DESTINY-Breast03 Phase 3 Study Results
Phase I, Multicenter, Open-Label, First-in-Human Study of DS-6157a in Patients with Advanced Gastrointestinal Stromal Tumor
Suzanne George, MD', Michael Heinrich, MD², Neeta Somaiah, MD³, Brian A Van Tine, MD, PhD, Robert McLeod, MD5, Abderrahmane Laadem, MD, PhD, Ben Cheng, MD5, Satoshi Nishioka, Madan G Kundu, PhD, Xiaozhong Qian, PhD, Yvonne Lau, PhD, Brittany Tran, PharmD5,
Prasanna Kumar, PhD, Ololade Dosunmu, MD, Julia Shi, Yoichi Naito, MD8
'Dana-Farber Cancer Institute, Boston, MA; 2OHSU Knight Cancer Institute, Portland, OR; ³The University of Texas MD Anderson Cancer Center, Houston TX;" Washington University in Saint Louis, St. Louis, MO; "Daiichi Sankyo, Inc., Basking Ridge, NJ; "Daiichi Sankyo, Co., Ltd, Tokyo, Japan; 'Sarah Cannon Research Institute, Nashville, TN; "National Cancer Center Hospital East, Kashiwa, Japan
BACKGROUND
⚫GPR20 is selectively and abundantly expressed in gastrointestinal
stromal tumors (GISTS), the most common sarcoma of the digestive
tract.
• DS-6157a is an anti-GPR20 antibody-drug conjugate with a novel
tetrapeptide-based linker and DNA topoisomerase I inhibitor
exatecan derivative (DXd) which target the drug-to-antibody ratio
(DAR) of -8.
• In nonclinical pharmacology studies, DS-6157a inhibited the growth
of GPR20-expressing GIST xenografted mouse models'.
• Here, we report the results from a Phase I trial of DS-6157a in
patients (pts) with advanced GIST (NCT04276415).
STUDY OBJECTIVES
Primary
.Dose Escalation (Part 1): Investigate the safety and tolerability of the
DS-6157a, and determine the maximum tolerated dose (MTD) and/or
the recommended dose for expansion (RDE)
Secondary
⚫ Characterize the pharmacokinetic (PK) properties of DS-6157a,
total anti-GPR20 antibody, and the drug component (MAAA-1181a)
• Investigate the efficacy of DS-6157a (Part 1 only)
STUDY DESIGN
⚫The dose-escalation portion of this study (Part 1) enrolled pts with
advanced GIST. DS-6157a was administered IV as monotherapy on
Day 1 of 21-day cycles.
• Part 1 assessed safety, tolerability, and MTD or RDE using Bayesian
logistic regression model (BLRM), with at least 3 dose-limiting
toxicity (DLT)-evaluable pts per dose level.
