and confirm its activity in this setting.

n OS data were not mature at the time of the primary analysis.

n AEs were consistent with the known safety profile of sunitinib.

n The study confirmed sunitinib is an efficacious and safe treatment option in progressive, locally advanced and/or metastatic, well-differentiated, unresectable pNETs.

The Efficacy and Safety of Sunitinib in Patients With Advanced Well-Differentiated Pancreatic Neuroendocrine TumorsEric Raymond1, Matthew H Kulke2, Shukui Qin3, Michael Schenker4, Antonio Cubillo5, Wenhui Lou6, Jiri Tomasek7, Espen Thiis-Evensen8, Jianming Xu9, Karoly Racz10, Adina E Croitoru11, Mustafa Khasraw12, Eva Sedlackova13, Ivan Borbath14, Paul Ruff15, Paul E Oberstein16, Tetsuhide Ito17, Kathrine C Fernandez18, Brad Rosbrook19, Nicola Fazio20 1Paris Saint-Joseph Hospital Group, Paris, France; 2Dana-Farber Cancer Institute, Boston, MA, USA; 3PLA Cancer Center of Nanjing Bayi Hospital, Nanjing, China; 4Centrul de Oncologie Sf. Nectarie, Oncologie Medicala, Craiova, Romania; 5Hospital Universitario Madrid Sanchinarro, Centro Integral Oncológico Clara Campal, Madrid, Spain; 6Zhongshan Hospital, Fudan University, Shanghai, China; 7Masaryk Memorial Cancer Institute, Faculty of Medicine, Masaryk University, Brno, Czech Republic; 8Oslo University Hospital, Department of Gastroenterology, Rikshospitalet, Oslo, Norway; 9No.307 Hospital, Academy of Military Medical Sciences, Beijing, China; 10Semmelweis University, Faculty of Medicine, 2nd Department of Internal Medicine, Budapest, Hungary; 11Fundeni Clinical Institute, Department of Medical Oncology, Bucharest, Romania; 12Andrew Love Cancer Center, Geelong Hospital, Victoria, Australia; 13Všeobecné Fakultní Nemocnice v Praze Onkologická Klinika, Praha, Czech Republic; 14Cliniques Universitaires Saint-Luc, King Albert II Institute Cancerology and Hematology, Brussels, Belgium; 15University of the Witwatersrand, Faculty of Health Sciences, Johannesburg, South Africa; 16Columbia University Medical Center, Division of Hematology/Oncology, New York, NY, USA; 17Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 18Pfizer Inc, Cambridge, MA, USA; 19Pfizer Inc, San Diego, CA, USA; 20IEO, European Institute of Oncology, Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, Milan, Italy

151

Table 3. Treatment-emergent, all-causality adverse events

Adverse events,* n (%)

Treatment-naïven=61

Previously Treated

n=45Total

N=106

All Grades

Grade 3/4

All Grades

Grade 3/4

All Grades

Grade 3/4

Neutropenia 37 (61) 13 (21) 22 (49) 10 (22) 59 (56) 23 (22)

Diarrhea 32 (52) 7 (11) 22 (49) 3 (7) 54 (51) 10 (9)

Leukopenia 25 (41) 4 (7) 21 (47) 3 (7) 46 (43) 7 (7)Hand–foot syndrome

19 (31) 5 (8) 14 (31) 2 (4) 33 (31) 7 (7)

Fatigue 19 (31) 1 (2) 14 (31) 0 33 (31) 1 (1)

Thrombocytopenia 18 (30) 6 (10) 14 (31) 2 (4) 32 (30) 8 (8)

Hypertension 16 (26) 4 (7) 11 (24) 2 (4) 27 (25) 6 (6)

Abdominal pain 16 (26) 2 (3) 10 (22) 3 (7) 26 (25) 5 (5)

Nausea 11 (18) 0 14 (31) 1 (2) 25 (24) 1 (1)

Dysgeusia 14 (23) 0 11 (24) 0 25 (24) 0

Headache 12 (20) 0 9 (20) 0 21 (20) 0

Dyspepsia 7 (11) 0 14 (31) 0 21 (20) 0

Stomatitis 13 (21) 2 (3) 6 (13) 1 (2) 19 (18) 3 (3)

Vomiting 8 (13) 1 (2) 10 (22) 1 (2) 18 (17) 2 (2)

Asthenia 10 (16) 0 7 (16) 2 (4) 17 (16) 2 (2)

* Adverse events reported by ≥15% of the all patients.

REFERENCES1. American Cancer Society Cancer Facts & Figures 2016. Atlanta, GA.2. Raymond E, et al. N Engl J Med 2011;364:501-13.3. Sutent® (sunitinib malate) prescribing information. New York, NY: Pfizer Inc; 2015.

ACKNOWLEDGMENTSWe thank the participating patients and their families, as well as the global network of research nurses, trial coordinators, and operations staff for their contributions, and investigators who participated in this trial, including: M. Michael (Australia); X. Yu, Y. Shen and L. Jia (China); P. Hammel (France); S. Skrikhande (India); C. Morizane (Japan); J. Sufliarsky (Slovakia); and G. Khan (United States). This study was sponsored by Pfizer. Medical writing support was provided by Mariko Nagashima, PhD, of Engage Scientific Solutions, and was funded by Pfizer.

Copyright © 2016

INTRODUCTION • Pancreatic neuroendocrine tumors (pNETs) are rare tumors. Of an

estimated 53,070 new cases of pancreatic cancers expected in the US in 2016, pNETs account for fewer than 5%.1

• Due to their relatively indolent nature, the majority of patients are diagnosed with metastatic pNETs, for whom treatment options are limited.

• pNETs are highly vascularized tumors; aberrant expression of vascular endothelial growth factor (VEGF) and its receptors, which play vital roles in tumor angiogenesis, has been observed.

• Sunitinib, a multi-targeted tyrosine kinase inhibitor (TKI) of angiogenesis, showed a significant increase in progression-free survival (PFS) over placebo in well-differentiated, advanced and/or metastatic pNETs in a pivotal phase III clinical trial (ClinicalTrials.gov NCT00428597).2

• The trial was terminated early after more-serious adverse events (AEs) and deaths were observed in the placebo arm and a difference in PFS favored the sunitinib arm (hazard ratio [HR] 0.42, 95% confidence interval [CI], 0.26–0.66; P<0.001; median: 11.4 vs 5.5 months).

– Sunitinib treatment was also associated with longer overall survival (OS) vs placebo (HR 0.41, 95% CI, 0.19–0.89; P=0.02).

• In 2010 and 2011, sunitinib was approved by the European Medicines Agency and US Food and Drug Administration (FDA), respectively, for the treatment of patients with progressive, locally advanced and/or metastatic, well-differentiated, unresectable pNETs.3

OBJECTIVES • This phase IV clinical trial (ClinicalTrials.gov NCT01525550) was

conducted as post-approval commitments to the FDA and other regulatory agencies to confirm the efficacy and safety of sunitinib in advanced and/or metastatic, well-differentiated, unresectable pNETs.

METHODSStudy Design

• This multinational, single-arm, open-label, phase IV clinical trial is ongoing.

• The primary endpoint is investigator-assessed PFS per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0.

• Secondary endpoints include PFS assessed by the independent radiological review, time to tumor progression (TTP), objective response rate (ORR), OS, and safety.

Key Eligibility Criteria • Histologically or cytologically confirmed, well-differentiated,

unresectable or metastatic pNETs with documented progression within 12 months of study enrollment.

• Not amenable to surgery, radiation, or combined modality therapy with curative intent.

• Presence of ≥1 measurable target lesion per RECIST v1.0.

• Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1.

• No pre-existing uncontrolled hypertension (ie, blood pressure >150/100 mmHg despite medical therapy)

• No prior treatment with TKIs, anti-VEGF, or other angiogenesis inhibitors.

Treatment and Assessments • Patients received 37.5 mg sunitinib orally once a day on a continuous

daily-dosing regimen.

– Sunitinib dose could be increased to 50 mg daily any time after 8 weeks of treatment initiation in patients without treatment response, who experienced only grade 1 or lower nonhematologic or grade 2 or lower hematologic treatment-related AEs.

– Dose could be temporarily interrupted or reduced to 25 mg daily to manage severe toxicity.

• Somatostatin analogs for control of symptoms were permitted at the investigator’s discretion.

• Radiologic tumor assessments were conducted at screening, Cycle 2 Day 1, Cycle 3 Day 1, and every 2 cycles thereafter; tumor responses were evaluated per RECIST v1.0 criteria.

• Safety was monitored throughout the study and AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0.

