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Datopotamab deruxtecan and Enhertu show promising clinical activity in NSCL

January 29, 2021: New data from AstraZeneca and Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo)’s datopotamab deruxtecan and Enhertu (trastuzumab deruxtecan) showed encouraging results from both antibody drug conjugates (ADCs) in patients with advanced or metastatic non-small cell lung cancer (NSCLC).

The data were presented today in two oral presentations during the World Conference on Lung Cancer (WCLC), hosted by the International Association for the Study of Lung Cancer (IASLC).

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Updated results from the TROPION-PanTumor01 Phase I trial showed promising clinical activity for datopotamab deruxtecan, a TROP2-directed ADC, in patients with advanced or metastatic NSCLC.

Additionally, an interim analysis of the HER2-overexpressing cohort of the DESTINY-Lung01 Phase II trial showed preliminary evidence of antitumour activity for Enhertu, a HER2-directed ADC, in patients with metastatic NSCLC.

Lung cancer is the leading cause of cancer death among both men and women, and accounts for about one-fifth of all cancer deaths globally, with 80-85% classified as NSCLC.

For patients with metastatic disease, prognosis is particularly poor, as only 6-10% live five years beyond diagnosis. 

Currently, there are no TROP2-directed or HER2-directed medicines approved for the treatment of NSCLC.

Cristian Massacesi, Senior Vice President, Head of Late-Stage Development, Oncology R&D, said: “Antibody drug conjugates have transformative potential for the targeted treatment of advanced lung cancer, and the early data for datopotamab deruxtecan and Enhertu suggest a promising durable benefit in patients who have limited treatment options.

Both are potent ADCs, and we look forward to further clinical data from these development programmes in patients with lung cancer.”

Antoine Yver, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo, said: “Developing innovative therapies for patients with lung cancer, including those that target TROP2 and HER2, are important as few treatment options remain once progression occurs in the metastatic setting following treatment with platinum-based chemotherapy and immune checkpoint inhibitors.

We are encouraged by these preliminary results, which may indicate a durability of effect of datopotamab deruxtecan. We remain committed with AstraZeneca to our bold development plan, particularly the ongoing pivotal Phase III trial of datopotamab deruxtecan monotherapy in patients with metastatic non-small cell lung cancer.”

TROPION-PanTumor01 trial results
In the TROPION-PanTumor01 Phase I trial, an objective response rate (ORR) ranging from 21 to 25%, as assessed by independent central review, was observed in 159 patients with advanced or metastatic NSCLC receiving different doses of datopotamab deruxtecan (4mg/kg, 6mg/kg or 8mg/kg), as of data cut-off on 4 September 2020.

Thirty two confirmed complete or partial responses were seen, and an additional five complete or partial responses are still too early to confirm.

Efficacy data were preliminary due to immaturity of follow-up across dose groups, but preliminary efficacy results may support durability of clinical activity.

A disease control rate (DCR) ranging from 67 to 80% was observed with a median progression-free survival (PFS) ranging from 4.3 to 8.2 months across the three doses of datopotamab deruxtecan.

Alexander Spira, MD, PhD, FACP, Oncologist, Virginia Cancer Specialists, US Oncology Research and Johns Hopkins Oncology, said: “These updated preliminary results from TROPION-PanTumor01 are encouraging, as responses were seen across all three doses of datopotamab deruxtecan, underscoring the potential of targeting TROP2 with an antibody drug conjugate in advanced or metastatic non-small cell lung cancer.

We look forward to seeing the results from the Phase III trial, which will further evaluate datopotamab deruxtecan versus chemotherapy, the current standard of care for patients with advanced disease that has progressed following treatment with platinum chemotherapy and immunotherapy.”

Summary of ROPION-PanTumor01 results

The majority of patients across all three doses were previously treated with three or more prior lines of therapy including platinum-based chemotherapy (94%) or immunotherapy (84%). Median duration of follow-up was 7.4 months.

As of data cut-off, 39% of patients remained on treatment with datopotamab deruxtecan.

Datopotamab deruxtecan demonstrated a manageable safety profile in the TROPION-PanTumor01 Phase I trial, which was consistent with what has been previously reported.

Overall, the 4mg/kg and 6mg/kg doses were better tolerated than the 8mg/kg dose. The most common Grade 3 or greater treatment-emergent adverse events (TEAEs) included mucosal inflammation, anaemia, stomatitis and fatigue, with patients treated at the 8mg/kg dose experiencing higher rates overall.

Fourteen cases (8%) of interstitial lung disease (ILD) occurred as determined by an independent adjudication committee.

The majority of ILD cases (12/14) were observed with the 8mg/kg cohort, including three deaths (Grade 5). One Grade 3 ILD event was seen with the 4mg/kg dose and one Grade 2 ILD event was seen with the 6mg/kg dose.

Based on the efficacy and safety findings, the 6mg/kg dose has been identified as the recommended dose for the registrational TROPION-Lung01 Phase III trial.

DESTINY-Lung01 trial results
In the interim results of cohort 1 from the DESTINY-Lung01 Phase II trial the primary endpoint of confirmed ORR, assessed by independent central review, was 24.5% for extensively treated patients with HER2-overexpressing (defined as IHC3+ or IHC2+) metastatic NSCLC treated with Enhertu (6.4mg/kg) (n=49).

Patients achieved a DCR of 69.4% with a median PFS of 5.4 months. After a median follow-up of 6.1 months, the estimated median duration of response (DoR) was 6.0 months, and the median overall survival (OS) was 11.3 months.

Patients were treated with a median of three prior lines of therapy with most receiving platinum-based chemotherapy (91.8%) or immunotherapy (73.5%).

Median treatment duration was 18 weeks. As of data cut-off on 30 May 2020, 22% of patients remained on treatment with Enhertu.

Interim data (n=42) from the HER2-mutant (HER2m) metastatic NSCLC cohort of DESTINY-Lung01 were previously presented during the 2020 American Society of Clinical Oncology (ASCO) virtual meeting, and also featured as an encore presentation at WCLC.

The results showed Enhertu achieved a clinically meaningful tumour response in patients with HER2m metastatic NSCLC.

The overall safety and tolerability profile of Enhertu was consistent with previous trials. In the HER2-overexpressing cohort of DESTINY-Lung01, the most common Grade 3 or greater TEAEs were decreased neutrophil count and fatigue.

There were eight cases of treatment-related ILD or pneumonitis, as determined by an independent adjudication committee including two Grade 1, three Grade 2 and three deaths (Grade 5).

In the HER2m cohort of DESTINY-Lung01, there were five cases of ILD or pneumonitis, as determined by an independent adjudication committee. All cases were Grade 2.”

https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2021/datopotamab-deruxtecan-and-enhertu-show-promising-early-clinical-activity-in-patients-with-advanced-non-small-cell-lung-cancer.html

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