Novel Targeted Therapies for Neuroendocrine Tumors Jennifer Chan, - PowerPoint PPT Presentation

Novel Targeted Therapies for Neuroendocrine Tumors Jennifer Chan, MD, MPH Director, Program in Carcinoid and Neuroendocrine Tumors Department of Medical Oncology Dana-Farber Cancer Institute Harvard Medical School October 11, 2019 1

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. Sunitinib B. Bevacizumab C. Lenvatinib D. Pazopanib E. Cabozantinib

Currently Approved Targeted Agents in NET Drug Target Indication Octreotide 1 SSTR Carcinoid syndrome, VIPoma Lanreotide 2 SSTR GEP-NET Carcinoid syndrome Lu-177-Dotatate 3 SSTR SSTR positive GEP-NET Sunitinib 4 VEGFR, PDGFR, KIT, RET Pancreatic NET Everolimus 5,6 mTOR Pancreatic NET GI 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 32 Panc NET 7/32 (22%) 14.4 (5.9-22.9) 20 Carcinoid 0/20 (0%) 12.2 (5.3-19.9) Grande et al, 44 GEP-NET 4/44 (9%) 9.5 (4.8-14.1) 2015 Bronchial or thymic (PAZONET)

A021202: Randomized Phase II Pazopanib vs. Placebo in Advanced Carcinoid Tumors Study population • Locally advanced or metastatic Pazopanib • G1-G2 non-pancreatic 800 mg/ day (carcinoid) NET arising in R foregut, midgut, hindgut • Measurable disease 1:1 • PD within 12 months Open-label PD* Placebo Pazopanib 800 mg/ day Primary endpoint Stratification factors: • Progression-free survival by • Primary tumor site central review (RECIST 1.1) • Enrollment June 2013-Oct 2015 • Concurrent SSA • 65% with small bowel primary Secondary endpoints • 87% concurrent SSA • Overall survival • Functional tumors: 58% for pazopanib • Objective response rate vs.37% placebo • Duration of response • Time to treatment failure • Safety and tolerability 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 Pazopanib Placebo RECIST 1.1 (N=97) (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 (%) 21 (21.6) 6 (8.1) No treatment 8 2 Did not reach 1 st re-staging 8 3 Pending receipt/review 5 1 P-value 0.0010 Bergsland et al, ASCO Annual Meeting, 2019

A021202: Safety of Pazopanib in NET Grades > 3, N (%) P-value Pazopanib Placebo (N=89) (N=72) Fatigue 7 (7.9) 2 (2.8) 0.1896 Nausea 4 (4.5) 1 (1.4) 0.3813 Hypertension 24 (26.9) 3 (4.2) <0.0001 Aspartate aminotransferase increased 8 (9) 0 0.0088 Alanine aminotransferase increased 8 (9) 0 0.0088 Diarrhea 4 (4.5) 3 (4.2) 1.0000 Blood bilirubin increased 2 (2.2) 1 (1.4) 1.0000 Vomiting 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 • Multikinase inhibitor of VEGFR, FGFR-1, CSFR-1 Adverse Event Grade ≥ 3 (%)* Hypertension 33 Proteinuria 12 Hyperuricemia 10 Hypertriglyceridemia 6 ORR (95% CI) = 19% (9-34) ORR (95% CI) = 15% (6-31) Diarrhea 6 ALT increase 5 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) Xu et al, Clin Cancer Res, 2019

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 14% • Radiologic documentation of PD within 12 mo prior to randomization 198 patients randomized Prior treatment in 69% GI: 47% (mostly rectal; Chemotherapy 40% • • 8% SI-NET) • SSA 34% Lung: 9% Everolimus 8% • • Unknown: 14% • • Other 29% Xu et al, ESMO, 2019

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 Central Radiology Review Investigator Radiology Review Xu et al, ESMO, 2019

SANET-ep: Secondary Endpoints ORR 10% ORR 0% Xu et al, ESMO, 2019

SANET-ep: Safety of Surufatanib in NET TEAE = treatment emergent adverse event Xu et al, ESMO, 2019