Statistical Analyses • More than 80 patients were to be enrolled: 40 treatment-naïve

(defined as those who never received systemic antitumor therapy; somatostatin analogs for symptomatic control was allowed) and 40 previously treated patients.

• Median PFS and 95% CI were estimated using the Kaplan–Meier method for the entire population as well as separately for treatment-naïve and previously treated patients.

• Descriptive statistics were used to summarize other parameters.

RESULTSPatients

• Of 123 patients screened, 106 (61 treatment-naïve and 45 previously treated) were enrolled at 24 centers in 15 countries (Figure 1).

Figure 1. Trial profile

123 patients screened

106 patients enrolled

61 txt-naïve patients treated 45 previously treated patients treated

39 previously treated patients discontinued txt 23 Objective progression/relapse 8 Adverse events 1 Refusal of txt for reason other than AE 2 Global health deterioration 1 Death 4 Other

43 txt-naïve patients discontinued txt 26 Objective progression/relapse 6 Adverse events 4 Refusal of txt for reason other than AE 2 Global health deterioration 1 Death 4 Other

Efficacy Analysis: 61 txt-naïve patientsSafety Analysis: 61 txt-naïve patients

45 previously treated patients45 previously treated patients

AE=adverse event; Txt=treatment

• Patient demographics and baseline characteristics are summarized in Table 1.

• More than half (n=64/106, 60.4%) of patients had a nonfunctioning tumor and 17.9% had a functioning tumor (unknown for 21.7% of patients).

• In regard to prior locoregional treatment, 18.9% of patients had trans-arterial chemoembolization; radiofrequency ablation (3.8%); or trans-arterial embolization, percutaneous injections, or microwave ablation (2.8% each).

• Median (range) treatment duration in the total population was 357.5 days (7–1226): 371.0 days (7–1092) in treatment-naïve vs 309.0 days (14–1226) in previously treated patients.

Efficacy • Median PFS assessed by investigators was 13.2 months (95% CI,

10.9–16.7); median PFS was similar in treatment-naïve and previously treated patients (13.2 months [95% CI, 7.4–16.8] and 13.0 months [95% CI, 9.2–20.4], respectively; Figure 2).

• Median PFS as assessed by independent radiological review was 11.1 months (95% CI, 7.4–16.6), in treatment-naive patients 11.1 months (95% CI, 5.5–16.7), and in previously treated patients 9.5 months (95% CI, 7.4–18.4).

– 7 patients were censored due to lack of adequate baseline assessments.

Table 1. Demographics and patient baseline characteristics

Characteristics


Previously Treated

n=45Total

N=106Age, years, mean (SD) 55.4 (8.9) 53.5 (9.1) 54.6 (9.0)Gender, n (%) Male 30 (49.2) 33 (73.3) 63 (59.4) Female 31 (50.8) 12 (26.7) 43 (40.6) Race, n (%) White 32 (52.5) 35 (77.8) 67 (63.2) Black 2 (3.3) 0 2 (1.9) Asian 27 (44.3) 10 (22.2) 37 (34.9)ECOG PS, n (%) 0 39 (63.9) 29 (64.4) 68 (64.2) 1 22 (36.1) 16 (35.6) 38 (35.8)No. of involved disease site,* n (%) 1 24 (39.3) 9 (20.0) 33 (31.1) 2 19 (31.1) 22 (48.9) 41 (38.7) 3 11 (18.0) 8 (17.8) 19 (17.9) ≥4 7 (11.5) 6 (13.3) 13 (12.3)Tumor site,* n (%) Liver 57 (93.4) 41 (91.1) 98 (92.5) Pancreas 22 (36.1) 25 (55.6) 47 (44.3) Lymph node, distant 16 (26.2) 13 (28.9) 29 (27.4) Lymph node, regional 13 (21.3) 7 (15.6) 20 (18.9) Lung 3 (4.9) 3 (6.7) 6 (5.7)Prior systemic chemotherapy, n (%) Any 0 45 (100) 45 (42.5) Neoadjuvant 0 2 (4.4) 2 (1.9) Adjuvant 0 4 (8.9) 4 (3.8) Advanced/metastatic 0 39 (86.7) 39 (36.8)Prior SSA,† n (%) 24 (39.3) 27 (60.0) 51 (48.1)Ki-67 index, mean (SD) 6.72 (5.009) 8.35 (7.179) 7.41 (6.049)* Included both target and nontarget sites; sites with multiple lesions were counted once.† Patients with regimens that consist only of somatostatin analogs were considered treatment-naïve.ECOG PS, Eastern Cooperative Oncology Group performance status; SD=standard deviation; SSA=somatostatin analogs

Figure 2. Kaplan–Meier estimates of PFS in treatment-naïve and previously treated patients with pNETs assessed by the investigators

PFS

Dist

ribut

ion

Func

tion

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 5 10 15 20 25

Time (months)No. at risk:

Treatment-naivePreviously treated

6145

4129

3220

1410

88

64

04

02

01

00

30 35 40 45

Treatment-naïve 61 37 13.2 (7.4–16.8)Previously treated 45 28 13.0 (9.2–20.4)

n Events mPFS (95% CI), mo

CI=confidence interval; mPFS=median progression-free survival; PFS=progression-free survival; pNETs=pancreatic neuroendocrine tumors

• ORR was 24.5% (95% CI, 16.7–33.8) according to the investigator assessment (Table 2).

•

Table 2. Best observed response by RECIST, assessed by investigators


Previously Treated

n=45Total

N=106Best overall response, n (%) Complete response 2 (3.3) 1 (2.2) 3 (2.8) Partial response 11 (18.0) 12 (26.7) 23 (21.7) Stable disease 40 (65.6) 29 (64.4) 69 (65.1) Progressive disease 7 (11.5) 2 (4.4) 9 (8.5) Indeterminate 1 (1.6) 1 (2.2) 2 (1.9)ORR,* n (%) 13 (21.3) 13 (28.9) 26 (24.5) 95% CI 11.9–33.7 16.4–44.3 16.7–33.8* Complete response + partial response. CI=confidence interval; ORR=objective response rate; RECIST=Response Evaluation Criteria in Solid Tumors

Median TTP was 14.5 months (95% CI, 11.0–16.7); median TTP in treatment-naïve and previously treated patients was similar (14.8 [95% CI, 7.5–16.8] and 14.5 [95% CI, 9.2–20.4] months, respectively).

• OS data were not mature at the time of data cutoff date (Mar 19, 2016); 29 (27.4%) patients had died and median OS was 37.8 months (95% CI, 33.0–not estimable).

Safety • Most-common treatment-emergent, all-grade AEs experienced by all

patients treated with sunitinib included neutropenia, diarrhea, and leukopenia (Table 3).

– No major differences were observed in the incidence of AEs reported by treatment-naïve vs previously treated patients, except dyspepsia, nausea, and neutropenia.

• Percentage of treatment-naïve and previously treated patients who experienced Grade 3 or 4 AEs was comparable; serious AEs were also comparable: 25% (n=15) vs 24% (n=11), respectively.

• 15 (25%) treatment-naïve and 5 (11%) previously treated patients had sunitinib dose reductions due to AEs; 8 (13%) and 10 (22%) patients, rectively, discontinued treatment due to AEs.

Presented at the North American Neuroendocrine Tumor Society (NANETS) Symposium, September 30–October 1, 2016, Jackson Hole, WY

CONCLUSIONS n Median PFS of 13.2 months (95% CI, 10.9–16.7) and ORR of

24.5% (95% CI, 16.7–33.8) observed in this phase IV trial support the outcomes of the pivotal phase III of sunitinib in pNETs and confirm its activity in this setting.




