The TROPION-Lung04 Phase Ib trial has unveiled highly promising results. The trial showcases the potential of datopotamab deruxtecan (Dato-DXd), in conjunction with Imfinzi (durvalumab), an anti-PD-L1 therapy, either with or without carboplatin, for patients grappling with previously untreated advanced or metastatic non-small cell lung cancer (NSCLC) devoid of actionable genomic alterations.
This significant breakthrough was brought to light during a late-breaking oral presentation at the prestigious International Association for the Study of Lung Cancer (IASLC) 2023 World Conference on Lung Cancer (WCLC).
Datopotamab deruxtecan is a cutting-edge, TROP2-targeted DXd antibody drug conjugate (ADC) that has been collaboratively developed by pharmaceutical giants AstraZeneca and Daiichi Sankyo.
“Most patients with advanced non-small cell lung cancer experience disease progression after initial treatment, underscoring the need for more effective first-line treatment options. The TROPION-Lung04 results offer preliminary evidence for the efficacy of datopotamab deruxtecan in combination with durvalumab and chemotherapy in first-line advanced non-small cell lung cancer with no new safety signals. We eagerly await enrolment and results from the Phase III programme evaluating various datopotamab deruxtecan and immune checkpoint inhibitor combinations in this setting.”
– Saiama Waqar, MD, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, and investigator in the trial
Every year, over one million individuals worldwide are diagnosed with advanced NSCLC, making this a matter of global significance. While the first-line treatment with immune checkpoint inhibitors, either standalone or combined with chemotherapy, has marked an improvement in outcomes for NSCLC patients without actionable genomic alterations (such as EGFR or ALK mutations), many still face the harsh reality of disease progression. Enter TROP2, a protein found in a vast majority of NSCLC tumors. It is noteworthy that, currently, there are no approved TROP2-targeted ADCs for lung cancer patients.
In previously untreated patients, the combination of datopotamab deruxtecan and durvalumab (known as the doublet) demonstrated an impressive objective response rate (ORR) of 50.0%. This included 7 partial responses (PR), and a disease control rate (DCR) of 92.9%. Even more remarkable, patients receiving datopotamab deruxtecan alongside durvalumab and carboplatin (the triplet) saw their ORR skyrocket to 76.9%, with 10 PRs, and a DCR of 92.3%. These remarkable responses were observed across varying levels of PD-L1 expression.
“Following the positive high-level results of TROPION-Lung01, these initial TROPION-Lung04 results in the first-line setting reinforce our confidence in datopotamab deruxtecan as a potential treatment option for patients with advanced non-small cell lung cancer. Through our robust clinical programme we are eager to continue evaluating this TROP2-directed antibody drug conjugate in lung cancer across treatment settings, alone and in novel combinations.”
– Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca
Equally reassuring, the safety profiles of datopotamab deruxtecan and Imfinzi, both individually and in combination with carboplatin, remained consistent with findings from other clinical trials, maintaining the expected safety standards for these agents. Notably, Grade 3 or greater treatment-emergent adverse events (TEAEs) were seen in 42.1% of patients on doublet therapy and 71.4% on triplet therapy. In the triplet therapy group, the most common Grade 3 or greater TEAEs were anemia (36%) and thrombocytopenia (21%). Importantly, no Grade 3 or greater TEAEs occurred in more than 15% of patients in the doublet therapy group. Remarkably, across the treatment cohorts, only four interstitial lung disease (ILD) events were attributed to the drugs by an independent committee, including one Grade 1 event, two Grade 2 events, and one Grade 4 event. No Grade 5 ILD events were reported.
In the doublet cohort, a substantial 73.7% of patients had not received prior treatment, while an even higher percentage of 92.9% in the triplet cohort were previously untreated. Both cohorts exhibited diverse PD-L1 expression levels, ranging from less than 1%, 1-49%, to 50% or greater.
“These early trial results further demonstrate the potential for datopotamab deruxtecan to enhance response to immune checkpoint inhibitors in patients with advanced non-small cell lung cancer and without actionable genomic alterations. We look forward to continuing to evaluate this promising TROP2-directed antibody drug conjugate in multiple ongoing Phase III trials to address what has long been an unmet need for the lung cancer community across treatment settings.”
– Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo
As of the data cut-off date on March 6, 2023, the median study duration for both cohorts stood at six months, and ongoing treatment was reported in 31.6% and 50.0% of patients in the doublet and triplet cohorts, respectively.
AstraZeneca and Daiichi Sankyo are now steering the way forward with three Phase III trials, all aimed at evaluating datopotamab deruxtecan-based combinations as potential first-line treatment options for patients with advanced or metastatic NSCLC without actionable genomic alterations, in comparison to the respective standard of care for each specific patient population.
The AVANZAR trial is casting a wide net, assessing datopotamab deruxtecan alongside Imfinzi and carboplatin in patients, regardless of their PD-L1 expression or tumor histology. Meanwhile, TROPION-Lung07 zeroes in on patients with non-squamous disease and PD-L1 expression less than 50%, evaluating datopotamab deruxtecan combined with pembrolizumab, with or without chemotherapy. Lastly, TROPION-Lung08 takes a precision approach, honing in on patients with PD-L1 expression of 50% or greater, examining the effectiveness of datopotamab deruxtecan paired with pembrolizumab.
These groundbreaking findings from the TROPION-Lung04 trial offer hope and a potential turning point in the fight against advanced NSCLC. Stay tuned as further developments pave the way for a brighter future for lung cancer patients worldwide.