SANET-p Trial: Randomized Phase III Trial Surufatinib in Advanced NETs – pancreatic Study population • G1-2 advanced pancreatic NET Surufatanib 300 mg/day • No more than 2 prior systemic R treatments • Radiologic documentation of 2:1 PD within 12 mo prior to randomization Placebo Primary endpoint • Progression-free survival Secondary endpoints • ORR, disease control rate, TTR, duration of response, OS, safety, tolerability • ClinicalTrials.gov ID: NCT02589821

TALENT Trial: Phase II Trial of Lenvatinib in Metastatic NET • Multikinase inhibitor of VEGFR1-3, FGFR1-4 Safety Profile: Pancreatic NET Most common grade 3/4 GI- NET 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 Median Progression-Free Survival 5.3% Panc NET 15.8 months GI NET 15.4 months Capdevila et al, ESMO 2018 and ASCO 2019

Phase II Trial of Cabozantinib in Advanced NET • Multikinase inhibitor of VEGFR, MET, AXL, RET Adverse Event Grade ≥ 3* (n=61) HTN 8 (13%) Hypophosphatemia 7 (11%) Diarrhea 6 (10%) Lipase or amylase 4 (7%) increase Lymphocyte 4 (7%) decrease Fatigue 3 (5%) Progression-Free Survival, Thrombocytopenia 3 (5%) mo. (95% CI) Panc NET (n=20) 21.8 (8.5- 32) Non-pancreatic NET 31.4 (8.5- NR) (n=41) 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 Primary Endpoint Cabozantinib PFS (Central R  60 mg daily A Panc NET Review) n=185 N D 2:1 O Secondary Endpoints M Carcinoid OS, RR, Safety, n=210  I Tolerability Z Placebo daily E 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 ClinicalTrials.gov ID: NCT03375320

Phase II Trial of Axitinib in Advanced Non-Panc NET • Multikinase inhibitor of VEGFR1-3, PDGFR Safety Profile: Most common grade 3/4 adverse events were HTN PR: 1/30 (3%) (63%), fatigue (7%), SD: 21/30 (70%) headache (7%) Progression-Free Survival, 12-mo PFS rate (95% CI) 26.7 mo (11.4-35.1) 74.5% (+/- 10) Strosberg et al, Endocrine-Related Cancer, 2016

AXINET Trial: Randomized Phase II-III Trial Axitinib and Octerotide vs. Placebo and Octreotide in Advanced G1-2 Non-Pancreatic NET Study population n=253 • Well-or moderately- Axitinib 5 mg bid + differentiated G1-2 NET of non- Octreotide LAR 30 mg/ 4 weeks pancreatic origin R • Functioning or non-functioning • Disease progression within 12 1:1 months Placebo bid + • Up to 2 lines prior systemic rx Octreotide LAR 30 mg/4 weeks • No prior VEGF/VEGFR targeted rx Stratification factors: • Primary tumor site (GI vs non-GI • Ki- 67 (≤ 5% vs >5%) •Time from dx to study entry Primary endpoint • Progression-free survival • PI: Rocio Garcia-Carbonero • ClinicalTrials.gov ID: NCT01744249

Ongoing/Recent Trials of Targeted Agents in NET Agent Mechanism Population NCT Identifier Regorafenib BRAF, VEGFR, KIT, G1/G2 GEP NETs NCT02259725 TIE-2 Nintedanib VEGFR, PDGFR, Non pancreatic G1/G2 NCT02399215 FGFR NET Famitinib VEGFR, PDGFR, KIT, G1/G2 GEP NETs NCT01994213 (TERMINATED) Ramucirumab VEGFR2 Non pancreatic G1/G2 NCT02795858 NET Sapanisertib TORC1 and 2 G1/G2 pancreatic NET NCT02893930 refractory to mTOR LEE011 (ribociclib) + CDK4/6 + mTOR WDNETs of foregut NCT03070301 everolimus origin CC-90011 LSD1 inhibitor Solid tumors including NCT02875223 NET

Somatostatin Receptor Targeting Agents Approved In Development Octreotide PEN-221 Lanreotide XmAb18087 Lu-177-Dotatate New radiolabeled agents