recent advances in the treatments of …...recent advances in the treatments of gastrointestinal...

The Royal Marsden

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Recent advances in the treatments of gastrointestinal stromal tumours (GIST)

Dr Spyridon Gennatas

Consultant Medical Oncologist

The Royal Marsden

The Royal Marsden Change Presentation title and date in Footer dd.mm.yyyy 2

Plan

– Adjuvant Tx

– Metastatic Tx

– Blu-285

• Phase I data

• Phase III

– DCC-2618

• Phase I data

• Phase III

o 4th line

o 2nd line

– Other Agents

– Conclusion


Localised GIST

– Localised Disease

• Mainstay of treatment is surgical resection

• Despite complete resection 5-year OS ~50%

De Matteo R et al, Annals Surg 231(1); 51-8: 2000


Adjuvant imatinib: ACOSOG trial

– Randomized Phase III, double-blind, placebo controlled trial (n=713)

– Localized GIST >3cm

– One year RFS:

• Imatinib: 98% (95%CI 96-100)

• Placebo:83% (95%CI 78-88)

o Hazard ratio 0.35 [0.22-0.53], p<0.0001


One Year Adjuvant Imatinib versus Placebo: Recurrence-free survival

DeMatteo R et al Lancet 373; 1097-1104: 2009

http://www.sciencedirect.com.offcampus.lib.washington.edu/science?_ob=MiamiCaptionURL&_method=retrieve&_udi=B6T1B-4VW1YC3-1&_image=B6T1B-4VW1YC3-1-6&_ba=&_user=582538&_coverDate=04/03/2009&_rdoc=1&_fmt=full&_orig=gateway&_cdi=4886&_pii=S0140673609605006&view=c&_isHiQual=Y&_acct=C000029718&_version=1&_urlVersion=0&_userid=582538&md5=b29836446b2b417c32b8f04c45e7bd62


Adjuvant imatinib: SSG XVIII/ AIO trial

– High risk by NIH criteria:

• Longest tumour diameter > 10cm

• Mitotic count > 10 mitoses/ 50 HPF

• Tumour > 5cm + Mitotic count > 5

• Tumour rupture

– Patients with operable intra abdominal metastatic disease included until Oct 2006


Adjuvant imatinib: SSG XVIII/ AIO trial

– Randomised open-label Phase III trial (n=400)

– 5-year RFS: • 47.9% one year adjuvant imatinib • 65.6% three years of adjuvant imatinib

o Hazard ratio: 0.46, 95%CI 0.32-0.65, p<0.001

– 5-year OS

• 81.7% one year adjuvant imatinib • 92% three years of adjuvant imatinib

o Hazard ratio: 0.45, 95%CI 0.22-0.89, p=0.02

Joensuu H et al, JAMA 307; 1265-1272: 2012


Blu-285


Patients with tumors harboring PDGFRA D842V mutation

Heinrich M et al. ASCO 2019


Cognitive effects

– Low mood

– Changes in concentration

– Memory disturbance

– Ability to carry on routine administrative work impaired


DCC-2618

The Royal Marsden

DCC-2618, a novel pan-KIT and PDGFRa Kinase switch control inhibitor

demonstrates encouraging activity in patients (pts) with Gastrointestinal

Stromal Tumors (GIST) N. Somaiah, A. Razak, M. Gordon, F. Janku, D. Flynn, M. Kaufman,

J. Pitman, R. Ruiz-Soto, B. Smith, D. Westwood, J. Jennings, D. Greensmith, J. Jacobson, O. Rosen, S. George


Background

– DCC-2618 is a KIT and PDGFRA inhibitor resilient to gain-of-function

and drug resistance mutations

• Potency independent of ATP concentration

– DCC-2618 was designed to potently inhibit a broad range of mutations in KIT and PDGFRA kinases

– Gastrointestinal stromal tumor (GIST):

• Achieve proof-of-concept in the FIH study due to the multiplicity and heterogeneity of resistance mutations within KIT

Deciphera’s Switch Control Inhibition


DCC-2618-01-001: Design and objectives

– Design (NCT02571036)

• Pharmacologically-guided 3+3 escalation phase I study of oral DCC-2618 administered BID every 28 days

– Objectives

• Primary: Safety, tolerability, maximum tolerated dose (MTD), dose-limiting toxicities (DLT)

• Secondary: Pharmacokinetic profile, antitumor efficacy

• Exploratory: Determination of KIT and/or PDGFRA mutations in plasma cell-free DNA (NGS) and serum tryptase

– Major eligibility criteria

• Patients with advanced refractory cancers + molecular rationale for activity

• ECOG 0-1

• Adequate organ function

• Prior KIT/PDGFRA inhibitors were allowed


DCC-2618: RECIST RESPONSES

MRI after cycle 12

CT after cycle 2 Baseline CT

Baseline MRI

— Widely metastatic GIST with KIT Exon 11 deletion, who received 6 different prior KIT inhibitors