The Efficacy and Safety of Sunitinib in Patients With Advanced Well-Differentiated Pancreatic Neuroendocrine TumorsEric Raymond1, Matthew H Kulke2, Shukui Qin3, Michael Schenker4, Antonio Cubillo5, Wenhui Lou6, Jiri Tomasek7, Espen Thiis-Evensen8, Jianming Xu9, Karoly Racz10, Adina E Croitoru11, Mustafa Khasraw12, Eva Sedlackova13, Ivan Borbath14, Paul Ruff15, Paul E Oberstein16, Tetsuhide Ito17, Kathrine C Fernandez18, Brad Rosbrook19, Nicola Fazio20 1Paris Saint-Joseph Hospital Group, Paris, France; 2Dana-Farber Cancer Institute, Boston, MA, USA; 3PLA Cancer Center of Nanjing Bayi Hospital, Nanjing, China; 4Centrul de Oncologie Sf. Nectarie, Oncologie Medicala, Craiova, Romania; 5Hospital Universitario Madrid Sanchinarro, Centro Integral Oncológico Clara Campal, Madrid, Spain; 6Zhongshan Hospital, Fudan University, Shanghai, China; 7Masaryk Memorial Cancer Institute, Faculty of Medicine, Masaryk University, Brno, Czech Republic; 8Oslo University Hospital, Department of Gastroenterology, Rikshospitalet, Oslo, Norway; 9No.307 Hospital, Academy of Military Medical Sciences, Beijing, China; 10Semmelweis University, Faculty of Medicine, 2nd Department of Internal Medicine, Budapest, Hungary; 11Fundeni Clinical Institute, Department of Medical Oncology, Bucharest, Romania; 12Andrew Love Cancer Center, Geelong Hospital, Victoria, Australia; 13Všeobecné Fakultní Nemocnice v Praze Onkologická Klinika, Praha, Czech Republic; 14Cliniques Universitaires Saint-Luc, King Albert II Institute Cancerology and Hematology, Brussels, Belgium; 15University of the Witwatersrand, Faculty of Health Sciences, Johannesburg, South Africa; 16Columbia University Medical Center, Division of Hematology/Oncology, New York, NY, USA; 17Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 18Pfizer Inc, Cambridge, MA, USA; 19Pfizer Inc, San Diego, CA, USA; 20IEO, European Institute of Oncology, Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, Milan, Italy

151

Table 3. Treatment-emergent, all-causality adverse events

Adverse events,* n (%)


Previously Treated

n=45Total

N=106

All Grades

Grade 3/4

All Grades

Grade 3/4

All Grades

Grade 3/4

Neutropenia 37 (61) 13 (21) 22 (49) 10 (22) 59 (56) 23 (22)

Diarrhea 32 (52) 7 (11) 22 (49) 3 (7) 54 (51) 10 (9)

Leukopenia 25 (41) 4 (7) 21 (47) 3 (7) 46 (43) 7 (7)Hand–foot syndrome

19 (31) 5 (8) 14 (31) 2 (4) 33 (31) 7 (7)

Fatigue 19 (31) 1 (2) 14 (31) 0 33 (31) 1 (1)

Thrombocytopenia 18 (30) 6 (10) 14 (31) 2 (4) 32 (30) 8 (8)

Hypertension 16 (26) 4 (7) 11 (24) 2 (4) 27 (25) 6 (6)

Abdominal pain 16 (26) 2 (3) 10 (22) 3 (7) 26 (25) 5 (5)

Nausea 11 (18) 0 14 (31) 1 (2) 25 (24) 1 (1)

Dysgeusia 14 (23) 0 11 (24) 0 25 (24) 0

Headache 12 (20) 0 9 (20) 0 21 (20) 0

Dyspepsia 7 (11) 0 14 (31) 0 21 (20) 0

Stomatitis 13 (21) 2 (3) 6 (13) 1 (2) 19 (18) 3 (3)

Vomiting 8 (13) 1 (2) 10 (22) 1 (2) 18 (17) 2 (2)

Asthenia 10 (16) 0 7 (16) 2 (4) 17 (16) 2 (2)

* Adverse events reported by ≥15% of the all patients.

REFERENCES1. American Cancer Society Cancer Facts & Figures 2016. Atlanta, GA.2. Raymond E, et al. N Engl J Med 2011;364:501-13.3. Sutent® (sunitinib malate) prescribing information. New York, NY: Pfizer Inc; 2015.

ACKNOWLEDGMENTSWe thank the participating patients and their families, as well as the global network of research nurses, trial coordinators, and operations staff for their contributions, and investigators who participated in this trial, including: M. Michael (Australia); X. Yu, Y. Shen and L. Jia (China); P. Hammel (France); S. Skrikhande (India); C. Morizane (Japan); J. Sufliarsky (Slovakia); and G. Khan (United States). This study was sponsored by Pfizer. Medical writing support was provided by Mariko Nagashima, PhD, of Engage Scientific Solutions, and was funded by Pfizer.

Copyright © 2016






• The trial was terminated early after more-serious adverse events (AEs) and deaths were observed in the placebo arm and a difference in PFS favored the sunitinib arm (hazard ratio [HR] 0.42, 95% confidence interval [CI], 0.26–0.66; P<0.001; median: 11.4 vs 5.5 months).

– Sunitinib treatment was also associated with longer overall survival (OS) vs placebo (HR 0.41, 95% CI, 0.19–0.89; P=0.02).




METHODSStudy Design




Key Eligibility Criteria • Histologically or cytologically confirmed, well-differentiated,

unresectable or metastatic pNETs with documented progression within 12 months of study enrollment.




• No pre-existing uncontrolled hypertension (ie, blood pressure >150/100 mmHg despite medical therapy)



daily-dosing regimen.

– Sunitinib dose could be increased to 50 mg daily any time after 8 weeks of treatment initiation in patients without treatment response, who experienced only grade 1 or lower nonhematologic or grade 2 or lower hematologic treatment-related AEs.





Statistical Analyses • More than 80 patients were to be enrolled: 40 treatment-naïve

(defined as those who never received systemic antitumor therapy; somatostatin analogs for symptomatic control was allowed) and 40 previously treated patients.



RESULTSPatients


Figure 1. Trial profile






Efficacy Analysis: 61 txt-naïve patientsSafety Analysis: 61 txt-naïve patients


AE=adverse event; Txt=treatment




• Median (range) treatment duration in the total population was 357.5 days (7–1226): 371.0 days (7–1092) in treatment-naïve vs 309.0 days (14–1226) in previously treated patients.

Efficacy • Median PFS assessed by investigators was 13.2 months (95% CI,

10.9–16.7); median PFS was similar in treatment-naïve and previously treated patients (13.2 months [95% CI, 7.4–16.8] and 13.0 months [95% CI, 9.2–20.4], respectively; Figure 2).



Table 1. Demographics and patient baseline characteristics

Characteristics


Previously Treated

n=45Total

N=106Age, years, mean (SD) 55.4 (8.9) 53.5 (9.1) 54.6 (9.0)Gender, n (%) Male 30 (49.2) 33 (73.3) 63 (59.4) Female 31 (50.8) 12 (26.7) 43 (40.6) Race, n (%) White 32 (52.5) 35 (77.8) 67 (63.2) Black 2 (3.3) 0 2 (1.9) Asian 27 (44.3) 10 (22.2) 37 (34.9)ECOG PS, n (%) 0 39 (63.9) 29 (64.4) 68 (64.2) 1 22 (36.1) 16 (35.6) 38 (35.8)No. of involved disease site,* n (%) 1 24 (39.3) 9 (20.0) 33 (31.1) 2 19 (31.1) 22 (48.9) 41 (38.7) 3 11 (18.0) 8 (17.8) 19 (17.9) ≥4 7 (11.5) 6 (13.3) 13 (12.3)Tumor site,* n (%) Liver 57 (93.4) 41 (91.1) 98 (92.5) Pancreas 22 (36.1) 25 (55.6) 47 (44.3) Lymph node, distant 16 (26.2) 13 (28.9) 29 (27.4) Lymph node, regional 13 (21.3) 7 (15.6) 20 (18.9) Lung 3 (4.9) 3 (6.7) 6 (5.7)Prior systemic chemotherapy, n (%) Any 0 45 (100) 45 (42.5) Neoadjuvant 0 2 (4.4) 2 (1.9) Adjuvant 0 4 (8.9) 4 (3.8) Advanced/metastatic 0 39 (86.7) 39 (36.8)Prior SSA,† n (%) 24 (39.3) 27 (60.0) 51 (48.1)Ki-67 index, mean (SD) 6.72 (5.009) 8.35 (7.179) 7.41 (6.049)* Included both target and nontarget sites; sites with multiple lesions were counted once.† Patients with regimens that consist only of somatostatin analogs were considered treatment-naïve.ECOG PS, Eastern Cooperative Oncology Group performance status; SD=standard deviation; SSA=somatostatin analogs

Figure 2. Kaplan–Meier estimates of PFS in treatment-naïve and previously treated patients with pNETs assessed by the investigators

PFS

Dist

ribut

ion

Func

tion

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 5 10 15 20 25

Time (months)No. at risk:

Treatment-naivePreviously treated

6145

4129

3220

1410

88

64

04

02

01

00

30 35 40 45



CI=confidence interval; mPFS=median progression-free survival; PFS=progression-free survival; pNETs=pancreatic neuroendocrine tumors


•

Table 2. Best observed response by RECIST, assessed by investigators


Previously Treated

n=45Total

N=106Best overall response, n (%) Complete response 2 (3.3) 1 (2.2) 3 (2.8) Partial response 11 (18.0) 12 (26.7) 23 (21.7) Stable disease 40 (65.6) 29 (64.4) 69 (65.1) Progressive disease 7 (11.5) 2 (4.4) 9 (8.5) Indeterminate 1 (1.6) 1 (2.2) 2 (1.9)ORR,* n (%) 13 (21.3) 13 (28.9) 26 (24.5) 95% CI 11.9–33.7 16.4–44.3 16.7–33.8* Complete response + partial response. CI=confidence interval; ORR=objective response rate; RECIST=Response Evaluation Criteria in Solid Tumors


• OS data were not mature at the time of data cutoff date (Mar 19, 2016); 29 (27.4%) patients had died and median OS was 37.8 months (95% CI, 33.0–not estimable).

