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Home , Belantamab mafodotin, Brentuximab vedotin, CEACAM6, Enfortumab vedotin, Inotuzumab ozogamicin, Loncastuximab tesirine

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. emtansine (Padcev, / 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. -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+ . most recently approved ADC is six have gained regulatory approval since A second HER2-targeted​ ADC, sarotalocan (Akalux, Rakuten Medical), 2019. Most ADCs comprise a cytotoxic (Enhertu, Daiichi an epidermal receptor agent attached to a 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 . This approach combines and trastuzumab photoactivation; it was granted conditional the targeted delivery of the mAb with the deruxtecan differ in their cytotoxic payloads approval for 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 (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 , Trastuzumab duocarmazine (Byondis) mAb– 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 (Adcetris, Mirvetuximab ImmunoGen FRα Ovarian cancer Phase III Seagen/Takeda), a CD30-specific​ mAb soravtansine linked to (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 / TROP2 NSCLC Phase III Europe and Japan for Hodgkin deruxtecan AstraZeneca and anaplastic large cell lymphoma. SAR408701 Sanofi CEACAM5 NSCLC Phase III There are also two ADCs approved that ADC Therapeutics CD19 DLBCL Phase III target CD22: Camidanlumab tesirine ADC Therapeutics/ CD25 Phase II (Besponsa, Pfizer) for relapsed/refractory Genmab (R/R) acute lymphoblastic leukaemia and deruxtecan Daiichi Sankyo HER3 NSCLC, colorectal Phase II (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 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 sarcoma lymphoma (DLBCL). BT1718 Bicycle Therapeutics MT1-​MMP Solid tumours Phase II targets BCMA (also known as TNFRSF17) CEACAM5, -related​ 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, . non-small-​ cell​ lung cancer; TF, .

Nature Reviews | Drug DISCovery volume 20 | August 2021 | 583

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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 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 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 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 (Rituxan/MabThera, expected label expansions for previously Mirvetuximab soravtansine (ImmunoGen) Roche/) 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 the effects of the ADC, addressable markets (previously treated February 2021. and may also benefit from improved acute lymphoblastic leukaemia and hairy cell Datopotamab deruxtecan (Daiichi exposure of the payload. CX-2029 (CytomX leukaemia). The market for ADCs is set to Sankyo/AstraZeneca) and SAR408701 Therapeutics/AbbVie) and CX-2009 grow further beyond 2026, as novel agents (Sanofi) are ADCs in phase III development (CytomX Therapeutics) are probody enter clinical practice across several oncology for previously treated metastatic NSCLC. drug conjugates in phase II development; indications. Datopotamab deruxtecan is a TROP2- ​ CX-2029 and CX-2009 are directed to Carolina do Pazo, Khurram Nawaz directed ADC being evaluated in patients CD71 and CD166, respectively. Many and Rachel M. Webster ✉ without actionable genomic alterations. other ADCs are in phase II development Clarivate, London, UK. SAR408701 is an anti-CEACAM5​ mAb with novel targets including LIV1 ✉e-mail:​ [email protected] coupled to a maytansinoid agent DM4 (ladiratuzumab vedotin), AXL (BA3011), https://doi.org/10.1038/d41573-021-00054-2 via a cleavable linker; the phase III trial and MT1-MMP​ (membrane type 1-matrix​ Competing interests is ongoing in patients whose tumours metalloprotease; BT1718). The authors declare no competing interests.

584 | AUGUST 2021 | volume 20 www.nature.com/nrd

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