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Antibody-drug conjugates for solid tumours: Current understanding and future directions Disclaimer
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Prof. Giuseppe Curigliano
Associate Professor of Medical Oncology University of Milan, Milan, Italy How do antibody-drug conjugates differ from other treatments for solid tumours? Antibody-drug conjugate mechanism of action1
Lysosome Endocytosis
Drug Cell External drug death release Binding to Drug Linker intracellular release target
Tumour cell surface-specific monoclonal antibody Binding to ‘Bystander intracellular effect’2 target Cell death
1. Bouchard et al, Bioorg Med Chem Lett. 2014;24:5357–63; 2. Staudacher AH, Brown MP. Br J Cancer. 2017;117:1736–42. What were the key efficacy findings in solid tumours for emerging antibody-drug conjugates in 2020? Summary of key efficacy data
DESTINY-Lung01, phase II study of trastuzumab DESTINY-Gastric01, phase II study of trastuzumab deruxtecan in HER2 overexpressing NSCLC1 deruxtecan in HER2+ gastric cancer2 (N=49) (N=125) Median PFS: 5.4 months Median PFS: 5.6 months (95% CI, 2.8–7.0) (95% CI, 4.3–6.9) 100 100 90 80 80 80 20 66 60 60 52 20 40 40 20 Indicates upper and Trastuzumab deruxtecan 20 20 29
Probability of PFS(%) lower 95% CI Physician’s choice of 10 Censored cases Percentage of patients (%) chemotherapy 0 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 0 3 6 9 12 15 18 21 24 No. of patients at risk Time (months) No. of patients at risk Time (months) 49 45 29 26 23 17 10 7 5 3 2 2 2 0 Trastuzumab deruxtecan 125 115 88 54 33 14 7 3 0 Physician’s choice of 62 54 37 19 10 2 2 0 0 chemotherapy
CI, confidence interval; HER2, human epidermal growth factor receptor 2; NSCLC, non-small cell lung cancer; PFS, progression-free survival. 1. Nakagawa K et al. Presented at World Conference on Lung Cancer Annual Meeting: 28–31 January 2021 2. Shitara K, et al. N Engl J Med. 2020;382:2419–30. Summary of key efficacy data EV-301, phase III study of enfortumab vedotin in bladder cancer
EV (n=301) ChT (n=307) 100 Number of deaths 134 167 90 Median OS, months 12.88 8.97 80 (95% CI) (10.58–15.21) (8.05–10.74) 70 HR (95% CI), p-value 0.70 (0.56–0.89), p=0.001 60 50 40 30 20 Enfortumab vedotin
Percentage of patients alive Chemotherapy 10 Censored 0 0 1 2 3 4 5 6 7 8 9 0 11 12 13 14 15 16 17 18 19 20 21 22 23 24 No. of patients at risk Time (months) Enfortumab 301 286 272 257 246 234 222 190 158 130 105 85 63 52 42 33 23 15 7 4 3 2 1 1 0 vedotin Chemotherapy 307 288 274 250 238 219 198 163 131 101 84 66 51 44 32 29 16 11 6 4 2 2 1 0 0
ChT, chemotherapy; CI, confidence interval; EV, enfortumab vedotin; HR, hazard ratio; OS, overall survival. 1. Powles T, et al. N Engl J Med. 2021; doi: 10.1056/NEJMoa2035807. Summary of key efficacy data ASCENT, phase III study of sacitzuzmab govitecan in metastatic TNBC
100 SG (n=235) TPC (n=233) Number of events 166 150 80 Median PFS, months 5.6 1.7 (95% CI) (4.3–6.3) (1.5–2.6) HR (95% CI), p-value 0.41 (0.32–0.52), p<0.0001 60 ORR, % 35 5
40 p-value p<0.0001
Probability of PFS(%) 20 SG TPC Censored 0 0 3 6 9 12 15 18 21 24 No. of patients at risk Time (months) SG 235 222 166 134 127 104 81 63 54 37 33 24 22 16 15 13 9 8 8 5 3 1 0 TPC 233 179 78 35 32 19 12 9 7 6 4 2 2 2 2 1 0 0 0 0 0 0 0 CI, confidence interval; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; ORR, objective response rate; PFS, progression-free survival; SG, sacituzumab govitecan; TNBC, triple-negative breast cancer; TPC, treatment of physician’s choice. 1. Bardia A, et al. LBA17, presented at ESMO 2020. What are the key adverse events associated with antibody-drug conjugates? Common AEs in approved ADCs Conjunctivitis 1–4 Grade ≥3 Nausea Trastuzumab duocarmazine: 3% Enfortumab vedotin: 3% Trastuzumab deruxtecan: 7% Vomiting Sacituzumab govitecan: 6% Enfortumab vedotin: 2% Trastuzumab deruxtecan: 3.8% Anaemia Sacituzumab govitecan: 6% Trastuzumab deruxtecan 7% Sacituzumab govitecan: 12% Diarrhoea Neutropenia Enfortumab vedotin: 6% Enfortumab vedotin: 4% Trastuzumab deruxtecan: 1.7% Trastuzumab duocarmazine: 6% Sacituzumab govitecan: 9% Trastuzumab deruxtecan: 16% Sacituzumab govitecan: 43%
Fatigue Rash Enfortumab vedotin: 6% Enfortumab vedotin: 13% Trastuzumab duocarmazine: 4% Sacituzumab govitecan: 3% Trastuzumab deruxtecan: 6% Sacituzumab govitecan: 8% ADC, antibody-drug conjugate; AE, adverse event. 1. RxList. 2020. Available at: www.rxlist.com/padcev-side-effects-drug-center.htm (accessed 12 February 2021); 2. RxList. 2020. Available at: www.rxlist.com/enhertu-side-effects- drug-center.htm (accessed 12 February 2021); 3. Banerji U, et al. Lancet Oncol. 2019;20:1124–35; 4. RxList. 2020. Available at: www.rxlist.com/trodelvy-side-effects-drug- center.htm (accessed 12 February 2021). What are the benefits of antibody-drug conjugates over other available treatments for solid tumours in clinical practice? Antibody-drug conjugate pros and cons1,2
Off-target toxicity Efficient targeting agent Target antigen must be on all tumour Tumour cell specificity cells Nanoscale drug carrier MDRPs can remove released drug from target cell Higher therapeutic index mAb size makes solid tumour Bystander effect penetration difficult
mAb, monoclonal antibody; MDRP, multi-drug resistance pump. 1. Nagayama A, et al. Target Oncol. 2017;12:719–39; 2. Tarcsa E, et al. Drug Discov Today Technol. 2020;doi:10.1016/j.ddtec.2020.07.002 What’s next for ADCs in 2021 and beyond?