Safety • Most-common treatment-emergent, all-grade AEs experienced by all

patients treated with sunitinib included neutropenia, diarrhea, and leukopenia (Table 3).


• Percentage of treatment-naïve and previously treated patients who experienced Grade 3 or 4 AEs was comparable; serious AEs were also comparable: 25% (n=15) vs 24% (n=11), respectively.

• 15 (25%) treatment-naïve and 5 (11%) previously treated patients had sunitinib dose reductions due to AEs; 8 (13%) and 10 (22%) patients, rectively, discontinued treatment due to AEs.

Presented at the 14th Annual European Neuroendocrine Tumor Society (ENETS) Conference, March 8–10, 2017, Barcelona, Spain

CONCLUSIONS n Median PFS of 13.2 months (95% CI, 10.9–16.7) and ORR of 24.5% (95% CI, 16.7–33.8) observed in this phase IV trial support the outcomes of the pivotal phase III trial of sunitinib in pNETs and confirm its activity in this setting.




The Efficacy and Safety of Sunitinib in Patients With Advanced Well-Differentiated Pancreatic Neuroendocrine Tumors: Focus on Response RateE Raymond1, MH Kulke2, S Qin3, X Yu4, M Schenker5, A Cubillo6, W Lou7, J Tomasek8, E Thiis-Evensen9, K Fernandez10, B Rosbrook11, N Fazio12

1Paris Saint-Joseph Hospital Group, Paris, France; 2Dana-Farber Cancer Institute, Boston, MA, USA; 3PLA Cancer Center of Nanjing Bayi Hospital, Nanjing, China; 4Fudan University Shanghai Cancer Center, Shanghai, China; 5Centrul de Oncologie Sf. Nectarie, Oncologie Medicala, Craiova, Romania; 6Hospital Universitario Madrid Sanchinarro, Centro Integral Oncológico Clara Campal, Madrid, Spain; 7Zhongshan Hospital, Fudan University, Shanghai, China; 8Masarykuv onkologicky ustav/Klinika komplexní onkologické péče, Brno, Czech Republic; 9Oslo University Hospital, Department of Gastroenterology, Rikshospitalet, Oslo, Norway; 10Pfizer Inc, Cambridge, MA, USA; 11Pfizer Inc, San Diego, CA, USA; 12IEO, European Institute of Oncology, Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, Milan, Italy

REFERENCES1. American Cancer Society. Cancer Facts & Figures 2016. Atlanta, GA.2. Raymond E, et al. N Engl J Med 2011;364:501-13.3. Faivre S, et al. Ann Oncol 2016; Nov 10 [Epub ahead of print]. 4. Sutent® (sunitinib malate) prescribing information. New York, NY: Pfizer Inc; 2015.

ACKNOWLEDGMENTSWe thank the participating patients and their families, as well as the global network of research nurses, trial coordinators, and operations staff for their contributions, and investigators who participated in this trial, including: M. Michael (Australia); X. Yu, Y. Shen and L. Jia (China); P. Hammel (France); S. Skrikhande (India); C. Morizane (Japan); J. Sufliarsky (Slovakia); and G. Khan (United States). This study was sponsored by Pfizer. Medical writing support was provided by Mariko Nagashima, PhD, and Anne Marie Reid, PhD, of Engage Scientific Solutions, and was funded by Pfizer. Previously presented in part at the 2017 American Society of Clinical Oncology Gastrointestinal Cancer Symposium (ASCO GI), January 19–21, 2017, San Francisco, CA

For information on this poster, contact Eric Raymond, [email protected]

Copyright © 2017






• The trial was terminated early after more-serious adverse events (AEs) and deaths were observed in the placebo arm and a difference in PFS favored the sunitinib arm (hazard ratio [HR] 0.42; 95% confidence interval [CI], 0.26–0.66; P<0.001; median: 11.4 vs 5.5 months).

– The median (95% CI) 5-year overall survival (OS) was 38.6 (25.6–56.4) months for sunitinib and 29.1 (16.4–36.8) months for placebo (HR 0.73; 95% CI, 0.50–1.06; P=0.094), with 69% of placebo patients having crossed over to sunitinib.3




METHODSStudy Design

• This multinational, single-arm, open-label, phase IV clinical trial is ongoing. • The primary endpoint is investigator-assessed PFS per the Response

Evaluation Criteria in Solid Tumors (RECIST) v1.0. • Secondary endpoints include PFS assessed by the independent radiologic

review and per Choi criteria, time to tumor progression (TTP), objective response rate (ORR), OS, and safety.

Key Eligibility Criteria • Histologically or cytologically confirmed, well-differentiated, unresectable or

metastatic pNETs with documented progression within 12 months of study enrollment.


• Presence of ≥1 measurable target lesion per RECIST v1.0. • Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1. • No pre-existing uncontrolled hypertension (ie, blood pressure >150/100

mmHg despite medical therapy). • No prior treatment with TKIs, anti-VEGF, or other angiogenesis inhibitors.

Treatment and Assessments • Patients received 37.5 mg sunitinib orally once a day on a continuous daily

dosing regimen. – Sunitinib dose could be increased to 50 mg daily any time after 8 weeks

of treatment initiation in patients without treatment response who experienced only grade 1 or lower nonhematologic or grade 2 or lower hematologic treatment-related AEs.





Statistical Analyses • More than 80 patients were to be enrolled: 40 treatment-naïve (defined

as those who never received systemic antitumor therapy; somatostatin analogs for symptomatic control were allowed) and 40 previously treated patients.



RESULTSPatients




Figure 1: Trial Profile






Efficacy analysis: 61 txt-naïve patientsSafety analysis: 61 txt-naïve patients


AE=adverse event; txt=treatment


• Median (range) treatment duration in the total population was 11.7 months (0.2–40.3): 12.2 months (0.2–35.9) in treatment-naïve vs 10.2 months (0.5–40.3) in previously treated patients.

Efficacy • Median (95% CI) PFS as assessed by investigators was 13.2 months

(10.9–16.7); median (95% CI) PFS was similar in treatment-naïve and previously treated patients (13.2 months [7.4–16.8] and 13.0 months [9.2–20.4], respectively).

• Median (95% CI) PFS per Choi criteria was 18.7 months (5.6–not estimable) and 16.5 months (7.4–22.9) in treatment-naïve and previously treated patients, respectively (Figure 2).

• Median (95% CI) PFS as assessed by independent radiological review was 11.1 months (7.4–16.6), in treatment-naive patients 11.1 months (5.5–16.7), and in previously treated patients 9.5 months (7.4–18.4).


Table 1: Demographics and Patient Baseline Characteristics

CharacteristicsTreatment-Naïve

n=61Previously Treated

n=45Total

N=106Age, years, mean (SD) 55.4 (8.9) 53.5 (9.1) 54.6 (9.0)Gender, n (%) Male 30 (49.2) 33 (73.3) 63 (59.4) Female 31 (50.8) 12 (26.7) 43 (40.6) Race, n (%) White 32 (52.5) 35 (77.8) 67 (63.2) Black 2 (3.3) 0 2 (1.9) Asian 27 (44.3) 10 (22.2) 37 (34.9)ECOG PS, n (%) 0 39 (63.9) 29 (64.4) 68 (64.2) 1 22 (36.1) 16 (35.6) 38 (35.8)No. of involved disease sites,* n (%) 1 24 (39.3) 9 (20.0) 33 (31.1) 2 19 (31.1) 22 (48.9) 41 (38.7) 3 11 (18.0) 8 (17.8) 19 (17.9) 4 3 (4.9) 3 (6.7) 6 (5.7) >4 4 (6.6) 3 (6.7) 7 (6.6) Tumor site,* n (%) Liver 57 (93.4) 41 (91.1) 98 (92.5) Pancreas 22 (36.1) 25 (55.6) 47 (44.3) Lymph node, distant 16 (26.2) 13 (28.9) 29 (27.4) Lymph node, regional 13 (21.3) 7 (15.6) 20 (18.9) Lung 3 (4.9) 3 (6.7) 6 (5.7) Other 10 (16.4) 10 (22.2) 20 (18.9)

Any prior systemic chemotherapy, n (%)

0 45 (100) 45 (42.5)

Prior SSA, n (%) 24 (39.3) 27 (60.0) 51 (48.1)Ki-67 index, mean (SD) 6.7 (5.0) 8.4 (7.2) 7.4 (6.0)* Included both target and nontarget sites; sites with multiple lesions were counted once.ECOG PS, Eastern Cooperative Oncology Group performance status; SD=standard deviation; SSA=somatostatin analogs

Figure 2: Kaplan–Meier Estimates of PFS Based on the Independent Third-Party Radiology According to Choi Criteria PFS in Treatment-Naïve and Previously Treated Patients With pNETs

PF

S D

istr

ibu

tio

n F

un

cti

on

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 5 10 15 20 25

Time (Months)No. at risk:

Treatment-naïvePreviously treated

6145

2925

2217

1111

68

45

14

02

00

00

30 35 40 45

Treatment-naïve 61 25 18.7 (5.6–NE)Previously treated 45 24 16.5 (7.4–22.9)


CI=confidence interval; mPFS=median progression-free survival; PFS=progression-free survival; NE=not estimable; pNET=pancreatic neuroendocrine tumor

• ORR (95% CI) was 24.5% (16.7–33.8) according to the investigator assessment.

