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The Oncology Market for Antibody–Drug Conjugates

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NEWS & ANALYSIS FROM THE ANALyst’s COUCH The oncology market for + antibody–drug conjugates Carolina do Pazo, Khurram Nawaz and Rachel M. Webster caracterdesign/E Credit: Antibody–drug conjugates (ADCs) are Solid tumours. Trastuzumab emtansine Enfortumab vedotin (Padcev, Seagen/ becoming increasingly prominent in the (T- DM1; Kadcyla, Roche) was the first Astellas Pharma) is an MMAE-conjugated oncology landscape. Eleven ADCs are ADC to be approved for any solid tumour. nectin-4- directed mAb and the first ADC marketed worldwide for haematological This therapy is approved for early-stage and to enter the urothelial cancer market. The and solid tumour malignancies, of which metastatic, HER2+ breast cancer. most recently approved ADC is cetuximab six have gained regulatory approval since A second HER2- targeted ADC, sarotalocan (Akalux, Rakuten Medical), 2019. Most ADCs comprise a cytotoxic trastuzumab deruxtecan (Enhertu, Daiichi an epidermal growth factor receptor agent attached to a monoclonal antibody Sankyo/AstraZeneca), is approved for previ- (EGFR)- targeted mAb conjugated to a (mAb) that targets a specific tumour- ously treated metastatic HER2+ breast cancer. dye that induces tumour cell death upon associated antigen. This approach combines Trastuzumab emtansine and trastuzumab photoactivation; it was granted conditional the targeted delivery of the mAb with the deruxtecan differ in their cytotoxic payloads approval for head and neck cancer in Japan tumour- killing potential of the payload, (a tubulin inhibitor and topoisomerase I in September 2020. which is generally too toxic to be systemically inhibitor, respectively). Trastuzumab derux- administered. tecan is also approved for previously treated Late- phase pipeline metastatic HER2+ gastric cancer. A plethora of ADCs directed at both existing Approved ADCs Sacituzumab govitecan (Trodelvy, Gilead and novel targets are currently in clinical Haematological malignancies. Gemtuzumab Sciences), an anti-TROP2 mAb conjugated development (Table 1). ozogamicin (Mylotarg, Pfizer), an anti-CD33 to SN-38, the active metabolite of irinotecan, Trastuzumab duocarmazine (Byondis) mAb–calicheamicin conjugate and the first is approved for previously treated metastatic is an investigational anti-HER2 ADC in ADC for oncology, was granted accelerated triple- negative breast cancer. phase III development for metastatic HER2+ approval for relapsed CD33+ acute myeloid leukaemia (AML) in 2000. The drug was Table 1 | Select antibody- drug conjugates in late-phase development withdrawn in 2010 for toxicity and lack of efficacy in a phase III trial, but the FDA Drug Company Target Indication Status approved a lower, fractionated dose in Trastuzumab Byondis HER2 Breast cancer Phase III 2017. This drug is also approved in Japan duocarmazine and Europe. Disitamab vedotin RemeGen HER2 Breast cancer Phase III Brentuximab vedotin (Adcetris, Mirvetuximab ImmunoGen FRα Ovarian cancer Phase III Seagen/Takeda), a CD30- specific mAb soravtansine linked to monomethyl auristatin E (MMAE), Tisotumab vedotin Seagen/Genmab TF Cervical cancer Phase III became the second ADC to enter the oncology market. It is approved in the USA, Datopotamab Daiichi Sankyo/ TROP2 NSCLC Phase III Europe and Japan for Hodgkin lymphoma deruxtecan AstraZeneca and anaplastic large cell lymphoma. SAR408701 Sanofi CEACAM5 NSCLC Phase III There are also two ADCs approved that Loncastuximab tesirine ADC Therapeutics CD19 DLBCL Phase III target CD22: inotuzumab ozogamicin Camidanlumab tesirine ADC Therapeutics/ CD25 Hodgkin lymphoma Phase II (Besponsa, Pfizer) for relapsed/refractory Genmab (R/R) acute lymphoblastic leukaemia and Patritumab deruxtecan Daiichi Sankyo HER3 NSCLC, colorectal Phase II moxetumomab pasudotox (Lumoxiti, cancer AstraZeneca/Innate Pharma) for R/R hairy L- DOS47 Helix BioPharma CEACAM6 NSCLC, pancreatic Phase II cell leukaemia. cancer In the past 2 years, two ADCs with novel targets have been approved: polatuzumab Ladiratuzumab vedotin Seagen/Merck & Co. LIV1 Breast cancer Phase II vedotin (Polivy, Roche) and belantamab CX-2029 CytomX /AbbVie CD71 DLBCL, select solid Phase II mafodotin (Blenrep, GlaxoSmithKline). tumours Polatuzumab vedotin delivers MMAE to CX-2009 CytomX CD166 Breast cancer Phase II B cells expressing