May 30, 2024

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The DXd Platform: Daiichi Sankyo’s ADC Breakthrough in Lung Cancer

The DXd Platform: Daiichi Sankyo’s ADC Breakthrough in Lung Cancer



 

The DXd Platform: Daiichi Sankyo’s ADC Breakthrough in Lung Cancer.

The recent conclusion of the 2023 World Conference on Lung Cancer (WCLC) marked a significant moment in the field of oncology.

During the conference, Daiichi Sankyo showcased its core ADC (Antibody-Drug Conjugate) products developed on the innovative DXd platform, highlighting the latest clinical advancements in the treatment of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

So, what groundbreaking developments did Daiichi Sankyo bring to the table in the realm of lung cancer?

 

 

HER3-DXd: Breaking the Unmet Medical Need for Targeting HER3

The human epidermal growth factor receptor (HER) family consists of four members: EGFR (ERBB1/HER1), HER2 (ERBB2), HER3 (ERBB3), and HER4 (ERBB4). These receptors, transmembrane proteins, play a crucial role in regulating cell growth, division, and repair, and are closely linked to the development and progression of various cancers.

While EGFR and HER2 have emerged as star targets in the field of cancer therapy, HER3 has long remained a less explored option. For three decades since the discovery of the HER3 target in 1989, there have been no approved targeted therapies for HER3. This was primarily due to the extremely low kinase activity of HER3’s tyrosine kinase domain, leading researchers to believe that HER3 heavily relied on the activity of its family members and had little individual significance. Consequently, HER3 remained largely overlooked in cancer treatment.

However, as research delved deeper, scientists discovered that although HER3 alone does not exert oncogenic effects when overexpressed, it forms heterodimers with other receptor tyrosine kinases (RTKs), particularly HER2, upon binding with the neuregulin (NRG) ligand. This results in the activation of downstream PI3K/AKT and MEK/MAPK signaling pathways, promoting tumorigenesis and metastasis. Additionally, HER3 exhibits high expression in various cancer types, including colorectal cancer, gastric cancer, head and neck squamous cell carcinoma, breast cancer, and lung cancer, with up to 83% expression in NSCLC. Furthermore, HER3 has been implicated in resistance mechanisms related to EGFR and HER2 treatments. Therefore, targeting HER3 holds promise as a new therapeutic approach for late-stage, metastatic NSCLC, among other conditions.

In the early stages of drug development, due to HER3’s low intrinsic kinase activity and inability to form homodimers, it could not be developed into small molecule kinase inhibitors. Consequently, most pioneering pharmaceutical companies focused on monoclonal antibodies (mAbs) targeting HER3. However, the development of HER3 mAbs or combination therapies ultimately resulted in mostly failed endeavors, even involving industry giants like Roche, AstraZeneca, and Daiichi Sankyo.

HER3 targeting faced questions about whether it could become a drug. After a period of silence, bispecific antibodies and ADC (Antibody-Drug Conjugate) technology offered new hope for HER3 targeting, with ADCs, in particular, showing promise. In comparison to mAbs, ADCs induce receptor internalization and degradation, leading to cancer cell death without relying solely on HER3-induced apoptosis, highlighting the advantage of ADCs.

Currently, Daiichi Sankyo’s HER3 ADC product, HER3-DXd, has demonstrated promising clinical results in lung cancer. HER3-DXd combines the previously discontinued HER3 mAb Patritumab (U3-1287) with the toxin Dxd (identical to DS-8201’s toxin) through a cleavable linker to create the ADC product HER3-DXd (U3-1402), with a Drug Antibody Ratio (DAR) of 8.

At this year’s WCLC, Daiichi Sankyo presented the results of HER3-DXd in a study called HERTHENA-Lung01 for advanced EGFR-mutated NSCLC patients who had previously received EGFR TKIs and platinum-based chemotherapy. In this Phase II clinical trial, within a median follow-up time of 18.9 months (range: 14.9-27.5), 225 patients treated with HER3-DXd (5.6 mg/kg) achieved an objective response rate (ORR) of 29.8%, a median progression-free survival (mPFS) of 5.5 months, and a preliminary median overall survival (mOS) of 11.9 months.

