Datopotamab deruxtecan

With the potential to become the best-in-class TROP2-targeted antibody drug conjugate (ADC), datopotamab deruxtecan is set to be second to market (after TRODELVY®; Gilead Sciences Inc) for both HR-positive/HER2-negative and triple-negative breast cancer, and to enter the non-small cell lung cancer (NSCLC) market. The collaboration between AstraZeneca and Daiichi Sankyo combines the former’s strategic focus on NSCLC and breast cancers and investment in ADCs with the latter’s proprietary DXd ADC technology.

Label expansions for datopotamab deruxtecan, either as monotherapy or in combination with IMFINZI® (AstraZeneca), are expected in various triple-negative breast cancer populations, including in the early-stage and first-line metastatic settings.

In NSCLC, we expect that datopotamab deruxtecan will gain initial approval for previously treated metastatic NSCLC without actionable genomic alterations. The ADC could earn a label expansion for first-line treatment (in combination with IMFINZI and chemotherapy) if the phase 3 AVANZAR trial is positive.

datopotamab deruxtecan

  1. AstraZeneca and Daiichi Sankyo
  2. TROP2-directed ADC
  3. Intravenous administration every 3 weeks to treat metastatic NSCLC or metastatic HR-positive/HER2-negative breast cancer
  4. Also being evaluated to treat ovarian cancer, pancreatic cancer, prostate cancer, SCLC, colorectal cancer, bladder cancer, gastric cancer, biliary cancer, cervical cancer, endometrial cancer, transitional cell carcinoma of the urothelium, HER2-negative gastroesophageal cancer, esophageal cancer and squamous cell carcinoma
  5. ~168K new cases of previously treated metastatic HR-positive/HER2-negative breast cancer in the G7 markets in 2023
  6. ~86K new cases of early-stage and previously untreated metastatic triple-negative breast cancer in the G7 markets in 2023
  7. ~329K new cases of previously treated metastatic NSCLC in the G7 markets in 2023

Why is it a drug to watch?

TROP2 is highly expressed (>80%) on epithelial cancer cells, including NSCLC, with limited expression in healthy human tissues, making it an attractive target. Positive results were reported from two pivotal phase 3 trials, one each for HR-positive/HER-negative breast cancer and NSCLC:

  1. TROPION-Breast01 compared datopotamab deruxtecan with the investigator’s choice of chemotherapy in patients with inoperable or metastatic HR-positive/HER2-low or negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer previously treated with endocrine-based therapy and one or two lines of chemotherapy.
  • 37% reduction in the risk of disease progression or death (vs chemotherapy)
  • Median progression-free survival (PFS) of 6.9 months (vs 4.9 months with chemotherapy)
  • 36.4% objective response rate (ORR; vs 22.9% with chemotherapy)
  • Assessment of overall survival (OS; dual primary endpoint) ongoing
  • Grade 3 or higher treatment-related adverse events (TRAEs) in 21% of patients (vs 45% with chemotherapy)
  1. TROPION-Lung01 compared datopotamab deruxtecan with docetaxel in patients with metastatic NSCLC treated with at least one prior line of therapy (including immunotherapy, chemotherapy and, if applicable, a targeted therapy for driver mutations).
  • 25% reduction in the risk of disease progression or death (vs docetaxel)
  • Median PFS of 4.4 months (vs 3.7 months with docetaxel)
  • 26% ORR (vs 13% with docetaxel)
  • Interim median OS of 12.4 months with datopotamab deruxtecan (vs 11.0 months with docetaxel) corresponding to a 10% reduction in the risk of death
  • Clinical response
  • Grade 3 or higher TRAEs in 25% of patients (vs 41% with chemotherapy)

AstraZeneca is also researching a potential diagnostic test to help identify patients most likely to benefit from treatment with datopotamab deruxtecan.

In addition, the following phase 3 trials are evaluating potential label expansions for datopotamab deruxtecan):

  1. TROPION-Breast02: datopotamab deruxtecan compared with the investigator’s choice of chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer who are not candidates for PD-1/PD-L1 inhibitor therapy
  2. TROPION-Breast03: datopotamab deruxtecan plus durvalumab compared with the investigator’s choice of chemotherapy in patients with early (stage I-III) triple-negative breast cancer with residual invasive disease after neoadjuvant therapy
  3. TROPION-Breast04: datopotamab deruxtecan plus durvalumab followed by adjuvant durvalumab with/without chemotherapy compared with pembrolizumab plus chemotherapy followed by pembrolizumab with/without chemotherapy in patients with previously untreated triple-negative or HR-low/HR2-negative breast cancer
  4. TROPION-Breast05: datopotamab deruxtecan with/without durvalumab compared with the investigator’s choice of chemotherapy plus pembrolizumab in patients with PD-L1-positive locally recurrent inoperable or metastatic triple-negative breast cancer
  5. AVANZAR: datopotamab deruxtecan plus durvalumab and carboplatin for first-line treatment of patients with advanced NSCLC without actionable genomic alterations

Review and
approval status

Metastatic breast cancer
Expected launch:

  • 2025: United States, Europe, Japan, South Korea
  • 2026: Mainland China
  • 2030: Singapore

Expected launch:

  • 2025: United States, Europe, Japan, Mainland China, South Korea, Singapore

How will datopotamab deruxtecan impact the market for breast cancer and NSCLC?

