Integrating ADCs into the Current Paradigm - Gottfried E. Konecny Professor of Medicine and OB/GYN David Geffen School of Medicine University of ...
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Integrating ADCs into the Current Paradigm Gottfried E. Konecny Professor of Medicine and OB/GYN David Geffen School of Medicine University of California Los Angeles Monday, March 22nd 2021
Antibody Drug Conjugate Tactic
Determinants of Success ADC drug specific:
Determinants of Success
ADC drug specific:
Tumor selectivity
Tumor Normal
Determinants of Success ADC drug specific: Tumor selectivity Endocytosis
Determinants of Success ADC drug specific: Tumor selectivity Endocytosis Intracellular activation
Determinants of Success ADC drug specific: Tumor selectivity Endocytosis Intracellular activation Bystander effects
Determinants of Success
ADC drug specific:
Tumor selectivity
Endocytosis Payload
Intracellular activation Drug A
Bystander effects
Efficacy of payload
Payload
Drug B
Determinants of Success ADC drug specific: Tumor selectivity Endocytosis Intracellular activation Bystander effects Efficacy of payload Patient specific: Target expression level Prior treatments Folate receptor α expression: Negative (a), Performance status low (b), moderate (c), and high (d).
Multiple Variables
Antibody Targets HER2
MUC16 (CA125)
MSLN (Mesothelin)
TROP2 (Tumor-associated calcium signal transducer 2)
FOLR1 (Folate receptor alpha)
NaPi2b (Sodium-dependent phosphate transport protein 2B)
TF (Tissue factor, thromboplastin, CD142)
PTK7 (Tyrosine-protein kinase-like 7)
TIM (T cell immunoglobin and mucin domain)
NOTCH3 (Neurogenic locus notch homolog protein 3)
CD166 (ALCAM, activated leucocyte cell adhesion molecule)
Linker Cleavable linkers (lysosomal proteases, acidic pH, disulfide bridges)
Non-cleavable linkers
Hydrophilic linkers
Cytotoxic Payload Auristatins (MMAE, MMAF)
Maytansinoids (DM1, DM4)
Pyrrolobenzodiazepines
SN-38Lessons learned
Mirvetuximab Soravtansine - FORWARD I
• N= 366, 2:1 randomization
• PFS, ITT (HR 0.98, P = 0.897); FRα high population (HR 0.69, P = 0.049)
• Superior outcomes for mirvetuximab soravtansine over chemotherapy
in all secondary endpoints in the Frα high population:
• ORR (24% v 10%),
• CA-125 responses (53% v 25%),
• PRO (27% v 13%).
• Grade ≥3 AEs (25.1% v 44.0%),
• Dose reductions (19.8% v 30.3%)
• Treatment discontinuation (4.5% v 8.3%)
Moore K et al. Ann Oncol. 2021 Mar 2:S0923-7534Need Validated Biomarkers with Defined Cut-offs
The Payload Counts!
• MSLN - Anetumab Ravtansine
• Anti-mesothelin mAb, maytansinoid DM4, reducible SPDB linker
• Metastatic mesothelin-positive malignant pleural mesothelioma
• Progressed after first-line platinum/pemetrexed chemotherapy
• The trial randomized 248 patients in a 2:1 ratio to receive either
anetumab ravtansine or vinorelbine
Hassan R et al. JCO 34;15, suppl. TPS8576Combination Strategies
Mirvetuximab + Bevacizumab
Maximum % Change from Baseline
N = 60 Medium FRα
1-2 prior lines (70%)
High FRα
Plat. resistent (50%)
Medium or high FRα membrane staining with IHC -PS2+ scoring (intensity and %)
Medium expressors ≥ 50%Mirvetuximab + Bevacizumab
Total FRα Platinum status
Population Expression (High FRα)
69%
64% 59%
47%
26%
Gilbert L et al ASCO 2020 PresentationMirvetuximab + Carboplatin (Plat. Sens.)
CARBOPLATIN
CHARACTERISTIC
(n=18)
Prior lines of therapy
1-2 9 (50)
3+ 9 (50)
Platinum-free treatment interval, n
(%)*
≤ 12 months 11 (65)
> 12 months 6 (35)
FR⍺ expression, n (%)
High 7 (39)
Medium 4 (22)
Low 7 (39)
ORR, n (%)
All 71%
Folate receptor high 80%
Moore K et al GYN Oncology 2018Mirvetuximab + Carboplatin + Bevacizumab
• N= 41, platinum sensitive recurrence
• 71% One prior line of chemotherapy
• ORR 83% (34/41)
• 22 pts (54%) discontinued at least one
drug due to treatment-related AEs
O’Malley DM et al. ESMO 2020 abstr. 833PBest Integration?
