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Novel Targeted Therapies for Neuroendocrine Tumors
Jennifer Chan, MD, MPHDirector, Program in Carcinoid and Neuroendocrine TumorsDepartment of Medical OncologyDana-Farber Cancer InstituteHarvard Medical School
October 11, 2019
Disclosures
• Consulting/Advisory Board Participation– Ipsen, Lexicon
• Institutional Research Support– Lilly, Novartis, Sanofi, Tarveda
Question #1
Which of the following targeted agents has been shown to improve progression-free survival compared to placebo in non-pancreatic NET?
A. SunitinibB. BevacizumabC. LenvatinibD. PazopanibE. Cabozantinib
Currently Approved Targeted Agents in NET
Drug Target Indication
Octreotide1 SSTR Carcinoid syndrome, VIPoma
Lanreotide2 SSTR GEP-NETCarcinoid syndrome
Lu-177-Dotatate3 SSTR SSTR positive GEP-NET
Sunitinib4 VEGFR, PDGFR, KIT, RET Pancreatic NET
Everolimus5,6 mTOR Pancreatic NETGI and Lung NET
1. PROMID: Rinke et al, JCO, 2009 2. CLARINET: Caplin, NEJM, 2014 3. NETTER-1: Strosberg et al, NEJM 2017 4. SUN-111: Raymond et al, NEJM 2011 5. RADIANT-3: Yao, NEJM, 2011 6. RADIANT-4: Yao et al, Lancet 2016
Multi-targeted Tyrosine Kinase Inhibitors in NET
surufatanib
Grillo et al, Endocrine Rel Cancer, 2018
Phase II Trials of Pazopanib in Patients with Advanced NET
• Multi-kinase inhibitor of VEGFR-1/2/3, PDGFR-α/β, c-Kit
Study N Study population ORR PFS mo (95% CI)
Ahn et al, 2013 37 GEP-NET 18.9% 9.1 (4.9-13.3)
Phan et al, 2015 3220
Panc NETCarcinoid
7/32 (22%)0/20 (0%)
14.4 (5.9-22.9)12.2 (5.3-19.9)
Grande et al, 2015(PAZONET)
44 GEP-NETBronchial or thymic
4/44 (9%) 9.5 (4.8-14.1)
Pazopanib 800 mg/ day
A021202: Randomized Phase II Pazopanib vs. Placebo in Advanced Carcinoid Tumors
Placebo
Stratification factors:• Primary tumor site• Concurrent SSA
Study population• Locally advanced or metastatic • G1-G2 non-pancreatic
(carcinoid) NET arising in foregut, midgut, hindgut
• Measurable disease• PD within 12 months
Primary endpoint• Progression-free survival by
central review (RECIST 1.1)
Secondary endpoints• Overall survival• Objective response rate• Duration of response• Time to treatment failure• Safety and tolerability
Open-labelPazopanib 800 mg/ day
PD*
R 1:1
• Enrollment June 2013-Oct 2015• 65% with small bowel primary• 87% concurrent SSA• Functional tumors: 58% for pazopanib
vs.37% placebo
Bergsland et al, ASCO Annual Meeting, 2019
A021202: Progression-Free Survival and Overall Survival
Bergsland et al, ASCO Annual Meeting, 2019
A021202: Best Radiographic Response (Central Review)
Best Response (ITT) by RECIST 1.1
Pazopanib(N=97)
Placebo(N=74)
Partial Response*, N (%) 2 (2.1) 0
Stable Disease , N (%) 70 (72.2) 54 (73.0)Progressive Disease, N (%) 4 (4.1) 14 (18.9)Not Evaluable, N (%)
No treatmentDid not reach 1st re-staging
Pending receipt/review
21 (21.6)885
6 (8.1)231
P-value 0.0010
Bergsland et al, ASCO Annual Meeting, 2019
A021202: Safety of Pazopanib in NETGrades > 3, N (%)
Pazopanib(N=89)
Placebo(N=72)
P-value
Fatigue 7 (7.9) 2 (2.8) 0.1896Nausea 4 (4.5) 1 (1.4) 0.3813Hypertension 24 (26.9) 3 (4.2) <0.0001Aspartate aminotransferase increased 8 (9) 0 0.0088
Alanine aminotransferase increased 8 (9) 0 0.0088Diarrhea 4 (4.5) 3 (4.2) 1.0000Blood bilirubin increased 2 (2.2) 1 (1.4) 1.0000Vomiting 3 (3.4) 2 (2.8) 1.0000
No difference in Quality of Life between the arms
Bergsland et al, ASCO Annual Meeting, 2019
Phase Ib/II Trial of Surufatinib in Advanced NET
Progression-Free Survival, mo. (95% CI)
Panc NET (n=42) 21.2 (15.9-24.8)Non-pancreatic NET (n=39) 13.4 (7.6 – 19.3)
Adverse Event Grade ≥ 3 (%)*
Hypertension 33
Proteinuria 12
Hyperuricemia 10
Hypertriglyceridemia 6
Diarrhea 6
ALT increase 5
