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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