Age (years)
Medlan
Sex n(%)
Male
Race n(%)
Asian
Black or African American
Other
12.273
TEAEs
Table 4. TEAEs in ≥10% of Patients
Fatigue
Constipation
Platelet count decreased
Vomiting
Abdominal pain
Neutrophil count decreased
White blood cell count decreased
Alanine aminotransferase i
0
(n=4)
(n=34)
PHARMACOKINETIC RESULTS
1.6 MG/KG 3.2 MG/KG 4.8 MG/KG ■6.4 MG/KG 9.6 MG/KG 12.8 MG/KG
DS-6157a
MAAA-1181a
Total Anti-GPR20 Antibody
RESPONSE
KIT.PDOPRA WT with Tumor viage
DEMOGRAPHICS AND BASELINE DISEASE CHARACTERISTICS
Table 1. Demographics and Baseline Disease Status
Total Number of Patients
34
Primary Site Location n(%)
DS-6157a dose, mg/kg
Stomach
13 (38.2)
Small Intestine Jejunum
5 (14.7)
Parameter
1.6
4.8
64
12.8
Total
(n=5)
(n=13)
(n=2)
100000
Small intestine leum
3 (8.8)
60.5
Small Intestine Duodenum
2 (5.9)
Rectum
2 (5.9)
Any Adverse Events n(%)
4(100)
4(100)
5(100)
13 (100)
8 (100)
2(100)
34 (100)
10000
Other
9 (26.5)
19 (55.9)
Female
15 (44.1)
Nausea
375.0)
3 (75.0)
3(60.0)
11 (84.6)
6 (100)
2(100)
28 (824)
Metastatic Site at Study Entry n(%)
Decreased appetite
3(75.0)
250.0
360.0)
8(48.2)
4 (88.7)
2/100
20 (58.8)
1000-
Country of Enrollment n(%)
24 (70.6)
Anaemia
375.0)
250.0
3 (80.0)
8(48.2)
3 (50.0)
0
17 (50.0)
18 (52.9)
Peritoneum
22 (64.1)
22 (64.7)
Japan
16 (47.1)
3 (75.0)
1 (25.0)
2 (40.0)
8(48.2)
1(18.7)
2(100)
15 (44.1)
100
Bone
3 (8.8)
Lung
8 (23.5)
1 (25.0)
2 (50.0)
2(40.0
5 (38.5)
2 (33.3)
2(100)
14/41.2)
Other
13 (38.2)
125.0
2(400)
4130.8)
5 (83.3)
16 (47.1)
1 (50.0)
13 (38.2)
10
1 (2.9)
1 (25.0)
2 (50.0)
2 (40.01
4 (30.8)
1(16.7)
2(100)
12 (35.3)
16 (47.1)
GPR20 H-score at screening
1 (2.9)
Median
1 (25.0)
250.0)
1(20.0)
2(15.4)
1 (18.7)
2(100)
9 (28.5)
Min. Max
5 (38.5)
4(88.7)
0
9 (28.5)
Starting Dose Level 1.5 mg kg 3.2 mg/kg 4.8 mg/kg 8.4 mg/kg 9.5 mg kg 12.8 mg/kg
3(23.1)
5 (83.3)
1 (50.0)
9 (28.5)
18 (52.9)
GPR20 H-score values n(%)
2(50.0)
1(25.0)
1 (20.0)
3 23.1)
118.7
8 23.5
0.1
16 (47.1)
O to 100
5 (14.7)
>100 to $200
14 (41.2
Aspartate aminotransferase increased
1 (25.0)
1(25.0)
1 (20.0)
323.1)
1/18.7)
1 (50.0)
8 (23.5)
Figure 3. Waterfall Plot of Best Percentage Change in Sum of Diameters from
Baseline in Target Lesions
Number of Prior Systemic Regimens
Median
>200 to $300
Missing
11 (324)
Dizziness
4 30.8)
1/18.7)
2(100)
0.01
4 (11.8)
Insomnia
2/33.3
5.0
Oedema peripheral
17.7)
2 (100)
Dry skin
21400
Headache
4(30.8)
1 (50.0)
1 (500)
817.6)
0 7 14 21 28 35 42 49 56 63 0 7 14 21 28 35 42 49 56 63 0 7 14 21 28 35 42 49 56 63
Nominal time since first dose (d)
1.6 moko
17.7)
1(18.7)
2 (100)
5 14.7)
3.2 mg/kg
2(154)
150.0)
4.8 mg
1 (20.0)
177)
2 (33.3)
5114.7)
2(15.4)
118.7)
1 (50.0)
5 14.7
6.4 mg/kg
3/23.11
514.7)
4 11.8)
3 23.1)
1(50.0)
4 11.8)
2 15.4)
4(11.8)
1(18.7)
1(20.0)
2/15.4)
4 11.8)
3 23.1
1(18.71
4 11.8)
1/18.7
1 (500)
4/11.8)