CD79b and is approved BA3011 BioAtla AXL NSCLC, soft tissue Phase II for patients with R/R diffuse large B cell sarcoma lymphoma (DLBCL). Belantamab mafodotin BT1718 Bicycle Therapeutics MT1- MMP Solid tumours Phase II targets BCMA (also known as TNFRSF17) CEACAM5, carcinoembryonic antigen- related cell adhesion molecule 5; DLBCL, diffuse large B cell and is approved for patients with R/R lymphoma; FRα; folate receptor-α ; MT1- MMP, membrane type 1- matrix metalloprotease; NSCLC, multiple myeloma. non- small- cell lung cancer; TF, tissue factor. NATURE REVIEWS | DRUG DISCOVERY VOLUME 20 | AUGUST 2021 | 583 0123456789();: NEWS & ANALYSIS 6,500 Market indicators Trastuzumab deruxtecan (HER2) 6,000 Enfortumab vedotin (Nectin-4) Global sales of currently marketed ADCs 5,500 Trastuzumab emtansine (HER2) are forecast to exceed US$16.4 billion in 5,000 Brentuximab vedotin (CD30) (Fig. 1) Sacituzumab govitecan (TROP2) 2026 . In this analysis, trastuzumab 4,500 Polatuzumab vedotin (CD79b) deruxtecan will garner global 2026 sales 4,000 Belantamab mafodotin (BCMA) of $6.2 billion and will therefore be the Inotuzumab ozogamicin (CD22) 3,500 highest- selling ADC by a considerable Moxetumomab pasudotox (CD22) 3,000 Cetuximab sarotalocan (EGFR) margin. We predict that its sales will be 2,500 high primarily because it can be used in several subsets of breast cancer (HER2+, Sales (US$ millions) 2,000 + − 1,500 HR /HER2 and triple-negative) and it 1,000 has a long treatment duration. By contrast, sales of trastuzumab emtansine ($2.3 billion 500 in 2026) are forecast to be limited to 0 + 2019 2020 2021 2022 2023 2024 2025 2026 HER2 breast cancer and eroded from 2025 by the entry of biosimilars in the Fig. 1 | Forecast global sales of select approved antibody–drug conjugates. Sales from 2020 USA. Enfortumab vedotin, approved for to 2026 are forecast as of 1 December 2020. Sales of cetuximab sarotalocan reflect the following previously treated metastatic urothelial markets only: USA, France, Germany, Italy, Spain, United Kingdom, Japan. EGFR, epidermal growth cancer, is expected to gain label expansions factor receptor. for treating larger patient populations earlier in the disease course, propelling its global breast cancer. In January 2018, the agent overexpress CEACAM5 (approximately sales to $3.5 billion in 2026. Sacituzumab received FDA fast track designation based 20% of lung adenocarcinomas). CEACAM6 govitecan ($1.1 billion in 2026) is expected on phase I data in heavily pretreated HER2+ is overexpressed in various epithelial to experience uptake in breast and urothelial breast cancer. These findings supported the malignancies, and L-DOS47 (Helix cancers. Sales of cetuximab sarotalocan will initiation of the phase III TULIP trial, and BioPharma), which is targeted to CEACAM6, be constrained by the need for head and its readout is expected this year. Disitamab is in phase II development for NSCLC and neck cancer lesions to be accessible to light vedotin (RemeGen) is another anti-HER2 pancreatic cancer. illumination treatment. ADC in phase III development for breast Loncastuximab tesirine (ADC Brentuximab vedotin is forecast to cancer in China; it is also under investigation Therapeutics) is an anti-CD19 mAb garner global sales of $1.8 billion in 2026, in two registrational phase II trials for HER2+ conjugated to a pyrrolobenzodiazepine supported by use across several subsets of gastric and urothelial cancers. An anti-HER3 dimer. The Prescription Drug User Fee Hodgkin lymphoma and, to a lesser extent, ADC, patritumab deruxtecan (Daiichi Act date for this therapy as a monotherapy other niche haematological malignancies. Sankyo), is also in phase II development for for R/R DLBCL is 21 May 2021. The Polatuzumab vedotin will likely benefit from colorectal cancer and non-small- cell lung combination of loncastuximab tesirine limited competition in R/R DLBCL and cancer (NSCLC). and rituximab (Rituxan/MabThera, expected label expansions for previously Mirvetuximab soravtansine (ImmunoGen) Roche/Genentech) is under evaluation in untreated DLBCL; it is forecast to capture is an anti-folate receptor- α (FRα) mAb a phase III trial. Camidanlumab tesirine $850 million in 2026. In multiple myeloma, linked to the highly cytotoxic maytansinoid, (ADC Therapeutics/Genmab), an anti- CD25 belantamab mafodotin is forecast to see its currently being evaluated in two phase III ADC, is being assessed in a pivotal phase