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

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

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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

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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

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Disclosures

  • Consulting/Advisory Board Participation

– Ipsen, Lexicon

  • Institutional Research Support

– Lilly, Novartis, Sanofi, Tarveda

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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

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Currently Approved Targeted Agents in NET

Drug Target Indication Octreotide1 SSTR Carcinoid syndrome, VIPoma Lanreotide2 SSTR GEP-NET Carcinoid syndrome Lu-177-Dotatate3 SSTR SSTR positive GEP-NET Sunitinib4 VEGFR, PDGFR, KIT, RET Pancreatic NET Everolimus5,6 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
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Multi-targeted Tyrosine Kinase Inhibitors in NET

surufatanib

Grillo et al, Endocrine Rel Cancer, 2018

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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 20 Panc NET Carcinoid 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-NET Bronchial or thymic 4/44 (9%) 9.5 (4.8-14.1)

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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-label Pazopanib 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

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A021202: Progression-Free Survival and Overall Survival

Bergsland et al, ASCO Annual Meeting, 2019

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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) Stable Disease , N (%) 70 (72.2) 54 (73.0) Progressive Disease, N (%) 4 (4.1) 14 (18.9) Not Evaluable, N (%) No treatment Did not reach 1st re-staging Pending receipt/review 21 (21.6) 8 8 5 6 (8.1) 2 3 1

P-value 0.0010

Bergsland et al, ASCO Annual Meeting, 2019

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A021202: Safety of Pazopanib in NET

Grades > 3, N (%) Pazopanib (N=89) Placebo (N=72) P-value 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) 0.0088 Alanine aminotransferase increased 8 (9) 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

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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)

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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%
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SANET-ep: Progression-Free Survival (Investigator Review)

Xu et al, ESMO, 2019

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SANET-ep: PFS Subgroup Analyses

Xu et al, ESMO, 2019

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SANET-ep: Progression-Free Survival

Xu et al, ESMO, 2019

Central Radiology Review Investigator Radiology Review

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SANET-ep: Secondary Endpoints

Xu et al, ESMO, 2019

ORR 10% ORR 0%

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SANET-ep: Safety of Surufatanib in NET

Xu et al, ESMO, 2019 TEAE = treatment emergent adverse event

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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
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TALENT Trial: Phase II Trial of Lenvatinib in Metastatic NET

  • Multikinase inhibitor of VEGFR1-3, FGFR1-4

Median Progression-Free Survival Panc NET 15.8 months GI NET 15.4 months Pancreatic NET GI- NET Safety 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

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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

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CABINET (A021601): Randomized Double-Blinded Phase III Study of Cabozantinib vs. Placebo in Advanced NET after Progression on Everolimus

R A N D O M I Z 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 Carcinoid 2:1

n=185 n=210

ClinicalTrials.gov ID: NCT03375320

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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

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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

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Ongoing/Recent Trials of Targeted Agents in NET

Agent Mechanism Population NCT Identifier Regorafenib BRAF, VEGFR, KIT, TIE-2 G1/G2 GEP NETs NCT02259725 Nintedanib VEGFR, PDGFR, FGFR Non pancreatic G1/G2 NET NCT02399215 Famitinib VEGFR, PDGFR, KIT, G1/G2 GEP NETs NCT01994213 (TERMINATED) Ramucirumab VEGFR2 Non pancreatic G1/G2 NET NCT02795858 Sapanisertib TORC1 and 2 G1/G2 pancreatic NET refractory to mTOR NCT02893930 LEE011 (ribociclib) + everolimus CDK4/6 + mTOR WDNETs of foregut

  • rigin

NCT03070301 CC-90011 LSD1 inhibitor Solid tumors including NET NCT02875223

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Somatostatin Receptor Targeting Agents

Approved In Development Octreotide PEN-221 Lanreotide XmAb18087 Lu-177-Dotatate New radiolabeled agents

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Phase 1/2a Study of PEN-221 in advanced SSTR-pos NET or SCLC

SSTR2 targeting ligand

DM1 cytotoxic payload Optimized 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 types GI NET 9 PNET 5 Lung NET 5 Pheochromocytoma 2 NET of Unknown Primary 1 Small Cell Lung Cancer 1 Prior therapies, median (range) 3, (1-8)

ML Johnson et al, ASCO Annual Meeting 2018

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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

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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

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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

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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

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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 (and Surufatanib) E. Cabozantinib