• The ORR (95% CI) per Choi criteria was higher than the ORR per RECIST: 52.5% (39.3–65.4) and 55.6% (40.0–70.4) in treatment-naïve and previously treated patients, respectively (Table 2).

•

Table 2: Best Observed Response Based on Independent Third-Party Radiology According to Choi Criteria in Treatment-Naïve and Previously Treated Patients With pNETs

Treatment-Naïve


n=45Best overall response, n (%) Complete response 0 1 (2.2) Partial response 32 (52.5) 24 (53.3) Stable disease 12 (19.7) 17 (37.8) Progressive disease 9 (14.8) 2 (4.4) Indeterminate 8 (13.1) 1 (2.2)ORR,* n (%) 32 (52.5) 25 (55.6) 95% CI 39.3–65.4 40.0–70.4* Complete response + partial response. CI=confidence interval; ORR=objective response rate; pNET=pancreatic neuroendocrine tumor; RECIST=Response Evaluation Criteria in Solid Tumors

Median (95% CI) TTP was 14.5 months (11.0–16.7); median (95% CI) TTP in treatment-naïve and previously treated patients was similar (14.8 [7.5–16.8] and 14.5 [9.2–20.4] months, respectively).

– According to the Choi criteria, the median (95% CI) TTP was 18.7 months (5.6–not estimable) for treatment-naïve patients and 16.7 months (7.4–30.9) for previously treated patients.

• OS data were not mature at the time of data cutoff date (March 19, 2016); 29 (27.4%) patients had died and median (95% CI) OS was 37.8 months (33.0–not estimable).

Safety • Most-common treatment-emergent, all-grade AEs experienced by all patients

treated with sunitinib included neutropenia, diarrhea, and leukopenia (Table 3).


• Percentage of treatment-naïve and previously treated patients who experienced Grade 3 or 4 AEs was comparable; serious AEs were also comparable: 24.6% (n=15) vs 24.4% (n=11), respectively.

• 15 (24.6%) treatment-naïve and 5 (11.1%) previously treated patients had sunitinib dose reductions due to AEs; 8 (13.1%) and 10 (22.2%) patients, respectively, discontinued treatment due to AEs.

Table 3: Treatment-Emergent, All-Causality Adverse Events

Adverse Events,* n (%)

Treatment-Naïven=61

Previously Treatedn=45

TotalN=106

All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4Neutropenia 37 (60.7) 13 (21.3) 22 (48.9) 10 (22.2) 59 (55.7) 23 (21.7)Diarrhea 32 (52.5) 7 (11.5) 22 (48.9) 3 (6.7) 54 (50.9) 10 (9.4)Leukopenia 25 (41.0) 4 (6.6) 21 (46.7) 3 (6.7) 46 (43.4) 7 (6.6)Fatigue 19 (31.1) 1 (1.6) 14 (31.1) 0 (0.0) 33 (31.1) 1 (0.9)Hand–foot syndrome 19 (31.1) 5 (8.2) 14 (31.1) 2 (4.4) 33 (31.1) 7 (6.6)Thrombocytopenia 18 (29.5) 6 (9.8) 14 (31.1) 2 (4.4) 32 (30.2) 8 (7.5)Hypertension 16 (26.2) 4 (6.6) 11 (24.4) 2 (4.4) 27 (25.5) 6 (5.7)Abdominal pain 16 (26.2) 2 (3.3) 10 (22.2) 3 (6.7) 26 (24.5) 5 (4.7)Dysgeusia 14 (23.0) 0 (0.0) 11 (24.4) 0 (0.0) 25 (23.6) 0 (0.0)Nausea 11 (18.0) 0 (0.0) 14 (31.1) 1 (2.2) 25 (23.6) 1 (0.9)Dyspepsia 7 (11.5) 0 (0.0) 14 (31.1) 0 (0.0) 21 (19.8) 0 (0.0)Headache 12 (19.7) 0 (0.0) 9 (20.0) 0 (0.0) 21 (19.8) 0 (0.0)Stomatitis 13 (21.3) 2 (3.3) 6 (13.3) 1 (2.2) 19 (17.9) 3 (2.8)Vomiting 8 (13.1) 1 (1.6) 10 (22.2) 1 (2.2) 18 (17.0) 2 (1.9)Asthenia 10 (16.4) 0 (0.0) 7 (15.6) 2 (4.4) 17 (16.0) 2 (1.9)Abdominal pain upper 5 (8.2) 1 (1.6) 7 (15.6) 1 (2.2) 12 (11.3) 2 (1.9)ALT increased 2 (3.3) 1 (1.6) 9 (20.0) 0 (0.0) 11 (10.4) 1 (0.9)AST increased 4 (6.6) 1 (1.6) 7 (15.6) 1 (2.2) 11 (10.4) 2 (1.9)Constipation 3 (4.9) 0 (0.0) 7 (15.6) 0 (0.0) 10 (9.4) 0 (0.0)Dizziness 3 (4.9) 0 (0.0) 7 (15.6) 0 (0.0) 10 (9.4) 0 (0.0)Hypophosphatemia 2 (3.3) 2 (3.3) 7 (15.6) 3 (6.7) 9 (8.5) 5 (4.7)Myalgia 2 (3.3) 0 (0.0) 7 (15.6) 0 (0.0) 9 (8.5) 0 (0.0)Adverse events are listed by highest to lowest % for Total/All Grades patients. * Adverse events reported by ≥15% in any treatment group per MedDRA criteria. ALT=alanine aminotransferase; AST=aspartate aminotransferase; MedDRA=Medical Dictionary for Regulatory Activities

Presented at the 2017 American Society of Clinical Oncology Gastrointestinal Cancer Symposium (ASCO GI), January 19–21, 2017, San Francisco, CA

CONCLUSIONS n Median PFS of 13.2 months (95% CI, 10.9–16.7) and ORR of 24.5% (95% CI,

16.7–33.8) observed in this phase IV trial support the outcomes of the pivotal phase III trial of sunitinib in pNETs and confi rm its activity in this setting.


n AEs were consistent with the known safety profi le of sunitinib.

n The study confi rmed sunitinib is an effi cacious and safe treatment option in progressive, locally advanced and/or metastatic, well-differentiated, unresectable pNETs.

