Release date:2022/9/7 14:03:57

Kadcyla (ado-trastuzumab emtansine, T-DM1), a second-generation antibody-drug conjugate (ADC), is the most commercially successful ADC. In 2021, the global ADC market exceeded $5.2 billion, with Kadcyla sales reaching $2.17 billion.

Kadcyla was first approved by the U.S. Food and Drug Administration (FDA) in 2013, for patients with HER2-positive, late-stage (metastatic) breast cancer. It is the first ADC approved for solid tumors.

Introduction of Kadcyla

Kadcyla is a HER2-targeted antibody-drug conjugate that contains the humanized anti-HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitor DM1 (a maytansine derivative) via the stable thioether linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate). An average of 3.5 DM1 molecules are conjugated to each molecule of trastuzumab.


Figure 1. Structure of Kadcyla, source: reference [5]

DM1 is a maytansine derivative. Maytansine, first isolated from the bark of African shrub Maytenus ovatus in 1972, is a potent microtubule-targeted compound that induces mitotic arrest and kills tumor cells at sub-nanomolar concentrations. Therefore, this class of cytotoxic drugs also belongs to the class of microtubule protein inhibitors, and the two most commonly used in ADCs today are DM1 and DM4.

Clinical Efficacy and Market Performance of Kadcyla

The latest FDA approval in 2019 was based on KATHERINE (NCT01772472), a randomized, multicenter, open-label trial of 1486 patients with HER2-positive EBC who had residual invasive disease in the breast and/or axillary lymph nodes following neoadjuvant treatment with taxane + trastuzumab-based therapy.

The primary objective of the KATHERINE study is to evaluate, the effectiveness and safety of adjuvant treatment with Kadcyla versus trastuzumab in patients after surgery.

The primary endpoint of the study is invasive disease-free survival (IDFS), which is the time from randomization grouping to recurrence of invasive breast cancer or death from any cause. Secondary endpoints included disease-free survival (DFS) and overall survival (OS).

Patients were grouped 1:1 and received Kadcyla or Herceptin (trastuzumab), respectively, as well as radiation and/or hormonal therapy according to local treatment guidelines. At a median follow-up time of 40 months, patients in the Kadcyla group had a statistically significant improvement in IDFS compared to the Herceptin group and a 50% reduction in the risk of death or recurrence of invasive disease. At 3 years, 88.3% of patients in the Kadcyla group were relapse-free compared to 77.0% in the Herceptin group.


Figure 2. Efficacy Results from KATHERINE

Figure 3. 3-year iDFS rates were 88.3% for KADCYLA vs 77.0% for Herceptin, references [1]

The most common adverse reactions (ADRs) (≥25%) included nausea, fatigue, skeletal muscle pain, bleeding, headache, elevated transaminases, thrombocytopenia, and peripheral neuropathy, with most ADRs being mild to moderate grade 1 or 2 ADRs and the incidence of severe ADRs >0.5%.

In 2021, Kadcyla had global sales of $2.18 billion, ranking as the most commercially successful ADC. According to an ADC market size report by Nature Reviews Drug Discovery, sales of Kadcyla are expected to be $2.3 billion in 2026, indicating limited room for future growth.

Figure 4. Sales of ADC drugs

There are 2 main reasons for its limited room for future growth, one is the high pricing of Kadcyla. The pricing of Kadcyla in USA is $3,709 /100mg, $5,929/160mg, which limits the use of the drug for some patients.

On the other hand, biosimilars are coming to market one after another, further eroding Kadcyla's share. In India, an analogue, Ujvira, has been approved for 20% of the price of Kadcyla. ADCs with the same target, HER2, are also being developed and commercialized, undoubtedly posing a threat to Kadcyla.

Kadcyla (T-DM1) Compared to DS-8201 & RC48

Globally, two ADC products targeting HER2 have been launched: Enhertu (DS-8201) by Daiichi Sankyo and Disitamab Vedotin (RC48) by RemeGen Co.

Kadcyla (T-DM1) Compared to DS-8201 & RC48

Figure 5. Kadcyla (T-DM1) Compared to DS-8201 & RC48, source: reference [3]

1.Trastuzumab Deruxtecan(Enhertu,T-DXd,DS-8201)

  • ▶ Company: Daiichi Sankyo / AstraZeneca
  • ​ Target: HER2
  • ​ Antibody: Humanized IgG1 monoclonal antibody Trastuzumab
  • ​ Drug/payload: DXd (topoisomerase)
  • ​ Linker: GFLG (tetrapeptide)
  • ​ Indications: Breast cancer, gastric cancer, lung cancer, etc.
  • ​ Status: Available in 2019

Enhertu consists of an anti-HER2 antibody, Trastuzumab, coupled to the cytotoxic drug DXd via a linker, GFLG. The linker is a cleavable tetrapeptidyl linker (Gly-Phe-Leu-Gly (GFLG)), which is not only stable but also can be specifically cleaved and has a strong cell membrane permeability, allowing it to exert a "bystander effect".


Figure 6. Structure of Enhertu. Source: reference [2]

The cytotoxic drug employs DXd, a new DNA topoisomerase inhibitor that improves the hydrophobic properties of the drug, allowing each antibody to be loaded with 7 or 8 DXd molecules.  The high DAR allows the efficacy of Enhertu to be considered 2 to 4 times higher than previously approved marketed ADC drugs.

Enhertu was first approved for marketing in the United States in 2019 for the treatment of HER2-positive metastatic breast cancer.