1 (25.0)
1(25.0)
118.7)
4 11.8)
ECOG Performance status n(%)
0-Normal activity
1 - Symptoms. but ambulatory
PATIENT DISPOSITION SUMMARY
Table 2. Patient Disposition
Parameter
Treatment Status
Ongoing on the Study Treatment
Discontinued from Study Treatment
Primary Reason for discontinuation from Study
Treatment
Adverse Event
Clinical Progression
Other
Physician Decision
Progressive Disease
Withdrawal by Subject
"Other, finished per
Dehydration
Hypertension
Hyperuricaemia
DS-6157a dose, mg/kg
Hypokalaemia
Pyrexia
1.6
32
4.8
(n-4)
(n-4) (n-5)
64
(n-13)
9.6
(n-6) (n-2)
12.8
Total
Cough
(n-34)
Diarrhoea
Dysgeusia
2 (40.0)
0
0
2(5.9)
4 (100)
4 (100) 3 (60.0)
13 (100) 6 (100) 2 (100)
32 (94.1)
Infusion related reaction
Lymphocyte count decreased
Rash maculopapular
0
0
0
3 (23.1)
0
0
3 (8.8)
1 (25.0) 1 (25.0)
0 1 (16.7)
0
3 (8.8)
0
0
1 (7.7)
0
0
1 (2.9)
0
0
2 (15.4) 1 (16.7)
0
3 (8.8)
3 (75.0)
3 (75.0) 3 (60.0) 6 (46.2) 2 (33.3) 2 (100)
1 (7.7) 2 (33.3)
19 (55.9)
3 (8.8)
0
0
• At time of data cut-off, 34 pts were exposed to a median of
3.0 treatment cycles (range 1-18) with DS-6157a. The median
treatment duration was 9.9 weeks (wks) (range 3-56 wks).
Two pts (5.9%) continued to receive study treatment, having
completed 17 and 18 cycles, respectively.
• There were 2 on-treatment deaths. A TEAE of hepatic function
abnormality was the primary cause of death in 1 pt at 6.4 mg/kg
and progressive disease in a second pt at 9.6 mg/kg, respectively.
ADVERSE EVENTS
Table 3. Adverse Events Summary
Dyspnoea
Hypoalbuminaemia
0
The most common (≥35%) of all AEs were nausea (82%), decreased
appetite (59%), anemia (50%), fatigue (44%), constipation (41%),
decreased platelets (38%), and vomiting (35%).
CTCAE GRADE ≥3 TREATMENT RELATED TEAE
Table 5. CTCAE Grade ≥3 Treatment Related TEAE
Blood and lymphatic system disorders
D3-8167a doce, maka
Parameter
1.8
3.2
48
8.8
12.8
Total
Maximum CTCAE Grade -3 Treatment-Related
TEAE
1 (25.0)
1 (20.0)
8 (61.5)
1 (50.0)
15 (47.1)
1 (20.0)
3 (23.1)
1 (16.7)
1 (50.0)
7 (20.6)
1 (20.0)
3 (23.1)
1 (16.7)
6 (17.6)
1 (16.7)
1 (50.0)
2 (5.9)
1 (50.0)
1 (50.0)
1 (77)
1 (50.0)
2 (5.9)
1 (7.7
1 50.0)
150.0
1 (29)
Anaemia
Febrile neutropenia
Gastrointestinal disorders
Vomiting
General disorders and administration site conditions
Fatigue
Oedema peripheral
Hepatobiliary disorders
Hepatic function abnormal
Infections and infestations
122
1 (50.0)
12.8 mg kg
Ryndall Legend CR & PR = ED PONEDarth
Treatment Duration (Most)
Figure 4. A Swimmer Plot of Tumor Response over Time
Figure 2. Mean (SD) Plot of Plasma Concentration-Time Profiles of DS-6157a,
MAAA-1181a, anti-GPR20 Antibody, PK Analysis Set
⚫ PK results from 34 patients indicate that intact DS-6157a, total
anti-GPR20 antibody, and cytotoxic payload (MAAA-1181a) plasma
concentrations increased in a dose dependent manner.
