Antibody-drug conjugates for solid tumours: Current understanding and future directions

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What is the current status of ADCs for solid tumours?

Prof. Giuseppe Curigliano

Associate Professor of Medical OncologyUniversity of Milan, Milan, Italy

How do antibody-drug conjugates differ from other

treatments for solid tumours?

Antibody-drug conjugate mechanism of action1

1. Bouchard et al, Bioorg Med Chem Lett. 2014;24:5357–63; 2. Staudacher AH, Brown MP. Br J Cancer. 2017;117:1736–42.

Drug

Linker

Tumour cell surface-specific

monoclonal antibody

Endocytosis

Lysosome

Drug release

Binding to intracellular target

Celldeath

Binding to intracellular target Cell

death

External drug release

‘Bystander effect’2

What were the key efficacy findings in solid tumours for

emerging antibody-drug conjugates in 2020?

Summary of key efficacy data

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.

DESTINY-Lung01, phase II study of trastuzumab deruxtecan in HER2 overexpressing NSCLC1

(N=49)Median PFS: 5.4 months

(95% CI, 2.8–7.0)

DESTINY-Gastric01, phase II study of trastuzumab deruxtecan in HER2+ gastric cancer2

(N=125)Median PFS: 5.6 months

(95% CI, 4.3–6.9)100

0

40

60

80

20

Pro

bab

ility

of

PFS

(%

)

Time (months)0 1 132 3 4 10 11 125 6 7 8 9

Indicates upper andlower 95% CICensored cases

49 45 029 26 23 2 2 217 10 7 5 3No. of patients at risk

Trastuzumab deruxtecanPhysician’s choice of chemotherapy

100

0

40

60

80

20

10

20

20

20

90

Time (months)0 3 246 18 219 12 15

Trastuzumab deruxtecanPhysician’s choice of chemotherapy

No. of patients at risk

Pe

rce

nta

ge o

f p

atie

nts

(%

)

66

80

29

52

125 115 088 7 354 33 14

62 54 037 2 019 10 2

Summary of key efficacy data

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.

EV-301, phase III study of enfortumab vedotin in bladder cancer

EV (n=301) ChT (n=307)

Number of deaths 134 167

Median OS, months (95% CI)

12.88(10.58–15.21)

8.97 (8.05–10.74)

HR (95% CI), p-value 0.70 (0.56–0.89), p=0.001

100

0

40

50

80

10

20

30

60

70

90

Pe

rce

nta

ge o

f p

atie

nts

aliv

e

Time (months)No. of patients at riskEnfortumab

vedotinChemotherapy

0 3 246 9 12 15 18 211 2 4 5 7 0 11 13 14 16 17 19 20 22 238

301 257 0222 130 63 33 7 2286 272 246 234 190 105 85 52 42 23 15 4 3 1 1158

307 250 0198 101 51 29 6 2288 274 238 219 163 84 66 44 32 16 11 4 2 1 0131

Enfortumab vedotinChemotherapyCensored

Summary of key efficacy data

CI, confidence interval; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; ORR, objective response rate; PFS, progression-free survival; SG, sacituzumabgovitecan; TNBC, triple-negative breast cancer; TPC, treatment of physician’s choice.1. Bardia A, et al. LBA17, presented at ESMO 2020.

ASCENT, phase III study of sacitzuzmab govitecan in metastatic TNBC

SG (n=235) TPC (n=233)

Number of events 166 150

Median PFS, months (95% CI)

5.6(4.3–6.3)

1.7 (1.5–2.6)

HR (95% CI), p-value 0.41 (0.32–0.52), p<0.0001

ORR, % 35 5

p-value p<0.0001

100

0

40

60

80

20Pro

bab

ility

of

PFS

(%

)

Time (months)No. of patients at risk

SG

TPC

0 3 246 9 12 15 18 21

SGTPCCensored

235 134 81 37 22 13 8 1222 166 127 104 63 54 33 24 05 316 15 89

233 35 12 6 2 1 0 0179 78 32 19 9 7 4 2 00 02 2 00

What are the key adverse events associated with

antibody-drug conjugates?

Common AEs in approved ADCs

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).