The Effi cacy and Safety of Sunitinib in Patients With Advanced Well-Differentiated Pancreatic Neuroendocrine TumorsEric Raymond1, Matthew H Kulke2, Shukui Qin3, Michael Schenker4, Antonio Cubillo5, Wenhui Lou6, Jiri Tomasek7, Espen Thiis-Evensen8, Jianming Xu9, Karoly Racz10, Adina E Croitoru11, Mustafa Khasraw12, Eva Sedlackova13, Ivan Borbath14, Paul Ruff15, Paul E Oberstein16, Tetsuhide Ito17, Kathrine C Fernandez18, Brad Rosbrook19, Nicola Fazio20 1Paris Saint-Joseph Hospital Group, Paris, France; 2Dana-Farber Cancer Institute, Boston, MA, USA; 3PLA Cancer Center of Nanjing Bayi Hospital, Nanjing, China; 4Centrul de Oncologie Sf. Nectarie, Oncologie Medicala, Craiova, Romania; 5Hospital Universitario Madrid Sanchinarro, Centro Integral Oncológico Clara Campal, Madrid, Spain; 6Zhongshan Hospital, Fudan University, Shanghai, China; 7Masaryk Memorial Cancer Institute, Faculty of Medicine, Masaryk University, Brno, Czech Republic; 8Oslo University Hospital, Department of Gastroenterology, Rikshospitalet, Oslo, Norway; 9No.307 Hospital, Academy of Military Medical Sciences, Beijing, China; 10Semmelweis University, Faculty of Medicine, 2nd Department of Internal Medicine, Budapest, Hungary; 11Fundeni Clinical Institute, Department of Medical Oncology, Bucharest, Romania; 12Andrew Love Cancer Center, Geelong Hospital, Victoria, Australia; 13Všeobecné Fakultní Nemocnice v Praze Onkologická Klinika, Praha, Czech Republic; 14Cliniques Universitaires Saint-Luc, King Albert II Institute Cancerology and Hematology, Brussels, Belgium; 15University of the Witwatersrand, Faculty of Health Sciences, Johannesburg, South Africa; 16Columbia University Medical Center, Division of Hematology/Oncology, New York, NY, USA; 17Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 18Pfi zer Inc, Cambridge, MA, USA; 19Pfi zer Inc, San Diego, CA, USA; 20IEO, European Institute of Oncology, Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, Milan, Italy

380

REFERENCES1. American Cancer Society. Cancer Facts & Figures 2016. Atlanta, GA.2. Raymond E, et al. N Engl J Med 2011;364:501-13.3. Faivre S, et al. Ann Oncol 2016; Nov 10 [Epub ahead of print]. 4. Sutent® (sunitinib malate) prescribing information. New York, NY: Pfi zer Inc; 2015.

ACKNOWLEDGMENTSWe thank the participating patients and their families, as well as the global network of research nurses, trial coordinators, and operations staff for their contributions, and investigators who participated in this trial, including: M. Michael (Australia); X. Yu, Y. Shen and L. Jia (China); P. Hammel (France); S. Skrikhande (India); C. Morizane (Japan); J. Sufl iarsky (Slovakia); and G. Khan (United States). This study was sponsored by Pfi zer. Medical writing support was provided by Mariko Nagashima, PhD, and Anne Marie Reid, PhD, of Engage Scientifi c Solutions, and was funded by Pfi zer.

For information on this poster, contact Eric Raymond, [email protected]

Copyright © 2017

INTRODUCTION • Pancreatic neuroendocrine tumors (pNETs) are rare tumors. Of an estimated

53,070 new cases of pancreatic cancers expected in the US in 2016, pNETs account for fewer than 5%.1



• Sunitinib, a multi-targeted tyrosine kinase inhibitor (TKI) of angiogenesis, showed a signifi cant increase in progression-free survival (PFS) over placebo in well-differentiated, advanced and/or metastatic pNETs in a pivotal phase III clinical trial (ClinicalTrials.gov NCT00428597).2

• The trial was terminated early after more-serious adverse events (AEs) and deaths were observed in the placebo arm and a difference in PFS favored the sunitinib arm (hazard ratio [HR] 0.42; 95% confi dence interval [CI], 0.26–0.66; P<0.001; median: 11.4 vs 5.5 months).



OBJECTIVES • This phase IV clinical trial (ClinicalTrials.gov NCT01525550) was conducted

as post-approval commitments to the FDA and other regulatory agencies to confi rm the effi cacy and safety of sunitinib in advanced and/or metastatic, well-differentiated, unresectable pNETs.

METHODSStudy Design




Key Eligibility Criteria • Histologically or cytologically confi rmed, well-differentiated, unresectable or





• No pre-existing uncontrolled hypertension (ie, blood pressure >150/100 mmHg despite medical therapy).


Treatment and Assessments • Patients received 37.5 mg sunitinib orally once a day on a continuous daily-dosing

regimen.

– Sunitinib dose could be increased to 50 mg daily any time after 8 weeks of treatment initiation in patients without treatment response who experienced only grade 1 or lower nonhematologic or grade 2 or lower hematologic treatment-related AEs.





Statistical Analyses • More than 80 patients were to be enrolled: 40 treatment-naïve (defi ned as

those who never received systemic antitumor therapy; somatostatin analogs for symptomatic control were allowed) and 40 previously treated patients.



RESULTSPatients


Figure 1: Trial Profi le













Effi cacy • Median PFS as assessed by investigators was 13.2 months (95% CI, 10.9–16.7);

median PFS was similar in treatment-naïve and previously treated patients (13.2 months [95% CI, 7.4–16.8] and 13.0 months [95% CI, 9.2–20.4], respectively; Figure 2).




Characteristics


Previously Treated

n=45Total

N=106

Age, years, mean (SD) 55.4 (8.9) 53.5 (9.1) 54.6 (9.0)

Gender, n (%)

Male 30 (49.2) 33 (73.3) 63 (59.4)

Female 31 (50.8) 12 (26.7) 43 (40.6)

Race, n (%)

White 32 (52.5) 35 (77.8) 67 (63.2)

Black 2 (3.3) 0 2 (1.9)

Asian 27 (44.3) 10 (22.2) 37 (34.9)

ECOG PS, n (%)

0 39 (63.9) 29 (64.4) 68 (64.2)

1 22 (36.1) 16 (35.6) 38 (35.8)

No. of involved disease sites,* n (%)

1 24 (39.3) 9 (20.0) 33 (31.1)

2 19 (31.1) 22 (48.9) 41 (38.7)

3 11 (18.0) 8 (17.8) 19 (17.9)

4 3 (4.9) 3 (6.7) 6 (5.7)

>4 4 (6.6) 3 (6.7) 7 (6.6)

Tumor site,* n (%)

Liver 57 (93.4) 41 (91.1) 98 (92.5)

Pancreas 22 (36.1) 25 (55.6) 47 (44.3)

Lymph node, distant 16 (26.2) 13 (28.9) 29 (27.4)

Lymph node, regional 13 (21.3) 7 (15.6) 20 (18.9)

Lung 3 (4.9) 3 (6.7) 6 (5.7)

Other 10 (16.4) 10 (22.2) 20 (18.9)

Any prior systemic chemotherapy, n (%) 0 45 (100) 45 (42.5)

Prior SSA, n (%) 24 (39.3) 27 (60.0) 51 (48.1)

Ki-67 index, mean (SD) 6.7 (5.0) 8.4 (7.2) 7.4 (6.0)* Included both target and nontarget sites; sites with multiple lesions were counted once.ECOG PS, Eastern Cooperative Oncology Group performance status; SD=standard deviation; SSA=somatostatin analogs

Figure 2: Kaplan–Meier Estimates of PFS in Treatment-Naïve and Previously Treated Patients With pNETs, Assessed by Investigators

PFS

Dis

trib

utio

n Fu

ncti

on

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 5 10 15 20 25



6145

4129

3220

1410

88

64

04

02

01

00

30 35 40 45



CI=confi dence interval; mPFS=median progression-free survival; PFS=progression-free survival; pNETs=pancreatic neuroendocrine tumors


•

Table 2: Best Observed Response by RECIST, Assessed by Investigators

Treatment-naïve

n=61

Previously Treated

n=45Total

N=106

Best overall response, n (%)

Complete response 2 (3.3) 1 (2.2) 3 (2.8)

Partial response 11 (18.0) 12 (26.7) 23 (21.7)

Stable disease 40 (65.6) 29 (64.4) 69 (65.1)

Progressive disease 7 (11.5) 2 (4.4) 9 (8.5)

Indeterminate 1 (1.6) 1 (2.2) 2 (1.9)

ORR,* n (%) 13 (21.3) 13 (28.9) 26 (24.5)

95% CI 11.9–33.7 16.4–44.3 16.7–33.8* Complete response + partial response. CI=confi dence interval; ORR=objective response rate; RECIST=Response Evaluation Criteria in Solid Tumors


• OS data were not mature at the time of data cutoff date (March 19, 2016); 29 (27.4%) patients had died and median OS was 37.8 months (95% CI, 33.0–not estimable).

Safety • Most-common treatment-emergent, all-grade AEs experienced by all patients treated

with sunitinib included neutropenia, diarrhea, and leukopenia (Table 3). – No major differences were observed in the incidence of AEs reported by treatment-

naïve vs previously treated patients, except dyspepsia, nausea, and neutropenia. • Percentage of treatment-naïve and previously treated patients who experienced

Grade 3 or 4 AEs was comparable; serious AEs were also comparable: 24.6% (n=15) vs 24.4% (n=11), respectively.


