Datopotamab deruxtecan-based combinations show promising clinical activity

Initial results from the TROPION-Lung02 Phase Ib trial showed that datopotamab deruxtecan (Dato-DXd) in combination with pembrolizumab with or without platinum chemotherapy demonstrated promising clinical activity and a tolerable safety profile in patients with previously untreated or pretreated, advanced or metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations. Results were presented during a late-breaking presentation (#MA13.07) today at the International Association for the Study of Lung Cancer 2022 World Conference on Lung Cancer (WCLC).

Datopotamab deruxtecan is a specifically designed TROP2-directed DXd antibody drug conjugate (ADC) being jointly developed by AstraZeneca and Daiichi Sankyo.

NSCLC is diagnosed at an advanced stage in nearly 50% of patients and often has a poor prognosis with worsening outcomes after each line of subsequent therapy.1-3 While 1st-line treatment consisting of immunotherapy with or without chemotherapy has improved outcomes for patients with NSCLC without actionable genomic alterations, disease progression still occurs in majority of patients and additional treatment strategies in this setting are needed.4,5

Benjamin Philip Levy, MD, Clinical Director of Medical Oncology, Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital, Associate Professor of Oncology at Johns Hopkins University School of Medicine and investigator in the TROPION-Lung02 trial, said: “Many patients with advanced non-small cell lung cancer still experience disease progression following initial treatment, underscoring the need for new therapeutic approaches. The initial results from the TROPION-Lung02 trial show encouraging efficacy and safety results when combining datopotamab deruxtecan and pembrolizumab with or without platinum chemotherapy and warrant further study in the 1st-line metastatic setting.”

Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca, said: “Building on preliminary findings of datopotamab deruxtecan combination therapy in triple-negative breast cancer shared earlier this year, these initial results from TROPION-Lung02 reflect the broader promise of combining existing treatments with antibody drug conjugates. We look forward to continuing this important research with the goal of providing a new, effective treatment option for patients with advanced non-small cell lung cancer.”

Gilles Gallant, Senior Vice President, Global Head, Oncology Development, Oncology R&D, Daiichi Sankyo, said: “These early findings from TROPION-Lung02 are promising and represent the first lung cancer trial to report results combining a TROP2-directed ADC with an immune checkpoint inhibitor with or without platinum chemotherapy in patients with advanced or metastatic non-small cell lung cancer. These data support the initiation of the TROPION-Lung08 Phase III trial to further evaluate datopotamab deruxtecan in combination with pembrolizumab as a 1st-line combination treatment in patients with advanced non-small cell lung cancer without actionable genomic alterations.”

An interim analysis of the ongoing TROPION-Lung02 trial in patients with previously untreated or pretreated, advanced or metastatic NSCLC without actionable genomic alterations demonstrated a promising overall response rate (ORR) in the overall population of 37% (median follow-up of 6.5 months) in patients treated with datopotamab deruxtecan and pembrolizumab (doublet therapy) and an ORR of 41% (median follow-up of 4.4 months) in patients receiving datopotamab deruxtecan, pembrolizumab and platinum chemotherapy (triplet therapy). A disease control rate (DCR) of 84% was seen with both the doublet and triplet combination therapy in the overall population that comprised both 1st-line and 2nd-line settings.

In previously untreated patients, ORRs of 62% (eight of the 13 patients receiving doublet therapy) and 50% (10 of 20 patients receiving triplet therapy) were observed. Eight partial responses (PRs) were seen in patients receiving doublet therapy and 10 PRs (three pending confirmation) were seen in patients receiving triplet therapy. A DCR of 100% was observed with doublet therapy and a DCR of 90% was observed with triplet therapy.

Combinations with datopotamab deruxtecan demonstrated a tolerable safety profile, which supports further evaluation in ongoing studies. Grade 3 or greater treatment-emergent adverse events (TEAEs) occurred in 40% and 60% of patients in the doublet and triplet cohorts, respectively. The most frequent TEAEs of any Grade in the doublet and triplet cohorts respectively were stomatitis (56% and 29%), nausea (41% and 48%), decreased appetite (28% and 38%), fatigue (25% and 36%) and anaemia (16% and 36%). There were four interstitial lung disease (ILD) events determined as drug-related by an independent adjudication committee across both cohorts; two were adjudicated as Grade 1/2 events and two were adjudicated as Grade 3 events. No Grade 4 or Grade 5 ILD events were adjudicated as drug-related. At the time of the data cut-off, there were three potential ILD events pending adjudication. Three deaths occurred (two within the doublet cohort, one in the triplet cohort), none of which were determined as drug-related. Treatment discontinuations due to adverse events occurred in less than 22% of patients and datopotamab deruxtecan dose discontinuation occurred in 13% of patients.

Patients in TROPION-Lung02 receiving doublet therapy were previously treated with one median line of therapy, including platinum chemotherapy (60%) and immunotherapy (30%). In the triplet cohort, patients previously received platinum chemotherapy (35%) and immunotherapy (38%). Datopotamab deruxtecan-based combination as a 1st-line of therapy accounted for 33% and 63% of patients in doublet and triplet cohorts, respectively. As of the 2 May 2022 data cut-off, 53% and 77% of patients remained on the doublet and triplet therapy, respectively.

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