 

The DXd Platform: Daiichi Sankyo's ADC Breakthrough in Lung Cancer

 

 

 

In patients with brain metastases (n=30, not treated with radiotherapy), the results indicated that among central nervous system (CNS) treatment responders confirmed by an independent central review (BICR), the ORR was 33.3% (95% CI: 17.3-52.8%). Among these patients, 9 achieved intracranial complete response (CR), 1 achieved intracranial partial response (PR), and 13 had stable disease (SD). The observed duration of CNS response (DOR) was 8.4 months (95% CI: 5.8-9.2).

These clinical results suggest that HER3-DXd holds promise as a therapeutic option for advanced EGFR-mutated NSCLC patients who have previously received treatment, potentially reshaping the landscape of late-stage NSCLC treatment.

 

 

 

T-DXd (DS-8201): Establishing New Frontiers in Lung Cancer

T-DXd marks Daiichi Sankyo’s pioneering ADC drug, which has already transformed the treatment landscape in the field of breast cancer with its outstanding efficacy. Approved by the FDA in 2019, DS-8201 has received approvals for five indications, including late-stage HER2-positive breast cancer in later lines, advanced HER2-positive gastric cancer in second-line and beyond, advanced HER2-positive breast cancer in second-line, and HER2-low breast cancer. Furthermore, in August 2022, T-DXd achieved another milestone as it became the first ADC drug targeting HER2 to gain FDA accelerated approval for late-stage NSCLC with HER2 mutations.

At the 2023 WCLC, results of T-DXd used as a pretreatment for HER2-mutant metastatic NSCLC patients were unveiled. In the Phase II clinical study named DESTINY-Lung02, patients were divided into two groups, with 102 assigned to the T-DXd 5.4 mg/kg group and 50 to the T-DXd 6.4 mg/kg group. The median follow-up times were 11.5 months and 11.8 months, respectively.

The confirmed ORR, as assessed by BICR, was 49.0% (95% CI, 39.0%-59.1%) for the T-DXd 5.4 mg/kg group and 56.0% (95% CI, 41.3%-70.0%) for the T-DXd 6.4 mg/kg group. The median duration of response (DOR) was 16.8 months (95% CI, 6.4-NE) for the former and not evaluable (NE, 95% CI, 8.3-NE) for the latter. Median progression-free survival (PFS) was 9.9 months (95% CI, 7.4-NE) for the T-DXd 5.4 mg/kg group and 15.4 months (95% CI, 8.3-NE) for the T-DXd 6.4 mg/kg group.

 

 

The DXd Platform: Daiichi Sankyo's ADC Breakthrough in Lung Cancer

DESTINY-Lung02 clinical study phase II updated data (Source: WCLC official website)

 

These results demonstrate that both T-DXd 5.4 mg/kg and 6.4 mg/kg exhibit potent and enduring efficacy, along with an acceptable safety profile, in HER2-mutant metastatic NSCLC patients.

 

 

 

Dato-DXd (DS-1062): Exploring New Horizons in Targeting TROP2

Beyond the classic targets like HER2, TROP2 has gradually emerged as a second hotspot for ADC product development. TROP2 shows high expression in various solid tumors, with over 80% expression observed in breast cancer, urothelial carcinoma, cervical cancer, and endometrial cancer, and over 55% expression in NSCLC, gastric cancer, and ovarian cancer. Consequently, TROP2 ADCs are considered highly promising in the world of ADC drugs.

According to Frost & Sullivan data, the global market for TROP2 ADCs is expected to reach $25.9 billion by 2030. Currently, Trodelvy is the only TROP2 ADC approved for marketing worldwide. Daiichi Sankyo is keen on capitalizing on this opportunity.

Daiichi Sankyo’s Dato-DXd is a novel TROP2 ADC product. At this year’s WCLC, Daiichi Sankyo unveiled clinical data for Dato-DXd in advanced/ metastatic NSCLC patients without driver gene mutations. In the Phase Ib clinical study called TROPION-Lung04, enrolled patients received Dato-DXd (4 mg/kg, cohorts 1/3; 6 mg/kg, cohorts 2/4) in combination with durvalumab (PD-L1 inhibitor, 1120 mg, all cohorts) and four cycles of carboplatin (AUC 5, cohorts 3/4).