M I R V E T U X I M A B + B E VA C I Z U M A B
64% ORR
• Compelling activity in FRα-high recurrent ovarian cancer,
regardless of platinum status, compared to available
Move into earlier lines FRα-HIGH RECURRENT
OVARIAN CANCER
therapies
− 59% ORR (10/17) in the platinum-resistant subgroup
of therapy as
n= 33
− 69% ORR (11/16) in the platinum-sensitive subgroup
combination partner
M I R V E T U X I M A B + C A R B O P L AT I N
80% ORR
• Highly active in recurrent platinum-sensitive ovarian cancer
Or 15 MOS mPFS
FRα-MED and -HIGH
n= 10
Choice as later line of
therapy in recurrent MIRVETUXIMAB TRIPLET
MIRVETUXIMAB + BEVACIZUMAB + CARBOPLATIN
disease? 83% ORR • Efficacy outcomes encouraging relative to current standard
12.8 MOS mPFS of care triplet regimens
FRα-MED and -HIGH
n= 41TROP2 Sacituzumab Govitecan
• Anti–Trop-2 mAb, (SN38) irinotecan metabolite. pH-sensitive cleavable linker
• 108 TNBC patients, median 3 prior line of therapy, ORR 33%
• FDA approval in TNBC
Bardia A et al. N Engl J Med 2019;380:741-751.Sacituzumab Govitecan + PARPis
Preclinical study in TNBC models
Cardillo TM et al. Clin Cancer Res 2017;DOI:10.1158Sacituzumab Govitecan + PARPi (Rucaparib)
Yap T et al. ESMO 2020 abstr. 547P
(SEASTAR study NCT03992131)Mirvetuximab + PARPi (Rucaparib)
• Phase I, OC/EC
• N= 18
• Median 3 prior lines
• Phase II dose:
• Mirv. 5 mg/kg AIBW + rucaparib 400 BID
Backes F et al. SGO 2021ADC Targets Gene Expression By HRD Status
in Ovarian Cancer (TCGA)Broadening Indications
HER2 Trastuzumab Deruxtecan in OC/EC?
• HER2 mAb, topoisomerase I inhibitor, a tetrapeptide linker
• Phase II study in BC, HER2-low (IHC 1+ or IHC 2+/FISH-
Modi S et al. J Clin Oncol 2020;38(17):1887-1896.HER2 Trastuzumab Duocarmazine in OC/EC?
• HER2 mAb, duocarmazine, a cleavable linker
• Phase I Study, multiple tumor types
• N=39 (dose escalation), N=146 dose expansion
• ORR 40% (6/15) in HER2 low BC
• ORR 39% (5/13) in endometrial cancer
Banerji U et al. Lancet Oncol 2019;20(8):1124-1135TROP2 Sacituzumab Govitecan in EC?
• Anti–Trop-2-SN-38
• Preclinical study in endometrial cancer
Perrone E et al. Molecular Oncology 2020;14:645-656.TF – Tisotumab Vendotin
• 55 patients with cervical cancer
• 51% ≥ 2 prior lines, 67% prior bevacizumab and doublet
chemotherapy
• ORR 24%, PFS rate at 6 months was 29%
• Accelerated approval application submitted to the FDA
Hong DS et al. Clin Cancer Re 2020;26(6):1220.TF – Tisotumab Vendotin in OC?
• Anti – TF mAB, auristatin (MMAE), protease cleavable valine-citrulline linker
• 147 patient with solid tumors, unselected for TF expression
Cervix Ovary
ORR 9/34 26% ORR 5/36 14%
De Bono JS et al. Lancet Oncol 2019;37.15_suppl.5520.MSLN - Anetumab Ravtansine in OC?
• Anti-mesothelin mAb, maytansinoid DM4, reducible SPDB linker
• N=148, mesothelioma, ovarian, pancreatic, breast cancer, NSCLC
Hassan R et al. J Clin Oncol 2020;38.16:1830.ADC Targets Gene Expression By Tumor Type
ADC Targets Gene Expression By Histology in Endometrial Cancer
Novel ADC Targets
NaPi2b – Mersana XMT-1536 in OC
• Anti – NaPi2b mAB, auristatin-F, DolaLock linker
• 1-3 prior lines in platinum-resistant OC
• 4 prior lines regardless of platinum status
• N = 47
ORR 10/29 (34%)
DCR 23/29 (79%)
Hamilton E et al. ESMO 2020, abstr. 2365.PTK7 - Cofetuzumab Pelidotin
• Anti-PTK7 mAb linked to auristatin, Cleavable valine-citrulline linker
Damelin M et al. Science Translational Medicine 2017;9:1-11.CD166 - CX-2009
• Anti-CD166 monoclonal antibody linked to DM4, protease cleaved
linker
• Phase I/II Study, 7 tumor types
• 37 patients with platinum resistant OC or EC
• High CD166 was found in 14/24 tumors
• MTD not reached
• PRs seen in CD166 high tumors
Meric-Bernstam F et al. AACR; Cancer Res 2019;79:abstr LB-185Rational Trial Design in Ovarian Cancer
ADC Targets Gene Expression By Molecular Subtype in Ovarian Cancer
ADC Targets Gene Correlations in OC
Successful Integration of an ADC will depend on: • Tumor selectivity of the target • Target internalization, intracellular activation of the payload • DAR, by-stander effects and the final efficacy of the payload • Appropriate patient selection • Availability of integrated biomarkers and validated assays • Development of rational combination strategies • Low toxicity – (special attention to ocular toxicity) • Integration driven by science not marketing needs
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