Dato-DXd Shows Promising Intracranial Activity in Advanced NSCLC Subgroups

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Datopotamab deruxtecan was efficacious among patients with non-small cell lung cancer and baseline brain metastases who harbor actionable genomic alterations, according to an exploratory analysis of the phase 2 TROPION-Lung05 trial.

illustration of Lungs, medical concept© yodiyim - stock.adobe.com

Illustration of lungs, medical concept© yodiyim - stock.adobe.com

Treatment with datopotamab deruxtecan (Dato-DXd) demonstrated encouraging intracranial activity among previously treated patients with advanced/metastatic non-small cell lung cancer (NSCLC) with actionable genomic alterations, according to results from an exploratory analysis of the phase 2 TROPION-Lung05 trial (NCT04484142) presented at the 2024 ASCO Annual Meeting.1

“This is the first data to suggest [intracranial] antitumor activity with Dato-DXd in patients with heavily pretreated [advanced/metastatic] NSCLC,” the investigators wrote in their poster presentation of the data.

Overall Response to Dato-DXd

In the post hoc analysis, at the data cutoff of December 14, 2022, 53 patients with baseline brain metastases demonstrated an overall response rate (ORR) of 28% (95% CI, 17%-42%), including no complete responses (CRs), 28% with partial responses (PRs), 40% with stable disease (SD), and 19% with progressive disease (PD). In the group of 84 patients without baseline brain metastases, ORR was 40% (95% CI, 30%-52%), including 5% with CRs, 36% with PRs, 42% with SD, and 11% with PD.

In addition, the disease control rate (DCR) for those with baseline brain metastases was 72% (95% CI, 58%-83%) and 83% (95% CI, 74%-91%) for those without. Similarly, clinical benefit rates (CBR) were 40% (95% CI, 27%-54%) and 51% (95% CI, 40%-62%), respectively.

Median progression-free survival (PFS) was 5.4 months (95% CI, 3.1-7.0) for patients with baseline brain metastases and 5.6 months (95% CI, 4.9-8.3) for those without.

Intracranial Efficacy

When evaluating intracranial efficacy, the ORR for the 18 evaluable patients with baseline brain metastases was 22% (95% CI, 6%-48%), including 18% (95% CI, 2%-52%) for the EGFR-mutated subgroup (n = 11), 29% (95% CI, 4%-71%) for the non-EGFR-mutated subgroup (n = 7), and 20% (95% CI, 1%-72%) for the ALK rearrangement subgroup (n = 5).

Of note, among the 3 patients with brain metastasis target lesions who did not undergo previous local therapy, 1 patient experienced central nervous system response (ORR, 33%).

Among these 18 patients, DCR was 72% (95% CI, 47%-90%) and CBR was 44% (95% CI, 22%-69%). Lastly, intracranial PFS was 6.9 months (95% CI, 4.0-9.5).

Dato-DXd Safety

Any-grade treatment-related adverse events (TRAEs) occurred in 91% of patients with brain metastases at baseline, compared with 96% of those without, with grade 3 or higher TRAEs occurring in 23% and 32% of patients in the respective groups.

In patients with and without brain metastases at baseline, TRAEs led to dose reductions in 23% and 18%, respectively, dose delays in 17% and 24%, and treatment discontinuation in 4% and 6%. Serious TRAEs occurred in 8% of patients in both groups.

TROPION-Lung05 Trial

In the phase 2, multicenter, single-arm, open-label TROPION-Lung05 trial, 137 patients received 6 mg/kg Dato-DXd every 3 weeks.

Key eligibility criteria included stage IIIB, IIIC, or IV NSCLC; at least 1 actionable genomic alteration; ECOG performance status of 0 or 1; at least 1 line of targeted therapy; 1 or 2 prior cytotoxic agent-containing therapies including platinum-based therapy in the advanced/metastatic setting; and radiographic disease progression after the most recent therapy.

ORR by blind independent committee review (BICR) served as the primary end point. Secondary end points included duration of response, DCR, CBR, PFS, and time to response by BICR and investigator assessment, as well as confirmed ORR by investigator assessment, overall survival, safety, pharmacokinetics, and immunogenicity.

In this analysis, investigators focused on systemic efficacy and safety by central nervous system BICR baseline brain metastasis status and intracranial efficacy by mutation status.

Among those with and without brain metastases at baseline, median age was 58 years (range, 36-75) and 63 years (range, 29-79), respectively. The majority were women (53% vs 65%, respectively), Asian (55% vs 58%), had an ECOG performance score of 1 (64% vs 69%), and were never smokers (55% vs 56%).

Further, of those with and without baseline brain metastases, most had an EGFR mutation (55% vs 58%) or ALK rearrangement (28% vs 23%). In total, 72% of those with brain metastases at baseline had prior local therapy for their brain metastases, including radiation (59%), surgery (6%), and radiosurgery (23%).

Further Investigation

The median duration of treatment for those with baseline brain metastases was 3.2 months (range, 0.7-17.2) and 4.9 months (range, 0.7-20.6) for those without.

At data cutoff, 15% of patients with baseline brain metastases and 14% of patients without remained on study treatment. Disease progression (70% and 75%, respectively) was the most common reason for discontinued treatment.

“The data support further investigation of Dato-DXd in patients with brain [metastases],” the investigators concluded, adding that additional studies of the intracranial activity of the agent are ongoing, including the phase 2 TUXEDO-2 trial (NCT05866432) and the phase 2 DATO-BASE trial (NCT06176261).

REFERENCE:
Lisberg A, Ahn MJ, Kitazono S, et al. Intracranial efficacy of datopotamab deruxtecan (Dato-DXd) in patients (pts) with previously treated advanced/metastatic non-small cell lung cancer (a/m NSCLC) with actionable genomic alterations (AGA): Results from TROPION-Lung05. J Clin Oncol. 2024;42(suppl 16):abstr 8593. doi:10.1200/JCO.2024.42.16_suppl.8593.
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