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TotalN=106

All Grades

Grade 3/4

All Grades

Grade 3/4

All Grades

Grade 3/4

Neutropenia 37 (60.7) 13 (21.3) 22 (48.9) 10 (22.2) 59 (55.7) 23 (21.7)Diarrhea 32 (52.5) 7 (11.5) 22 (48.9) 3 (6.7) 54 (50.9) 10 (9.4)Leukopenia 25 (41.0) 4 (6.6) 21 (46.7) 3 (6.7) 46 (43.4) 7 (6.6)Fatigue 19 (31.1) 1 (1.6) 14 (31.1) 0 (0.0) 33 (31.1) 1 (0.9)Hand–foot syndrome 19 (31.1) 5 (8.2) 14 (31.1) 2 (4.4) 33 (31.1) 7 (6.6)Thrombocytopenia 18 (29.5) 6 (9.8) 14 (31.1) 2 (4.4) 32 (30.2) 8 (7.5)Hypertension 16 (26.2) 4 (6.6) 11 (24.4) 2 (4.4) 27 (25.5) 6 (5.7)Abdominal pain 16 (26.2) 2 (3.3) 10 (22.2) 3 (6.7) 26 (24.5) 5 (4.7)Dysgeusia 14 (23.0) 0 (0.0) 11 (24.4) 0 (0.0) 25 (23.6) 0 (0.0)Nausea 11 (18.0) 0 (0.0) 14 (31.1) 1 (2.2) 25 (23.6) 1 (0.9)Dyspepsia 7 (11.5) 0 (0.0) 14 (31.1) 0 (0.0) 21 (19.8) 0 (0.0)Headache 12 (19.7) 0 (0.0) 9 (20.0) 0 (0.0) 21 (19.8) 0 (0.0)Stomatitis 13 (21.3) 2 (3.3) 6 (13.3) 1 (2.2) 19 (17.9) 3 (2.8)Vomiting 8 (13.1) 1 (1.6) 10 (22.2) 1 (2.2) 18 (17.0) 2 (1.9)Asthenia 10 (16.4) 0 (0.0) 7 (15.6) 2 (4.4) 17 (16.0) 2 (1.9)Abdominal pain upper 5 (8.2) 1 (1.6) 7 (15.6) 1 (2.2) 12 (11.3) 2 (1.9)ALT increased 2 (3.3) 1 (1.6) 9 (20.0) 0 (0.0) 11 (10.4) 1 (0.9)AST increased 4 (6.6) 1 (1.6) 7 (15.6) 1 (2.2) 11 (10.4) 2 (1.9)Constipation 3 (4.9) 0 (0.0) 7 (15.6) 0 (0.0) 10 (9.4) 0 (0.0)Dizziness 3 (4.9) 0 (0.0) 7 (15.6) 0 (0.0) 10 (9.4) 0 (0.0)Hypophosphatemia 2 (3.3) 2 (3.3) 7 (15.6) 3 (6.7) 9 (8.5) 5 (4.7)Myalgia 2 (3.3) 0 (0.0) 7 (15.6) 0 (0.0) 9 (8.5) 0 (0.0)Adverse events are listed by highest to lowest % for Total/All Grades patients.* Adverse events reported by ≥15% in any treatment group per MedDRA criteria.ALT=alanine aminotransferase; AST=aspartate aminotransferase; MedDRA=Medical Dictionary for Regulatory Activities

TTP 14.8 14.5 TTP 18.7 16.7

Raymond et al., ENETS 2017, Poster session

RECIST-based Choi-based

Presented at the 14th Annual European Neuroendocrine Tumor Society (ENETS) Conference, March 8–10, 2017, Barcelona, Spain

CONCLUSIONS n Median PFS of 13.2 months (95% CI, 10.9–16.7) and ORR of 24.5% (95% CI, 16.7–33.8) observed in this phase IV trial support the outcomes of the pivotal phase III trial of sunitinib in pNETs and confirm its activity in this setting.




The Efficacy and Safety of Sunitinib in Patients With Advanced Well-Differentiated Pancreatic Neuroendocrine Tumors: Focus on Response RateE Raymond1, MH Kulke2, S Qin3, X Yu4, M Schenker5, A Cubillo6, W Lou7, J Tomasek8, E Thiis-Evensen9, K Fernandez10, B Rosbrook11, N Fazio12

1Paris Saint-Joseph Hospital Group, Paris, France; 2Dana-Farber Cancer Institute, Boston, MA, USA; 3PLA Cancer Center of Nanjing Bayi Hospital, Nanjing, China; 4Fudan University Shanghai Cancer Center, Shanghai, China; 5Centrul de Oncologie Sf. Nectarie, Oncologie Medicala, Craiova, Romania; 6Hospital Universitario Madrid Sanchinarro, Centro Integral Oncológico Clara Campal, Madrid, Spain; 7Zhongshan Hospital, Fudan University, Shanghai, China; 8Masarykuv onkologicky ustav/Klinika komplexní onkologické péče, Brno, Czech Republic; 9Oslo University Hospital, Department of Gastroenterology, Rikshospitalet, Oslo, Norway; 10Pfizer Inc, Cambridge, MA, USA; 11Pfizer Inc, San Diego, CA, USA; 12IEO, European Institute of Oncology, Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, Milan, Italy

REFERENCES1. American Cancer Society. Cancer Facts & Figures 2016. Atlanta, GA.2. Raymond E, et al. N Engl J Med 2011;364:501-13.3. Faivre S, et al. Ann Oncol 2016; Nov 10 [Epub ahead of print]. 4. Sutent® (sunitinib malate) prescribing information. New York, NY: Pfizer Inc; 2015.

ACKNOWLEDGMENTSWe thank the participating patients and their families, as well as the global network of research nurses, trial coordinators, and operations staff for their contributions, and investigators who participated in this trial, including: M. Michael (Australia); X. Yu, Y. Shen, and L. Jia (China); P. Hammel (France); S. Skrikhande (India); C. Morizane (Japan); J. Sufliarsky (Slovakia); and G. Khan (United States). This study was sponsored by Pfizer. Medical writing support was provided by Mariko Nagashima, PhD, and Anne Marie Reid, PhD, of Engage Scientific Solutions, and was funded by Pfizer. Presented in part at the 2017 American Society of Clinical Oncology Gastrointestinal Cancer Symposium (ASCO GI), January 19–21, 2017, San Francisco, CAFor information on this poster, contact Eric Raymond, [email protected] © 2017






• The trial was terminated early after more-serious adverse events (AEs) and deaths were observed in the placebo arm and a difference in PFS favored the sunitinib arm (hazard ratio [HR] 0.42; 95% confidence interval [CI], 0.26–0.66; P<0.001; median: 11.4 vs 5.5 months).





METHODSStudy Design

• This multinational, single-arm, open-label, phase IV clinical trial is ongoing. • The primary endpoint is investigator-assessed PFS per the Response

Evaluation Criteria in Solid Tumors (RECIST) v1.0. • Secondary endpoints include PFS assessed by the independent radiologic

review and per Choi criteria, time to tumor progression (TTP), objective response rate (ORR), OS, and safety.

Key Eligibility Criteria • Histologically or cytologically confirmed, well-differentiated, unresectable or



• Presence of ≥1 measurable target lesion per RECIST v1.0. • Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1. • No pre-existing uncontrolled hypertension (ie, blood pressure >150/100 mmHg

despite medical therapy). • No prior treatment with TKIs, anti-VEGF, or other angiogenesis inhibitors.


daily-dosing regimen. – Sunitinib dose could be increased to 50 mg daily any time after 8 weeks

of treatment initiation in patients without treatment response who experienced only grade 1 or lower nonhematologic or grade 2 or lower hematologic treatment-related AEs.





Statistical Analyses • More than 80 patients were to be enrolled: 40 treatment-naïve (defined

as those who never received systemic antitumor therapy; somatostatin analogs for symptomatic control were allowed) and 40 previously treated patients.



RESULTSPatients




Figure 1: Trial Profile









• In regard to prior locoregional treatment, 18.9% of patients had transarterial chemoembolization; radiofrequency ablation (3.8%); or trans-arterial embolization, percutaneous injections, or microwave ablation (2.8% each).


Efficacy • Median (95% CI) PFS as assessed by investigators was 13.2 months

(10.9–16.7); median (95% CI) PFS was similar in treatment-naïve and previously treated patients (13.2 months [7.4–16.8] and 13.0 months [9.2–20.4], respectively).

• Median (95% CI) PFS per Choi criteria was 18.7 months (5.6–not estimable) and 16.5 months (7.4–22.9) in treatment-naïve and previously treated patients, respectively (Figure 2).

• Median (95% CI) PFS as assessed by independent radiological review was 11.1 months (7.4–16.6), in treatment-naive patients 11.1 months (5.5–16.7), and in previously treated patients 9.5 months (7.4–18.4).