— RECIST: partial response (-37%) maintained for 5+ cycles on DL4 100mg BID

— Glioblastoma multiforme with PDGFRA / KIT / KDR co-amplification, who received prior XRT and temozolomide and progressed after 3 months

— RECIST: partial response (-49%), on study for 12+ cycles on DL1 20mg BID

— RANO: PR after cycle 12


Summary of efficacy (n=24)

– Recist

• PR in heavily pretreated patient with GIST KIT exon 11/17 mutation

• PR in pretreated patient with GBM with PDGFRA/KIT/KDR co-amplification (confirmed by RANO)

– PET metabolic responses

• PMR in 14 of 15 patients with heavily pretreated GIST and KIT mutation(s)

• 13 of these responses have been confirmed by central review

– Time on therapy

• A patient with GBM with PDGFRA/KIT/KDR co-amplification on therapy for 12+ months

• 3 patients with heavily pretreated GIST on therapy for > 6 months


DCC-2618 – GIST Patient Characteristics (N=57)

Median age: 62 years (range 28 - 85)

ECOG PS: 0: 18 (33% )

1: 37 (67%) [Note: 2 subjects missing screening ECOG]

Baseline mutations: KIT Exon 9: 13

(archival tissue*, N=57) KIT Exon 11: 27

KIT Exon 17: 4

PDGRa Exon18: 4

Other/UKN: 9 (2x KIT Ex13, 1x KIT UKN, 1x SDH, 5x not done)

Mean prior number of agents: 3.3 (median 3; range 1 - 7) -Imatinib: 49/49 (100%)

-Sunitinib: 43/49 (88%)

-Regorafenib: 36/49 (73%)

-Other: 35/49 (71%)

DCC-2618 treatment doses: <100 mg/day: 5 (9%)

100 mg/day: 52 (91%)

150 mg QD: 21 (37%)

*various methods used per institutional standards

DCC-2618 Safety Population - Summary of TEAEs (Treatment-Emergent AE / Regardless of Causality) ≥10% (N=70)

*Unconjugated bilirubin, both patients are homozygous for 28 *(TA)7/(TA)7 UGT1A1 polymorphism per local assessment

All DLT events were not clinically significant: 2 G3 lipase ↑ at 100 mg & 200 mg BID and a G4 CPK ↑ at 150 mg QD

ADVERSE EVENT GRADE

1/2 GRADE

3/4 TOTAL (n=70)

Lipase increased 20 13 33 (47%)

Fatigue 31 1 32 (46%)

Anemia 10 19 29 (41%)

Decreased appetite 18 1 20 (29%)

Diarrhea 16 0 16 (23%)

Alopecia 15 0 15 (21%)

Hypertension 9 6 15 (21%)

Amylase increased 13 1 14 (20%)

Myalgia 14 0 14 (20%)

Weight decreased 14 0 14 (20%)

Dyspnea 12 1 13 (19%)

Abdominal pain 10 1 11 (16%)

Constipation 11 0 11 (16%)

Nausea 11 0 11 (16%)

Palmar-plantar erythrodysaesthesia 11 0 11 (16%)

Arthralgia 10 0 10 (14%)

Blood bilirubin increased 8 2* 10 (14%)

Rash 8 0 8 (11%)

150 mg QD

GRADE 1/2

GRADE 3/4

TOTAL (n=21)

3 2 5 (24%)

5 0 5 (24%)

0 1 1 (5%)

3 0 3 (14%)

0 0 0 (0%)

4 0 4 (19%)

0 0 0 (0%)

1 0 1 (5%)

2 0 2 (10%)

1 0 1 (5%)

1 0 1 (5%)

0 0 0 (0%)

2 0 2 (10%)

1 0 1 (5%)

2 0 2 (10%)

0 0 0 (0%)

0 1 1 (5%)

1 0 1 (5%)


Waterfall Plot of KIT/PDGFRa GIST Patients (Best Response Per RECIST, N=37)

Heinrich M et al. ASCO 2019


Invictus: 4th+-Line GIST Phase 3 Trial

– Patients with a confirmed diagnosis of GIST

• Who have received at least 3 prior lines of therapy

– Phase 3 trial in 4th-line GIST will be a 2:1 randomized, double-blind, placebo-controlled study

– Primary endpoint : PFS determined by independent radiologic review of CT scans, as assessed by RECIST

• CT scans: every cycle for the first 3 cycles

o then every two cycles thereafter beginning with Cycle 4

• A secondary endpoint: Overall survival

– DCC-2618 or placebo QD (150 mg)

• 28-day cycles with best supportive care

– Placebo: Cross over to DCC-2618 upon PD with placebo.