• Multikinase inhibitor of VEGFR, FGFR-1, CSFR-1
Xu et al, Clin Cancer Res, 2019
ORR (95% CI) = 19% (9-34) ORR (95% CI) = 15% (6-31)
SANET-ep Trial: Randomized Phase III Trial Surufatinib in Advanced NETs – extra-pancreatic
Study population• G1-2 advanced extrapancreatic
NET, including lung, thymus, GI, and unknown origin
• No more than 2 prior systemic treatments
• Radiologic documentation of PD within 12 mo prior to randomization
Xu et al, ESMO, 2019
198 patients randomized• GI: 47% (mostly rectal;
8% SI-NET)• Lung: 9% • Unknown: 14%• Other 29%
14%
Prior treatment in 69%• Chemotherapy 40%• SSA 34%• Everolimus 8%
SANET-ep: Progression-Free Survival (Investigator Review)
Xu et al, ESMO, 2019
SANET-ep: PFS Subgroup Analyses
Xu et al, ESMO, 2019
SANET-ep: Progression-Free Survival
Xu et al, ESMO, 2019
Central Radiology ReviewInvestigator Radiology Review
SANET-ep: Secondary Endpoints
Xu et al, ESMO, 2019
ORR 10%
ORR 0%
SANET-ep: Safety of Surufatanib in NET
Xu et al, ESMO, 2019TEAE = treatment emergent adverse event
Surufatanib 300 mg/day
SANET-p Trial: Randomized Phase III Trial Surufatinib in Advanced NETs – pancreatic
Placebo
Study population
• G1-2 advanced pancreatic NET• No more than 2 prior systemic
treatments• Radiologic documentation of
PD within 12 mo prior to randomization
Primary endpoint• Progression-free survival
Secondary endpoints• ORR, disease control rate, TTR,
duration of response, OS, safety, tolerability
R 2:1
• ClinicalTrials.gov ID: NCT02589821
TALENT Trial: Phase II Trial of Lenvatinib in Metastatic NET
• Multikinase inhibitor of VEGFR1-3, FGFR1-4
Median Progression-Free SurvivalPanc NET 15.8 monthsGI NET 15.4 months
Pancreatic NET GI- NETSafety Profile:Most common grade 3/4 adverse events:• Panc NET = HTN
(18%), vomiting (7.2%), fatigue (7.2%), abdominal pain (5.4%), diarrhea (5.4%)
• GI-NET: HTN (23.2%), fatigue 19.6%, diarrhea 8.9%, abdominal pain 5.3%
Capdevila et al, ESMO 2018 and ASCO 2019
Phase II Trial of Cabozantinib in Advanced NET
Progression-Free Survival, mo. (95% CI)
Panc NET (n=20) 21.8 (8.5- 32)Non-pancreatic NET (n=41)
31.4 (8.5- NR)
Adverse Event (n=61) Grade ≥ 3*
HTN 8 (13%)
Hypophosphatemia 7 (11%)
Diarrhea 6 (10%)Lipase or amylase increase 4 (7%)
Lymphocyte decrease 4 (7%)
Fatigue 3 (5%)
Thrombocytopenia 3 (5%)
• Multikinase inhibitor of VEGFR, MET, AXL, RET
Chan et al, ASCO GI Symposium, 2017
CABINET (A021601): Randomized Double-Blinded Phase III Study of Cabozantinib vs. Placebo in Advanced NET after Progression on Everolimus
RANDOMIZ E
Cabozantinib 60 mg daily
Placebo daily
Primary Endpoint PFS (Central
Review)
Secondary Endpoints OS, RR, Safety,
Tolerability
Key inclusion criteria:• Well- to moderately differentiated NET, functional and nonfunctional• Disease progression by RECIST within 12 months prior to randomization• Failure of at least 1 prior systemic therapy including everolimus• Concurrent SSA allowed provided stable dose for ≥ 2 mo
Panc NET
Carcinoid2:1
n=185
n=210
ClinicalTrials.gov ID: NCT03375320
Phase II Trial of Axitinib in Advanced Non-Panc NET
Progression-Free Survival, (95% CI)
12-mo PFS rate
26.7 mo (11.4-35.1) 74.5% (+/- 10)
Safety Profile:Most common grade 3/4 adverse events were HTN (63%), fatigue (7%), headache (7%)
• Multikinase inhibitor of VEGFR1-3, PDGFR
PR: 1/30 (3%)SD: 21/30 (70%)
Strosberg et al, Endocrine-Related Cancer, 2016
Axitinib 5 mg bid + Octreotide LAR 30 mg/ 4 weeks
AXINET Trial: Randomized Phase II-III Trial Axitinib and Octerotide vs. Placebo and Octreotide in Advanced G1-2 Non-Pancreatic NET
Placebo bid + Octreotide LAR 30 mg/4 weeks
Stratification factors:• Primary tumor site (GI vs non-GI• Ki-67 (≤ 5% vs >5%)•Time from dx to study entry