HR-positive/HER-negative breast cancer

  1. HR-positive/HER-negative breast cancer is the most common subtype, accounting for around 60-75% of all cases.
  2. Datopotamab deruxtecan is expected to garner most uptake in the third- and later-line settings for the treatment of patients who have acquired resistance to endocrine therapy and have received at least one chemotherapy line for their metastatic disease. In such a setting, datopotamab deruxtecan will compete with TRODELVY for the treatment of patients who are not eligible to receive ENHERTU® (Daiichi Sankyo; i.e., non-HER2-low patients, who represent ~40% of the population).

Triple-negative breast cancer

  1. Datopotamab deruxtecan will be positioned both in the early and the metastatic triple-negative breast cancer settings. Its approval is expected to take patient share from current treatment with immunotherapy and chemotherapy.
  2. Datopotamab deruxtecan will face fierce competition from TRODELVY in both settings.


  1. For NSCLC, datopotamab deruxtecan is entering one of the busiest drug development pipelines that includes established drug classes (e.g., EGFR inhibitors, immune checkpoint inhibitors, angiogenesis inhibitors) as well as novel therapies (e.g., CD73-, NKG2A-, HER3- and TROP2-targeting agents).
  2. Datopotamab deruxtecan is initially positioned as a new therapy for patients with metastatic NSCLC who fail at least immunotherapy and chemotherapy, a setting with high unmet need and a lack of clear sequencing options. In that regard, offering an effective treatment with a novel mechanism of action would be attractive to prescribers.


What gaps in treatment does datopotamab deruxtecan fill?

Sequential chemotherapy regimens are widely utilized for management of endocrine-resistant metastatic HR-positive/HER-negative disease, but an unmet need remains in this setting, as chemotherapy is associated with low response rates and toxicity. Datopotamab deruxtecan has been shown to provide both improved efficacy and safety compared with chemotherapy.

There is high unmet need for improved treatment options in the triple-negative breast cancer setting due to the limited efficacy of current therapies in the metastatic setting and the high recurrence rate following curative treatment in the early stage. Datopotamab deruxtecan — as monotherapy or in combination with immunotherapy — is expected to improve the outcome of patients with this subtype of breast cancer.

Substantial unmet treatment needs also still exist for NSCLC, including effective therapies for previously treated metastatic NSCLC. The NSCLC treatment algorithm is rapidly evolving, as agents approved in later lines of therapy seek and gain label expansions for first-line use. Although this improves patient responses in the first-line setting, it depletes the options available when these patients experience progression, creating an urgent need for more treatment options in later lines of therapy.

What hurdles might it need to overcome to reach blockbuster status?

Datopotamab deruxtecan is likely to face stiff competition from various agents in both the HR-positive/HER-negative breast cancer and the NSCLC segments.

For HR-positive/HER-negative breast cancer, major hurdles in uptake and thus sales potential include competition from established earlier-to-market therapies (e.g., endocrine therapies, aromatase inhibitors, oral selective estrogen receptor degraders [SERDs]) and emerging novel therapies (e.g., other TROP2 inhibitors, immune checkpoint inhibitors, PARP inhibitors, vaccines). Multiple novel drug classes are being developed for metastatic HR-positive/HER-negative breast cancer with the aim of tackling endocrine resistance. These novel agents, including novel PI3K/AKT/mTOR inhibitors and ER-targeted therapies, could push the use of ADCs, including datopotamab deruxtecan, to later lines of treatment. In addition, the efficacy of sequential use of ADCs (e.g., use of datopotamab deruxtecan following treatment with ENHERTU) is uncertain and could potentially hamper the use of TROP2-agents after treatment with ENHERTU. The market entry of multiple agents creates a growing need to optimize treatment sequencing across lines of therapy, and physicians may experience challenges determining the best treatment sequence following first-line therapy.

In triple-negative breast cancer, datopotamab deruxtecan is expected to face fierce competition from TRODELVY, which has the advantage of being the first of its class to market.

For NSCLC, similar competition from entrenched therapies (e.g., immune checkpoint inhibitors, monoclonal antibodies) and emerging therapies (e.g., antibody-drug conjugates) will need to be overcome. In first-line metastatic NSCLC, treatment choices are increasingly fragmented depending on biomarker status, and combined immunochemotherapy is a standard of care for patients without driver mutations. The addition of datopotamab deruxtecan to existing combinations will need to demonstrate convincing efficacy improvements (and a favorable benefit-risk profile) if it is to get a slice of this fiercely competitive but lucrative market segment.

expected sales in 2029 (for breast cancer and NSCLC combined)
probability of success for metastatic NSCLC in the U.S.
Source: Cortellis Competitive Intelligence, Drug Timeline & Success Rates Prediction current as of December 15, 2023

Drug Timeline &
Success Rates

– Source: Cortellis Competitive Intelligence, Drug Timeline & Success Rates Prediction current as of December 15, 2023

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