Prof. Giuseppe Curigliano
Associate Professor of Medical Oncology University of Milan, Milan, Italy When and how would emerging antibody-drug conjugates be incorporated into the treatment paradigm? Sequence of treatment Treatment of HER2+ advanced breast cancer
Unsuitable for ChT or with long DFI, Previous treatment with (neo) First line minimal disease burden, and ER+ adjuvant pertuzumab + trastuzumab with a DFI <6–12 months Anti-HER2 + ET
Progression
Second line T-DM1 (if available)
Tucatinib Trastuzumab Trastuzumab Trastuzumab + Trastuzumab Third line + trastuzumab + unused ET deruxtecan lapatinib + unused ChT + capecitabine if ER+
Fourth line Other option not previously used to block HER2 and beyond ADC, antibody-drug conjugate; ChT, chemotherapy; DFI, disease-free interval; ER, oestrogen receptor; HER2, human epidermal growth factor receptor 2; ET, endocrine treatment. 1. Cardoso F, et al. Ann Oncol. 2020;31:1623–49. How do you manage adverse events and monitor patients receiving ADCs? How to manage common adverse events Grade ≥3 haematological toxicities, such as neutropenia
Enfortumab vedotin1 Trastuzumab duocarmazine2 Trastuzumab deruxtecan3 Sacituzumab govitecan4
Interrupt dose until Interrupt dose until grade ≤1 grade ≤2 Reduce dose by 25% at Resume at same dose Dose reduction Dose reduction first occurrence or consider dose 1.2 mg/kg Q3W → 5.4 mg/kg → Reduce dose by 50% at reduction by one level 0.9 mg/kg Q3W 4.4 mg/kg → second occurrence 1.25 mg/kg → or 3.2 mg/kg Discontinue treatment 1.0 mg/kg → 1.2 mg/kg Q6W Discontinue treatment at third occurrence 0.75 mg/kg → if further dose 0.5 mg/kg reduction required
Q3W, every 3 weeks; Q6W, every 6 weeks. 1. US Food and Drug Administration. 2020. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2019/761137s000lbl.pdf (accessed 12 February 2021); 2. Banerji U, et al. Lancet Oncol. 2019;20:1124–35; 3. US Food and Drug Administration. 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761139s000lbl.pdf (accessed 12 February 2021); 4. US Food and Drug Administration. 2020. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2020/761115s000lbl.pdf (accessed 12 February 2021). Which ongoing clinical trials of emerging antibody-drug conjugates are of most interest? Ongoing trials Estimated study completion date
Trastuzumab Trastuzumab Trastuzumab Enfortumab deruxtecan deruxtecan deruxtecan vedotin DESTINY- DESTINY- DESTINY- BAT8001 EV-301 Breast 04 Lung 03 Breast 02 NCT04185649 NCT03474107 NCT03734029 NCT04686305 NCT03523585
2021 2022 2023 2024
Trastuzumab ARX788 Datopotamab Trastuzumab Tisotumab Patritumab deruxtecan duocarmazine vedotin deruxtecan deruxtecan ACE-Pan DESTINY- Tumor-01 TROPION- TULIP ENGOT-cx6 HERTHENA-Lung01 NCT03262935 NCT03438396 Lung 02 NCT04619004 NCT03255070 PanTumor NCT04644237 NCT03401385 Datopotamab Trastuzumab deruxtecan deruxtecan TROPION- DESTINY- LUNG01 Breast 03 NCT04656652 NCT03529110 Clinical trials listed by their identifiers at: ClinicalTrials.gov What are the future directions for antibody-drug conjugates? Future directions
Drug-antibody New targets1 ratio improvement2
Antibody Next-generation fragment-drug sequencing4 conjugates3
1. Yamaguchi K, et al. Ann Oncol. 2020;31:S899–900; 2. Coats S, et al. Clin Cancer Res. 2019;25:5441–8; 3. Tarcsa E, et al. Drug Discov Today Technol. 2020; doi:10.1016/j.ddtec.2020.07.002; 4. Garczyk, S, et al. Am J Pathol 2020;190:323–32.