II use expanded to earlier lines of therapy trials in patients with platinum-resistant study in R/R Hodgkin lymphoma. but is anticipated to face fierce competition ovarian cancers that express high levels of Probody drug conjugates are masked from a number of established agents; FRα. Tisotumab vedotin (Seagen/Genmab), ADCs that become activated by proteases its global sales are expected to total nearly an anti- tissue factor ADC, is in phase III present in the tumour microenvironment. $400 million in 2026. Sales of inotuzumab development for recurrent or metastatic This technology has the potential to ozogamicin and moxetumomab pasudotox cervical cancer; a regulatory filing for this protect normal tissues expressing the are forecast to be low owing to small indication was submitted to the FDA in target antigen from
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    Supplementary Table 1: Adhesion genes data set PROBE Entrez Gene ID Celera Gene ID Gene_Symbol Gene_Name 160832 1 hCG201364.3 A1BG alpha-1-B glycoprotein 223658 1 hCG201364.3 A1BG alpha-1-B glycoprotein 212988 102 hCG40040.3 ADAM10 ADAM metallopeptidase domain 10 133411 4185 hCG28232.2 ADAM11 ADAM metallopeptidase domain 11 110695 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 195222 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 165344 8751 hCG20021.3 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 189065 6868 null ADAM17 ADAM metallopeptidase domain 17 (tumor necrosis factor, alpha, converting enzyme) 108119 8728 hCG15398.4 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 117763 8748 hCG20675.3 ADAM20 ADAM metallopeptidase domain 20 126448 8747 hCG1785634.2 ADAM21 ADAM metallopeptidase domain 21 208981 8747 hCG1785634.2|hCG2042897 ADAM21 ADAM metallopeptidase domain 21 180903 53616 hCG17212.4 ADAM22 ADAM metallopeptidase domain 22 177272 8745 hCG1811623.1 ADAM23 ADAM metallopeptidase domain 23 102384 10863 hCG1818505.1 ADAM28 ADAM metallopeptidase domain 28 119968 11086 hCG1786734.2 ADAM29 ADAM metallopeptidase domain 29 205542 11085 hCG1997196.1 ADAM30 ADAM metallopeptidase domain 30 148417 80332 hCG39255.4 ADAM33 ADAM metallopeptidase domain 33 140492 8756 hCG1789002.2 ADAM7 ADAM metallopeptidase domain 7 122603 101 hCG1816947.1 ADAM8 ADAM metallopeptidase domain 8 183965 8754 hCG1996391 ADAM9 ADAM metallopeptidase domain 9 (meltrin gamma) 129974 27299 hCG15447.3 ADAMDEC1 ADAM-like,
  • Anti-HER3 Monoclonal Antibody Patritumab Sensitizes Refractory Non-Small Cell Lung Cancer to the Epidermal Growth Factor Receptor Inhibitor Erlotinib

    Anti-HER3 Monoclonal Antibody Patritumab Sensitizes Refractory Non-Small Cell Lung Cancer to the Epidermal Growth Factor Receptor Inhibitor Erlotinib

    Oncogene (2016) 35, 878–886 © 2016 Macmillan Publishers Limited All rights reserved 0950-9232/16 www.nature.com/onc ORIGINAL ARTICLE Anti-HER3 monoclonal antibody patritumab sensitizes refractory non-small cell lung cancer to the epidermal growth factor receptor inhibitor erlotinib K Yonesaka1, K Hirotani2, H Kawakami1, M Takeda1, H Kaneda1, K Sakai3, I Okamoto4, K Nishio3, PA Jänne5,6,7 and K Nakagawa1 Human epidermal growth factor receptor (HER) 3 is aberrantly overexpressed and correlates with poor prognosis in non-small cell lung cancer (NSCLC). Patritumab is a monoclonal antibody against HER3 that has shown promising results in early-phase clinical trials, but an optimal target population for the drug has yet to be identified. In the present study, we examined whether heregulin, a HER3 ligand that is also overexpressed in a subset of NSCLC, can be used as a biomarker to predict the antitumorigenic efficacy of patritumab and whether the drug can overcome the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resistance induced by heregulin. Patritumab sensitivity was associated with heregulin expression, which, when abolished, resulted in the loss of HER3 and AKT activation and growth arrest. Furthermore, heregulin overexpression induced EGFR TKI resistance in NSCLC cells harbouring an activating EGFR mutation, while HER3 and AKT activation was maintained in the presence of erlotinib in heregulin-overexpressing, EGFR-mutant NSCLC cells. Sustained HER3-AKT activation was blocked by combining erlotinib with either anti-HER2 or anti-HER3 antibody. Notably, heregulin was upregulated in tissue samples from an NSCLC patient who had an activating EGFR mutation but was resistant to the TKI gefitinib.