2. Disitamab Vedotin (Aidixi, RC48)

  • ​ Company: RemeGen Co.
  • ​ Target: HER2
  • ​ Antibody: recombinant humanized IgG1 monoclonal antibody Hertuzumab
  • ​ Drug/Payload: Duocarmycin / Seco-DUBA
  • ​ Linker: MC-Val-Cit-PAB
  • ​ Indication: Gastric cancer
  • ​ Status: Available in 2021

Disitamab Vedotin, consists of a recombinant humanized HER2 IgG1 monoclonal antibody coupled to MMAE via a cleavable linker. It is indicated for the treatment of patients with locally advanced or metastatic HER2 overexpressing gastric cancer, including adenocarcinoma of the gastroesophageal junction, who have received at least 2 systemic chemotherapies.


Figure 7. Structure of Disitamab Vedotin, source: Reference [3]

In June 2021, the National Medical Products Administration (NMPA) granted conditional approval for Disitamab Vedotin.

As a novel agent, RC48 as monotherapy or adjuvant treatment in clinical practice for the therapy of other cancer in the world, including UC, biliary tract cancer (BTC), non-small cell lung cancer (NSCLC), and HER2+ and HER2-low expressing BC.

Anti-Her2 ADCs in Clinical Trials

Except for the three anti-Her2 ADC approved for marketing, there are more than 20 ADCs have entered clinical testing. Among them, trastuzumab duocarmazine (SYD985) making the best progress.

Figure 8. List of anti-Her2 ADCs in clinical trials or on the market, source: reference [4]

Trastuzumab Duocarmazine (SYD985)

  • ​ Company: Byondis
  • ​ Target: HER2
  • ​ Antibody: Monoclonal antibody trastuzumab
  • ​ Drug/Payload: MMAE (monomethyl auristatin E)
  • ​ Linker: vc-seco-DUBA
  • ​ Indication: Breast Cancer, Endometrial cancer
  • ​ Status: Phase III

SYD985 is an investigational next-generation HER2 ADC that was previously granted Fast Track Designation by the FDA in January 2018. In addition, its U.S. marketing application was accepted by the FDA on July 12, 2022, with a PDUFA date set for May 12, 2023.

SYD985 consists of the monoclonal antibody trastuzumab and a cleavable linker-drug called valine-citrulline-seco-DUocarmycin-hydroxyBenzamide-Azaindole (vc-seco-DUBA). which is designed using Byondis' proprietary ByonZine technology platform - - duocarmazine linker drug technology.


Figure 9. SYD985 formula, anti-HER2 trastuzumab conjugated to seco-DUBA via a cleavable linker sensitive to cathepsin B. Source: reference [5]

On July 18, 2022, Byondis announced that the European Medicines Agency (EMA) has validated the Marketing Authorization Application (MAA) for SYD985 in patients with HER2-positive unresectable locally advanced or metastatic breast cancer (MBC).

The MAA for SYD985 is based on data from the pivotal phase III TULIP. The trial was a randomized, multicenter, open-label clinical trial (n=436) comparing the efficacy of SYD985 with physician's choice (PC) for the treatment of patients with HER2-positive unresectable locally advanced or metastatic breast cancer. The primary endpoint is progression-free survival (PFS).

Byondis presented preliminary results from TULIP3 at the ESMO 2021 Congress. The results showed that SYD985 significantly improved PFS in patients with HER2-positive unresectable locally advanced or metastatic breast cancer, with a PFS of 7.0 months in the SYD985 group and 4.9 months in the PC group. In addition, the overall survival (OS) in the group receiving SYD985 showed a trend of improvement with an HR of 0.83.

Biopharma  PEG provides GMP standard PEG derivatives and bulk orders via custom synthesis, offering the opportunity to match customers' special quality requirements. ADC linkers with molecular weights, branching, and functional groups not listed in our online catalog may be available by custom synthesis.

[2] Nakada T, Sugihara K, Jikoh T, Abe Y, Agatsuma T. The Latest Research and Development into the Antibody-Drug Conjugate, [fam-] Trastuzumab Deruxtecan (DS-8201a), for HER2 Cancer Therapy. Chem Pharm Bull (Tokyo). 2019;67(3):173-185. doi:10.1248/cpb.c18-00744
[3] Shi F, Liu Y, Zhou X, Shen P, Xue R, Zhang M. Disitamab vedotin: a novel antibody-drug conjugates for cancer therapy. Drug Deliv. 2022 Dec;29(1):1335-1344. doi: 10.1080/10717544.2022.2069883. PMID: 35506447; PMCID: PMC9090390.
[4] Zhang X, Huang AC, Chen F, Chen H, Li L, Kong N, Luo W, Fang J. Novel development strategies and challenges for anti-Her2 antibody-drug conjugates. Antib Ther. 2022 Jan 27;5(1):18-29. doi: 10.1093/abt/tbac001. PMID: 35146330; PMCID: PMC8826051.
[5] Joubert, N.; Beck, A.; Dumontet, C.; Denevault-Sabourin, C. Antibody–Drug Conjugates: The Last Decade. Pharmaceuticals 2020, 13, 245.

Related Articles:
Global Antibody-drug Conjugates (ADCs): Approvals & Clinical Trails Review
HER2 Targeted Therapies In Breast Cancer
ADC Drugs Global Sales of 2021 and Future Prospects
The Bystander Effect of ADCs

Previous:Development of PD-L1 Antibody Drug Conjugates (ADC) Next:Therapeutic Antibody Derivatives: Antibody Conjugates & Multispecific Antibodies