Neutropenia

Enfortumab vedotin: 4%Trastuzumab duocarmazine: 6%Trastuzumab deruxtecan: 16%Sacituzumab govitecan: 43%

Anaemia

Trastuzumab deruxtecan 7%Sacituzumab govitecan: 12%

Vomiting

Enfortumab vedotin: 2%Trastuzumab deruxtecan: 3.8%

Sacituzumab govitecan: 6%

Fatigue

Enfortumab vedotin: 6%Trastuzumab duocarmazine: 4%

Trastuzumab deruxtecan: 6%Sacituzumab govitecan: 8%

Grade ≥31–4Nausea

Enfortumab vedotin: 3%Trastuzumab deruxtecan: 7%Sacituzumab govitecan: 6%

Conjunctivitis

Trastuzumab duocarmazine: 3%

Diarrhoea

Enfortumab vedotin: 6%Trastuzumab deruxtecan: 1.7%

Sacituzumab govitecan: 9%

Rash

Enfortumab vedotin: 13%Sacituzumab govitecan: 3%

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

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

Efficient targeting agent

Tumour cell specificity

Nanoscale drug carrier

Higher therapeutic index

Bystander effect

Off-target toxicity

Target antigen must be on all tumour cells

MDRPs can remove released drug from target cell

mAb size makes solid tumour penetration difficult

What’s next for ADCs in 2021 and beyond?

Prof. Giuseppe Curigliano

Associate Professor of Medical OncologyUniversity of Milan, Milan, Italy

When and how would emerging antibody-drug conjugates be

incorporated into the treatment paradigm?

Sequence of treatment

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.

Treatment of HER2+ advanced breast cancer

Trastuzumab deruxtecan

Other option not previously used to block HER2

Progression

T-DM1 (if available)

Previous treatment with (neo) adjuvant pertuzumab + trastuzumab

with a DFI <6–12 months

Unsuitable for ChT or with long DFI, minimal disease burden, and ER+

Anti-HER2 + ET

Trastuzumab + lapatinib

Trastuzumab + unused ChT

Trastuzumab + unused ET

if ER+

Tucatinib + trastuzumab + capecitabine

Second line

Third line

Fourth lineand beyond

First line

How do you manage adverse events and monitor patients

receiving ADCs?

Trastuzumab deruxtecan3

Interrupt dose until grade ≤2

Dose reduction 5.4 mg/kg→4.4 mg/kg →

3.2 mg/kg

Discontinue treatment if further dose

reduction required

How to manage common adverse eventsGrade ≥3 haematological toxicities, such as neutropenia

Sacituzumab govitecan4

Reduce dose by 25% at first occurrence

Reduce dose by 50% at second occurrence

Discontinue treatment at third occurrence

Trastuzumab duocarmazine2

Dose reduction 1.2 mg/kg Q3W→

0.9 mg/kg Q3W or

1.2 mg/kg Q6W

Enfortumab vedotin1

Interrupt dose until grade ≤1

Resume at same dose or consider dose

reduction by one level1.25 mg/kg →1.0 mg/kg→

0.75 mg/kg →0.5 mg/kg

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 trialsEstimated study completion date

Clinical trials listed by their identifiers at: ClinicalTrials.gov

2021 2022 2023 2024

Trastuzumab deruxtecanDESTINY-Breast 02NCT03523585

Trastuzumab deruxtecanDESTINY-Breast 03NCT03529110

Trastuzumab deruxtecan

DESTINY-Breast 04 NCT03734029

Trastuzumab deruxtecanDESTINY-Lung 02

NCT04644237

Trastuzumab deruxtecanDESTINY-Lung 03

NCT04686305

DatopotamabderuxtecanTROPION-LUNG01

NCT04656652

DatopotamabderuxtecanTROPION-PanTumorNCT03401385

ARX788ACE-Pan

Tumor-01 NCT03255070

Patritumabderuxtecan

HERTHENA-Lung01 NCT04619004

BAT8001 NCT04185649

Tisotumabvedotin

ENGOT-cx6 NCT03438396

EnfortumabvedotinEV-301

NCT03474107

Trastuzumab duocarmazine

TULIPNCT03262935

What are the future directions for

antibody-drug conjugates?

Future directions

New targets1 Drug-antibody ratio improvement2

Next-generation sequencing4

Antibody fragment-drug

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.