CharacteristicsTreatment-Naïve


n=45Total

N=106Age, years, mean (SD) 55.4 (8.9) 53.5 (9.1) 54.6 (9.0)Gender, n (%) Male 30 (49.2) 33 (73.3) 63 (59.4) Female 31 (50.8) 12 (26.7) 43 (40.6) Race, n (%) White 32 (52.5) 35 (77.8) 67 (63.2) Black 2 (3.3) 0 2 (1.9) Asian 27 (44.3) 10 (22.2) 37 (34.9)ECOG PS, n (%) 0 39 (63.9) 29 (64.4) 68 (64.2) 1 22 (36.1) 16 (35.6) 38 (35.8)No. of involved disease sites,* n (%) 1 24 (39.3) 9 (20.0) 33 (31.1) 2 19 (31.1) 22 (48.9) 41 (38.7) 3 11 (18.0) 8 (17.8) 19 (17.9) 4 3 (4.9) 3 (6.7) 6 (5.7) >4 4 (6.6) 3 (6.7) 7 (6.6) Tumor site,* n (%) Liver 57 (93.4) 41 (91.1) 98 (92.5) Pancreas 22 (36.1) 25 (55.6) 47 (44.3) Lymph node, distant 16 (26.2) 13 (28.9) 29 (27.4) Lymph node, regional 13 (21.3) 7 (15.6) 20 (18.9) Lung 3 (4.9) 3 (6.7) 6 (5.7) Other 10 (16.4) 10 (22.2) 20 (18.9)

Any prior systemic chemotherapy, n (%)

0 45 (100) 45 (42.5)

Prior SSA, n (%) 24 (39.3) 27 (60.0) 51 (48.1)Ki-67 index, mean (SD) 6.7 (5.0) 8.4 (7.2) 7.4 (6.0)* Included both target and nontarget sites; sites with multiple lesions were counted once.ECOG PS, Eastern Cooperative Oncology Group performance status; SD=standard deviation; SSA=somatostatin analogs

Figure 2: Kaplan–Meier Estimates of PFS Based on the Independent Third-Party Radiology According to Choi Criteria PFS in Treatment-Naïve and Previously Treated Patients With pNETs

PFS

Dist

ribut

ion

Func

tion

1.0

0.8

0.6

0.4

0.2

0.00 5 10 15 20 25



6145

2925

2217

1111

68

45

14

02

00

00

30 35 40 45

Treatment-naïve 61 25 18.7 (5.6–NE)Previously treated 45 24 16.5 (7.4–22.9)


CI=confidence interval; mPFS=median progression-free survival; PFS=progression-free survival; NE=not estimable; pNET=pancreatic neuroendocrine tumor

• ORR (95% CI) was 24.5% (16.7–33.8) according to the investigator assessment.

• The ORR (95% CI) per Choi criteria was higher than the ORR per RECIST: 52.5% (39.3–65.4) and 55.6% (40.0–70.4) in treatment-naïve and previously treated patients, respectively (Table 2).

•

Table 2: Best Observed Response Based on Independent Third-Party Radiology According to Choi Criteria in Treatment-Naïve and Previously Treated Patients With pNETs

Treatment-Naïve


n=45Best overall response, n (%) Complete response 0 1 (2.2) Partial response 32 (52.5) 24 (53.3) Stable disease 12 (19.7) 17 (37.8) Progressive disease 9 (14.8) 2 (4.4) Indeterminate 8 (13.1) 1 (2.2)ORR,* n (%) 32 (52.5) 25 (55.6) 95% CI 39.3–65.4 40.0–70.4* Complete response + partial response. CI=confidence interval; ORR=objective response rate; pNET=pancreatic neuroendocrine tumor; RECIST=Response Evaluation Criteria in Solid Tumors

Median (95% CI) TTP was 14.5 months (11.0–16.7); median (95% CI) TTP in treatment-naïve and previously treated patients was similar (14.8 [7.5–16.8] and 14.5 [9.2–20.4] months, respectively).

– According to the Choi criteria, the median (95% CI) TTP was 18.7 months (5.6–not estimable) for treatment-naïve patients and 16.7 months (7.4–30.9) for previously treated patients.

• OS data were not mature at the time of data cutoff date (March 19, 2016); 29 (27.4%) patients had died and median (95% CI) OS was 37.8 months (33.0–not estimable).

Safety • Most-common treatment-emergent, all-grade AEs experienced by all patients

treated with sunitinib included neutropenia, diarrhea, and leukopenia (Table 3).


• Percentage of treatment-naïve and previously treated patients who experienced grade 3 or 4 AEs was comparable; serious AEs were also comparable: 24.6% (n=15) vs 24.4% (n=11), respectively.




Treatment-Naïven=61


TotalN=106

All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4Neutropenia 37 (60.7) 13 (21.3) 22 (48.9) 10 (22.2) 59 (55.7) 23 (21.7)Diarrhea 32 (52.5) 7 (11.5) 22 (48.9) 3 (6.7) 54 (50.9) 10 (9.4)Leukopenia 25 (41.0) 4 (6.6) 21 (46.7) 3 (6.7) 46 (43.4) 7 (6.6)Fatigue 19 (31.1) 1 (1.6) 14 (31.1) 0 (0.0) 33 (31.1) 1 (0.9)Hand–foot syndrome 19 (31.1) 5 (8.2) 14 (31.1) 2 (4.4) 33 (31.1) 7 (6.6)Thrombocytopenia 18 (29.5) 6 (9.8) 14 (31.1) 2 (4.4) 32 (30.2) 8 (7.5)Hypertension 16 (26.2) 4 (6.6) 11 (24.4) 2 (4.4) 27 (25.5) 6 (5.7)Abdominal pain 16 (26.2) 2 (3.3) 10 (22.2) 3 (6.7) 26 (24.5) 5 (4.7)Dysgeusia 14 (23.0) 0 (0.0) 11 (24.4) 0 (0.0) 25 (23.6) 0 (0.0)Nausea 11 (18.0) 0 (0.0) 14 (31.1) 1 (2.2) 25 (23.6) 1 (0.9)Dyspepsia 7 (11.5) 0 (0.0) 14 (31.1) 0 (0.0) 21 (19.8) 0 (0.0)Headache 12 (19.7) 0 (0.0) 9 (20.0) 0 (0.0) 21 (19.8) 0 (0.0)Stomatitis 13 (21.3) 2 (3.3) 6 (13.3) 1 (2.2) 19 (17.9) 3 (2.8)Vomiting 8 (13.1) 1 (1.6) 10 (22.2) 1 (2.2) 18 (17.0) 2 (1.9)Asthenia 10 (16.4) 0 (0.0) 7 (15.6) 2 (4.4) 17 (16.0) 2 (1.9)Abdominal pain upper 5 (8.2) 1 (1.6) 7 (15.6) 1 (2.2) 12 (11.3) 2 (1.9)ALT increased 2 (3.3) 1 (1.6) 9 (20.0) 0 (0.0) 11 (10.4) 1 (0.9)AST increased 4 (6.6) 1 (1.6) 7 (15.6) 1 (2.2) 11 (10.4) 2 (1.9)Constipation 3 (4.9) 0 (0.0) 7 (15.6) 0 (0.0) 10 (9.4) 0 (0.0)Dizziness 3 (4.9) 0 (0.0) 7 (15.6) 0 (0.0) 10 (9.4) 0 (0.0)Hypophosphatemia 2 (3.3) 2 (3.3) 7 (15.6) 3 (6.7) 9 (8.5) 5 (4.7)Myalgia 2 (3.3) 0 (0.0) 7 (15.6) 0 (0.0) 9 (8.5) 0 (0.0)Adverse events are listed by highest to lowest % for Total/All Grades patients. * Adverse events reported by ≥15% in any treatment group per MedDRA criteria. ALT=alanine aminotransferase; AST=aspartate aminotransferase; MedDRA=Medical Dictionary for Regulatory Activities

Italian real world analysis of sunitinib in pNET

Rinzivillo et al., Pancreatology Dec 2017

73 pts with advanced pNET 90% pre-treated 82% prior Everolimus

•  PR 19% •  SD 53% •  PFS 11 mo •  mOS 36 mo

(71% >/= 3 lines)

Confirmed activity and toxicity profile even after Everolimus and/or PRRT

SSA

1

Everolimus or Sunitinib

Sunitinib or Everolimus

ChemotherapyPRRT

2 4 53

Clinical trials

Advanced non functioning well differentiated panNET: On the basis of the best evidence

European Institute of Oncology, IEO, Milan, Italy

ENETS Center of Excellence for GEP NETs

IEO NET MDT

esmo preceptorship programmeoncologypro.esmo.org/content/download/130960/2456023/file/2018... ·...

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