– DCC-2618: Opportunity to remain on DCC-2618 upon PD


Invictus: Phase 3 Trial Design

– A Phase 3, INterVentional, Double-Blind Study to Assess Safety and Efficacy of DCC-2618 In Patients with Advanced c-KIT/PDGFRA Gastrointestinal Stromal TUmorS Who Have Received Prior Treatment with Imatinib, Sunitinib, and Regorafenib

Primary endpoint PFS


Invictus: Phase 3 Trial Design

– Randomized, double blind, multi-center, trial comparing DCC-2816 to sunitinib

• prior treatment with imatinib

• 500 patients

• 1:1 ratio: DCC-2816 and sunitinib

• Primary end-point: PFS

– Randomization will be stratified by

• ECOG performance status (0-1 vs 2)

• Mutational status (KIT Exon 9 vs Exon 11 vs PDGFRα)

• Region (North America vs Ex-North America)

• Time on imatinib (≤12 months vs > 12 months)

– Patients randomized to sunitinib or DCC-2618 will be offered the opportunity to receive open-label DCC-2618 upon disease progression


Cabozantinib

The Royal Marsden

Activity and safety of cabozantinib in patients with gastrointestinal stromal

tumor after failure of imatinib and sunitinib: EORTC phase II trial 1317

“CaboGIST” P. Schöffski, O. Mir, B. Kasper, Z. Papai, J.-Y. Blay, A. Italiano, C. Benson, K. Kopeckova, N. Ali, P. Dileo, A. Le Cesne, F. Menge, S. Cousin, C. Charon-Barra, A. Wozniak, S. Marreaud, S. Litiere, A.

Nzokirantevye, H. Gelderblom

EORTC Soft Tissue and Bone Sarcoma Group (STBSG)

ASCO Annual Meeting, Abstract 11006, Chicago, 3 June 2019


Cabozantinib

– Multi-targeted TKI inhibiting KIT, MET, AXL and VEGFR2

– Antitumor activity in multiple solid tumors

– Approved for treatment of advanced renal cell carcinoma, hepatocellular carcinoma and advanced medullary thyroid cancer

Potentially relevant targets in GIST

Kinase Biochemical IC50 (nM) Cellular IC50 (nM)

KIT 4.6 5.0

MET 1.3 7.8

AXL 7 42

VEGFR2 0.035 1.9

Yakes et al. Mol Cancer Ther 2011 Schöffski et al. Eur J Cancer 2017

Schöffski et al. ASCO Annual Meeting 2012 Elisei et al. J Clin Oncol 2013

Choueiri et al. New Eng J Med 2015 Cabanillas et al. J Clin Oncol 2017

Abou-Alfa et al. New Engl J Med 2018


Progression-free survival (PFS) (Kaplan-Meier estimate)

Events/Total Median (95% CI) Time-Point KM Est (95% CI) 38/50 6.0 (3.6-7.7) 3 months 70.0 (55.3-80.7%)

6 months 51.0 (36.2-64.0%) 9 months 25.0 (13.1-39.0%)

12 months 21.9 (10.6-35.8%)

Median PFS 6.0 months, 95% CI 3.6-7.7

Shadow represents 95%CI


Overall survival (OS) (Kaplan-Meier estimate)

35

Median OS 14.4 months, 95% CI 14.1-NE

• NE, non evaluable

Shadow represents 95%CI

Time-Point KM Est (95% CI) 3 months 97.9 (86.1-99.7%) 6 months 92.7 (79.0-97.6%) 9 months 82.4 (64.3-91.9%) 12 months 78.5 (59.3-89.4%)

Events/Total Median (95% CI)

10/50 14.4 (14.1-NE)


Grade 1-4 treatment-related clinical adverse events occurring in >10% of pts

(n=50)

Grade 1

n (%)

Grade 2

n (%)

Grade 3

n (%)

Grade 4

n (%)

Grade ≥1

n (%)

ALL 8 (16.0) 7 (14.0) 32 (64.0) 47 (94)

Diarrhea 14 (28) 11 (22) 12 (24) 37 (74)

Palmar-plantar erythrodysesthesia 13 (26) 12 (24) 4 (8) 29 (58)

Fatigue 10 (20) 13 (26) 23 (46)

Hypertension 1 (2) 3 (6) 19 (38) 23 (46)

Weight loss 12 (24) 7 (14) 19 (38)

Mucositis oral 12 (24) 2 (4) 14 (28)

Abdominal pain 6 (12) 5 (10) 11 (22)

Anorexia 7 (14) 3 (6) 1 (2) 11 (22)

Hypothyroidism 5 (10) 3 (6) 1 (2) 9 (18)

Hoarseness 9 (18) 9 (18)

Dysgeusia 8 (16) 8 (16)

Other cutaneous AE 6 (12) 1 (2) 7 (14)

Nausea 2 (4) 4 (8) 6 (12)


Conclusion

– A number of promising agents in development

• Pre-treated and imatinib resistant

• Blu-285 and DCC-2618 in Phase III

– Early stage development

• Also a number of promising agents

– Encourage Phase I trial participation

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