⚫Mild accumulation for AUC 21 between Cycle 3 (at steady state) and
Cycle 1 (after a single dose) at 1.6 mg/kg and 6.4 mg/kg doses was
observed for both intact DS-6157a (1.3 and 1.6, respectively) and
MAAA-1181a (1.1 and 1.5, respectively).
On a molar basis, MAAA-1181a Cin Cycle 1 across 1.6 mg/kg to
9.6 mg/kg dose range were approximately 42-fold to 83-fold lower
than those for intact DS-6157a.
• Total anti-GPR20 antibody and intact DS-6157a have a similar PK
profile, indicating DS-6157a is stable in circulation.
• Preliminary immunogenicity results showed no treatment-emergent
ADA.
RESPONSE PER RECIST v1.1
Table 6. Best Overall Response (BOR) per RECIST v1.1
9.6 maka
10
11
12
13
Image courtesy of Dr. Yoichi Naito
Figure 5b. Cycle 3 CT scan 26 August 2021
Pneumonia
6.4
9.6
mg/kg
12.8
mg/kg
Injury, poisoning and procedural complications
Infusion related reaction
183
DS-6157a dose, makg
DS-6157a dose, mg/kg
Investigations
5 (38.5)
5 (83.3)
1 (50.0)
11 (324)
1.6
32
48
64
9.6
128
Total
Lymphocyte count decreased
1 (7.7)
1 (29)
Parameter
(n=4)
(TF)
(n=13)
(2)
(n=34)
Neutrophil count decreased
3 (500)
5 (14.7)
Platelet count decreased
4 (66.7)
1 (50.0)
1.6
3.2
8 (23.5)
3.2
4.8
mg/kg
mg/kg
Treatment-Emergent Adverse Events (TEAE)
4(100)
4 (100)
5(100)
13 (100)
6(100)
2(100)
34 (100)
White blood cell count decreased
4 (66.7
5(14.7)
Parameter
(n=4) (n=4)
4.8
(n=5)
TEAE associated with Drug Discontinuation*
0
0
0
3(23.1)
1(16.7)
0
4(11.8)
Musculoskeletal and connective tissue disorders
TEAE associated with Dose Interruption
0
0
0
0
1(16.7)
2(100)
3(88)
Muscular weakness
1 (77)
1 (29)
BOR, n (%)
1.6
mg/kg
mg/kg
Figure 1. Dose Level Cohorts
TEAE associated with Dose Reduction
0
0
0
1(50.0)
1(28)
Renal and urinary disorders
1 (16.7)
1 (29)
Renal disorder
1 (16.7)
1 (29)
CR
0
0
0
0
TEAE associated with Death as Outcome
0
17.7)
0
0
1(28)
PR
0
0
0
1 (7.7)
Related Treatment-Emergent Serious Adverse
0
0
17.7)
2(33.3)
1(50.0)
4(11.8)
Event (TESAE)
Adverse Events of Special Interest (AESIF
Interstitial lung disease (ILD/Pneumonitis
Infusion-related reactions (IRR)
D
Dose-Limiting Toxicities (Any Grade by Pasent
0
KEY INCLUSION CRITERIA
.Histopathologically-documented unresectable and/or metastatic
GIST, Part 1
• Enrollment in Part 1 was allowed regardless of GPR20 expression
• At least one measurable lesion per Response Evaluation Criteria in
Solid Tumors (RECIST) v1.1
• Adequate organ function
• Consent to provide fresh tumor biopsy tissue samples before and on
DS-6157a treatment for correlative testing
a Four pts (11.8%) experienced a TEAE leading to drug discontinuation. Three pts at 6.4 mg/kg discontinued; 1 each for interstitial lung disease, infusion-
related reaction, and hepatic function abnormality, while 1 pt discontinued at 9.6 mg/kg for white blood cell count reduction.
bOne pt death was related to an adverse event of hepatic function abnormality.