Study population• Well-or moderately-
differentiated G1-2 NET of non-pancreatic origin
• Functioning or non-functioning• Disease progression within 12
months• Up to 2 lines prior systemic rx• No prior VEGF/VEGFR
targeted rx
Primary endpoint• Progression-free survival
R 1:1
• PI: Rocio Garcia-Carbonero• ClinicalTrials.gov ID: NCT01744249
n=253
Ongoing/Recent Trials of Targeted Agents in NETAgent Mechanism Population NCT IdentifierRegorafenib BRAF, VEGFR, KIT,
TIE-2G1/G2 GEP NETs NCT02259725
Nintedanib VEGFR, PDGFR,FGFR
Non pancreatic G1/G2NET
NCT02399215
Famitinib VEGFR, PDGFR, KIT, G1/G2 GEP NETs NCT01994213 (TERMINATED)
Ramucirumab VEGFR2 Non pancreatic G1/G2NET
NCT02795858
Sapanisertib TORC1 and 2 G1/G2 pancreatic NETrefractory to mTOR
NCT02893930
LEE011 (ribociclib) +everolimus
CDK4/6 + mTOR WDNETs of foregutorigin
NCT03070301
CC-90011 LSD1 inhibitor Solid tumors including NET
NCT02875223
Somatostatin Receptor Targeting Agents
Approved In DevelopmentOctreotide PEN-221 Lanreotide XmAb18087Lu-177-Dotatate New radiolabeled agents
Phase 1/2a Study of PEN-221 in advanced SSTR-pos NET or SCLC
SSTR2 targeting ligand DM1 cytotoxic payloadOptimized cleavable linker
• PEN-221: Somatostatin Analog-DM1 conjugate
• On binding, PEN-221 triggers SSTR2 internalization resulting in the accumulation of the DM1 payload in tumor cells followed by cell cycle arrest and apoptosis.
Characteristic n
Tumor typesGI NET 9PNET 5Lung NET 5Pheochromocytoma 2NET of UnknownPrimary 1
Small Cell Lung Cancer 1
Prior therapies, median (range) 3, (1-8)
ML Johnson et al, ASCO Annual Meeting 2018
PEN-221 Phase 1 Results
Preliminary evidence of antitumor activity of PEN-221- Rapid and sustained decrease in chromogranin A, NSE, circulating tumor cells in 1 pt- 15 NET pts evaluable for response: 11 had stable disease (SD) at 9 weeks
- Stable disease sustained for 18 – 45 weeks in 8 pts- Target lesion shrinkage leading to minor responses were observed in 3/7 pts who
had either a GI or pancreatic NET - One SCLC pt had SD for 12 weeks
- PEN-221 is being evaluated in a phase II a cohort currently enrolling midgut NET (PRRT-naïve and PRRT-refractory) and SCLC
ML Johnson et al, ASCO Annual Meeting 2018
Phase 1 Study of XmAb18087: SSTR2 and CD3 Bispecific Antibody
• Phase 1 dose-escalation study in SSTR-positive NET and GIST is ongoing
ClinicalTrials.gov ID: NCT03411915
• XmAb18087 recruits T cells to kill SSTR2+ cancer cells in vitro
• Induces anti-tumor activity mouse models
Lee et al, AACR 2017, Abstract 3633
Conclusions: Novel Targeted Therapies in NET
• Multiple TKIs targeting VEGFR have demonstrated activity in advanced NET– Improved PFS in randomized, placebo-controlled trials for sunitinib
(pNET), surufatanib (non-pNET), pazopanib (non-pNET)– Phase III trials are ongoing for axitinib, cabozantinib, surufatanib (pNET)
• Novel targeted treatment strategies are in development: drug conjugates (PEN-221), bi-specific antibodies (XmAb18087), epigenome modifying agents
• Future directions– Identifying patients most likely to benefit from targeted therapy– Determining optimal sequence of therapy– Balancing toxicity of treatment
Question #1
Which of the following targeted agents has been shown to improve progression-free survival compared to placebo in non-pancreatic NET?
A. SunitinibB. BevacizumabC. LenvatinibD. PazopanibE. Cabozantinib
Question #1
Which of the following targeted agents has been shown to improve progression-free survival compared to placebo in non-pancreatic NET?
A. SunitinibB. BevacizumabC. LenvatinibD. Pazopanib (and Surufatanib)E. Cabozantinib
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