Results indicated that in treatment-naïve patients (1L), the ORR was 50.0% in cohort 2 (dual therapy) and 76.9% in cohort 4 (triple therapy), with disease control rates (DCR) of 92.9% and 92.3%, respectively. In the overall population (1L/2L+), cohort 2 achieved an ORR of 47.4%, while cohort 4 achieved an ORR of 71.4%. Improved ORR was observed in the triple combination group compared to the dual combination group, and responses were observed across all levels of PD-L1 expression.

The DXd Platform: Daiichi Sankyo's ADC Breakthrough in Lung Cancer

Tumor Response Results for Cohorts 2 and 4 (Source: 2023 WCLC)

 

In both cohort 2 and cohort 4, no new safety signals emerged. The most common adverse events included stomatitis, alopecia, and nausea. Grade ≥3 adverse events occurred more frequently in the triple combination group and were primarily hematologic events.

It’s worth noting that while T-DXd has been considered unattainable by many companies, several domestic enterprises in China have also ventured into the TROP2 ADC space. According to Shanghai Securities, nearly 10 ADC drugs targeting TROP2 are currently in development in China, with companies like Beigene, Hengrui Medicine, and NovoBiotics among them.

 

I-DXd (DS-7300): An ADC for Small Cell Lung Cancer

B7-H3 is a transmembrane immune checkpoint protein that is overexpressed in several tumor types, including SCLC (Small Cell Lung Cancer). In SCLC patients, 65% exhibit overexpression of B7-H3, which is associated with poor prognosis. Daiichi Sankyo’s I-DXd is a novel ADC drug targeting B7-H3. It combines a B7-H3 IgG1 monoclonal antibody with a stable linker and a potent topoisomerase I inhibitor payload to enhance tumor cell targeting and reduce systemic exposure of the payload.

At this year’s WCLC, preliminary results for I-DXd in the treatment of advanced metastatic SCLC patients from a Phase I/II clinical trial were disclosed. I-DXd demonstrated an ORR of 52.4%, a median progression-free survival (mPFS) of 5.6 months, and a median overall survival (mOS) of 12.2 months. These initial results highlight the clinical potential of I-DXd in treating SCLC.

The DXd Platform: Daiichi Sankyo's ADC Breakthrough in Lung Cancer

I-DXd preliminary treatment results (Source: 2023 WCLC)

 

 

 

In Conclusion

Lung cancer ranks among the world’s leading cancers, with a large patient population and a significant market size. In the field of oncology, lung cancer has often been referred to as the “king of cancers,” and this holds true in the realm of ADCs as well. Daiichi Sankyo has established itself as a global leader in ADC innovation, thanks to the success of T-DXd and its commercial achievements.

As research progresses on HER3-DXd, Dato-DXd, and I-DXd, Daiichi Sankyo is transitioning from breast cancer to lung cancer, contributing to the fight against cancer in its own unique way. This might just be the beginning, as continued technological breakthroughs may enable Daiichi Sankyo to expand its horizons further, continually expanding the therapeutic potential of ADCs.

 

 

 

The DXd Platform: Daiichi Sankyo’s ADC Breakthrough in Lung Cancer.

References:
1. OA05.03 Patritumab Deruxtecan (HER3-DXd) in EGFR-Mutated NSCLC Following EGFRTKI and Platinum-Based Chemotherapy: HERTHENA-Lung01. WCLC 2023.
2. MA13.10 Trastuzumab Deruxtecan in Patients with HER2-Mutant Metastatic Non-Small Cell Lung Cancer: Primary Results of DESTINY-Lung02. WCLC 2023.
3. P2.04-02 AVANZAR: Phase III Study of Datopotamab Deruxtecan (Dato-DXd)+ Durvalumab + Carboplatin as 1L Treatment of Advanced/mNSCLC. 2023 WCLC.
4. OA05.05Ifinatamab Deruxtecan (I-DXd; DS-7300) in Patients with Refractory SCLC: A Subgroup Analysis of a Phase 1/2 Study. WCLC 2023.

(source:internet, reference only)


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