cOne IRR event at 6.4 mg/kg was Grade 3, while the others were Grade 1. One ILD event at 6.4 mg/kg was Grade 1, which occurred after Cycle 6 and the
pt recovered in 1 month.
d Four pts experienced 1 or more DLTs during Cycle 1 at dose levels 6.4 mg/kg and above as follows: a pt receiving 6.4 mg/kg experienced Grade 3
anemia, Grade 4 hepatic function abnormality, Grade 4 platelet decrease and Grade 5 hepatic function death, a pt at the 9.6 mg/kg dose experienced
Grade 3 anemia, Grade 3 febrile neutropenia, Grade 4 hepatic function abnormality, and Grade 4 platelet decrease and recovered, a pt at the 12.8 mg/kg
dose experienced Grade 3 neutropenic fever and recovered, and a second pt at the 12.8 mg/kg dose experienced Grade 2 dehydration, diarrhea, nausea
and vomiting and recovered. The MTD for DS6157a was determined to be 6.4 mg/kg, per the DLT information.
We thank all of the patients and family members for their participation in this trial.
We thank all of the investigators and their support staff who participated in this work.
REFERENCES
SDa
2 (50.0)
3 (75.0)
3 (60.0)
7 (53.8)
0
0
4(308)
1(16.7)
0
5(14.7)
0
1(7.7)
0
0
1(28)
1. Ilda K, et al. Poster presented at: Annual American Association for Cancer Research Meeting; June 22-24, 2020.
Abstract 5181.
PD
2 (50.0)
0
2 (40.0)
3 (23.1)
NE
0 1 (25.0)
0
2(15.4)
0
0
3(23.1)
1(16.7)
0
4(11.8)
0
0
1 (9.1)
1/16.7)
2 (100)
4(12.9)
ACKNOWLEDGMENTS
Copies of this [poster/slide deck] obtained through Quick Response
(QR) Code are for personal use only and may not be reproduced without
permission from ASCO or the author of this (poster/slides].
*BOR for 30 is considered confimed resoonseen assesment occured >5 weeks from starting treatment
Tumor shrinkage was observed in 4 pts with KIT/PDGFRA wild-type
GIST who had at least one restaging scan, and were treated at different
doses. These included a confirmed PR at the MTD of 6.4 mg/kg in a
patient with SDH-deficient GIST with both SDH B and NF1 mutations
(See Figure 5).
Figure 5a. Screening CT scan 22 June 2021
Figure 5. SDH-deficient GIST Patient with Pathological PR
⚫A 29 y/o female pt with SDH-deficient GIST diagnosed in 2020 without
any prior cancer systemic therapies, demonstrated a maximum 87%
decrease in tumor size, following treatment with DS-6157a, at the MTD
confirmed dose of 6.4 mg/kg.
•The target lesion, an abdominal mass, was 150 mm at baseline
(Figure 5a) which decreased to 33 mm in Cycle 3, and decreased further
to 20 mm 4 weeks later (Figure 5b).
• The pt discontinued from study to undergo a surgical resection of the
remaining small lesion to become tumor-free. The resected tumor
showed a pathological CR per the Investigator's assessment.
CONCLUSIONS
DS-6157a was generally well-tolerated with early signs of moderate
clinical activity. Tumor shrinkage was observed in only 4 pts with
KIT/PDGFRA wild-type GIST treated at different doses. One pt with
SDH-deficient GIST with both SDH-B and NF1 mutations achieved
a PR per CT scan, and then complete pathological response after
surgical resection.
The study did not proceed to the Part 2 expansion phase, because the
efficacy targets were not met in Part 1.
6.4
(n=13) (n=6)
9.6
12.8
Total
(n=2)
(n=34)
0
0
0
0
0
1(29)
2 (33.3)
0
17 (50.0)
1 (16.7)
2 (100)
10 (29.4)
3 (50.0)
0
6 (17.6)
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