Highly encouraging anti-tumour activity of the TROP-2 directed antibody drug conjugate datopotamab deruxtecan in heavily pre-treated advanced NSCLC patients

Updated results of a phase I trial evaluating the TROP-2 directed antibody drug conjugate datopotamab deruxtecan indicate an overall response rate of 21-25% in a population of heavily pre-treated advanced non-small-cell lung cancer (NSCLC) patients. When dosed at 4 or 6 mg/kg the drug also proved to be tolerable, with low rates of toxicity-related treatment discontinuation. These promising findings justify the further evaluation of datopotamab deruxtecan in the phase III TROPION-Lung01 trial in which this agent will be compared to docetaxel in 590 advanced NSCLC patients who previously received platinum-based chemotherapy and anti-PD(L)1 therapy.

Introduction

TROP2 is a transmembrane glycoprotein that is highly expressed in various tumour types, including non-small cell lung cancer (NCSLC). Datopotamab Deruxtecan (DS-1062) is a TROP2-specific antibody-drug-conjugate (ADC), consisting of a humanised anti-TROP2 IgG1 monoclonal antibody, a topoisomerase 1 inhibitor payload and a tetrapeptide-based cleavable linker. Previously, the phase I TROPION-PanTumour01 study indicated a promising antitumour activity of this agent in advanced NSCLC patients with a manageable safety profile. During the 2020 WCLC meeting, updated results of this trial were presented.

The TROPION-PanTumour01 study enrolled patients with relapse/refractory advanced NSCLC with an ECOG performance status of 0 or 1. In the initial dose escalation phase of the trial a maximum tolerated dose of 8mg/kg every 3 weeks was determined, In the subsequent dose expansion phase, a total of 180 patients were enrolled and treated with DS-1062 at 4 mg/kg (N= 50), 6 mg/kg (N= 50) or 8 mg/kg (N= 80) every 3 weeks.

Promising antitumour activity

Baseline characteristics were well balanced between the three cohorts with a median age of 61-64 years and 50-64% of patients having received three or more previous lines of therapy.  Approximately 80% (84-88%) of patients in the study previously received immunotherapy, while more than 90% received prior platinum-based chemotherapy (88-98%). At a median follow-up of 7.4 months, 32 of the 159 response-evaluable patients had a confirmed complete or partial response (CR/PR) (4 mg/kg: 7 ;6 mg/kg: 6; 8mg/kg: 19). A further 6 patients had an unconfirmed CR/PR (4 mg/kg: 2 ;6 mg/kg: 2; 8mg/kg: 1). This corresponded with an objective response rate of 23%, 21% and 25% in the 4, 6 and 98 mg/kg cohort, respectively. When also considering the patients with disease stabilization, a disease control rate of 19%, 26% and 64% was reported for the three dose cohorts. The preliminary median progression-free survival in each cohort mounted to 4.3, 8.2 and 5.4 months, respectively.

Importantly, 15% of 8 mg/kg participants experienced adverse events that led to treatment discontinuation, which is markedly higher than the 4% and 7% adverse event related treatment discontinuations in the 4 and 6 mg/kg cohorts. Any-grade treatment-emergent adverse events were reported in 96%, 91% and 99% of participants in the 4, 6 and 8mg/kg, respectively. Grade ≥3 treatment related adverse events were reported in 10% and 16% of patients treated with 4 or 6 mg/kg, while this increased o 34% in the 8 mg/kg cohort. The most common adverse events consisted of nausea, stomatitis, alopecia and fatigue. Overall, 8% of patients experienced treatment-related interstitial lung disease (4mg/kg: 1 patient grade 3; 6mg/kg: 1 patient grade 2; 8mg/kg: 8 patients grade 1-2, 1 patient 3 grade, 3 patients grade 5). Regardless of dose, the pharmacokinetic profile was consistent throughout 3 cycles of treatment, with a half-life of 4.6 days and systemic exposure to the payload drug was low throughout all treatment doses.

Conclusion

In this ongoing phase I study, TROP-2 ADC DS-1062 has demonstrated encouraging antitumour activity and a manageable safety profile in a heavily pre-treated NSCLC cohort. These results have informed the study design of the phase III TROPION-PanTumour01 study, which will use DS-1062 at a dose of 6mg/kg.

Reference

Spira A et al., Datopotamab Deruxtecan, a TROP2 ADC, in Patients With Advanced NSCLC: Updated Results of TROPION-PanTumour01 Phase I Study. Presented at WCLC 2020. Abstract OA03.03.