It is quite well known that the entrance of antibody-drug conjugates (ADCs) in cancer space is not much older and since then they have been in use so widely that today we have more than ten ADCs approved with a robust pipeline activity. With the promising scope, ADCs are the new targeting platforms in oncology that are driving many pharma giants to further investigate the platform. Daiichi Sankyo and AstraZeneca together are co-developing datopotamab deruxtecan (DS-1062), one of three lead DXd ADCs in the oncology pipeline of the company including Trastuzumab deruxtecan and Patritumab deruxtecan. The company presented updated results from the ongoing Phase I study (TROPION-PanTumor01) of DS-1062 in patients with NSCLC at ESMO 2021. The drug is being explored in different indications such as NSCLC, TNBC, and HR-positive breast cancer.
The efficacy of the drug in Phase I was presented under the late-breaking abstracts, which suggest its explored potential through its interim trial results. The results demonstrated an OS rate of 35% across all doses, with a median Duration of response (DOR) of 9.5 months, indicating a significant level of efficacy in heavily previously treated advanced NSCLC patients with actionable genomic alterations. The results further reported that the most common any-grade AEs observed throughout the study included stomatitis and nausea. Researchers reported one incidence of ILD related to treatment with Dato-DXd, which was considered a grade 5 event at a dose of 8 mg/kg. It is worth mentioning that since the 8 mg/kg dose did not have a favorable efficacy-to-toxicity ratio, it is no longer being developed throughout this program. Additionally, it is being further evaluated in NSCLC with actionable genomic alterations after both targeted therapy and platinum-based chemotherapy are a part of the TROPION-Lung05 study (NCT04484142).
Insight: The late-breaking presentation highlighted promising efficacy results in patients with a/mNSCLC and actionable genomic alterations in solid tumors. However, the drug couldn’t provide a favorable safety profile. As per Delveinsight’s analysis, it would be quite early to comment on anything about the scope of the drug in this target population as we believe that upcoming data is still required from the study.
Not only with datopotamab deruxtecan, we have been eagerly evaluating the scope of other ADCs by Daiichi. At ESMO 2021, the company unveiled data from its Phase II study evaluating trastuzumab deruxtecan (T-DXd, DS-8201) in patients with HER2-mutated mNSCLC (DESTINY-Lung01). The data from the full cohort suggested that the treatment with T-DXd at a dose of 6.4 mg/kg every 3 weeks led to an OR – as assessed by independent review – in just over half (54.9%) of the cohort. An additional 37.4% of patients had SD, giving a disease control rate of 92.3%. Responses lasted for a median of 9.3 months and were observed across HER2 mutation subtypes. In this analysis, conducted at a median follow-up of 13.1 months, the median PFS and OS durations were 8.2 and 17.8 months, respectively. Drug-related ILD and pneumonitis which remains an important identified risk of T-DXd treatment occurred in 26.4% of patients.
Expert Opinion: “In my opinion, even though the median PFS of 8.2 months is somewhat more modest compared with the 14.0 months observed in the interim analysis, the median PFS and OS times are clinically meaningful in the setting of refractory disease. There is a need to further evaluate the safety profile of the agent to determine the optimal dosing and allow T-DXd to be used in combination with other therapies to improve the DoR. Until we can properly characterize this and other important aspects such as CNS activity, we need to be cautious about transitioning to the front-line setting. Nevertheless, I believe that due consideration needs to be given to improve HER2 testing rates to expand on the clinical experience.”
– Discussant, National Cancer Centre Singapore
Insight: Let’s see what the scope of ADC platform holders is in the future and how graphic we can remain with the ADCs where we already know that these assets are packed with black box warnings issuing toxicities within the patients. We believe that further study of T-DXd is necessary to evaluate the risk of ILD and pneumonitis. It is recommended that effective early detection and management are critical in preventing high-grade ILD and pneumonitis associated with T-DXd to further optimize the dosing regimen of T-DXd in patients with HER2-mutant lung cancers, the 5.4 mg/kg lower dose is currently being explored in the DESTINY-Lung02 clinical trial. Additionally, the drug displayed promising results in the other oncologic indications namely pretreated, advanced breast cancer (DESTINY-BREAST03 study), and HER2 Positive Advanced Gastric Cancer (DESTINY-Gastric06). Thus, we are optimistic with regard to the performance of the drug in patients with HER2 mutated mNSCLC. Conclusively, T-DXd achieved durable responses in individuals who have received prior treatment for mNSCLC harboring HER2 mutations.
*Non-small cell lung cancer (NSCLC), Triple-negative breast cancer (TNBC), Objective response rate (ORR), Disease control rate (DCR), Progression-free survival (PFS), Treatment-emergent adverse events (TEAEs), Antibody-drug conjugates (ADCs), Interstitial lung disease (ILD)