Dato-DXd Improves Antitumor Intracranial Responses in NSCLC Subgroups

Patients with advanced or metastatic non-small cell lung cancer (NSCLC) who were previously treated demonstrated promising antitumor intracranial (within the skull) activity after receiving treatment with Dato-DXd (datopotamab deruxtecan).

These findings from the phase 2 TROPION-Lung05 trial were presented at the 2024 ASCO Annual Meeting. Patients involved in the study all had actionable genomic alterations, including EGFR mutations and ALK rearrangements.

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

Dato-DXd is an antibody-drug conjugate that targets and binds onto the TROP2 protein expressed on tumor cells, according to the National Cancer Institute.

TROPION-Lung05 Trial

In the phase 2 TROPION-Lung05 trial, 137 patients received Dato-DXd every 3 weeks.

Key eligibility criteria included having:

• Stage 3B, 3C or 4 NSCLC.
• At least one actionable genomic alteration.
• An ECOG performance status of 0 or 1, meaning patients could complete daily tasks independently.
• Received at least one line of targeted therapy.
• Treatment with one or two prior cytotoxic agent-containing therapies including platinum-based therapy in the advanced/metastatic setting
• Radiographic disease progression after the most recent therapy.

Among patients with and without brain metastases at baseline, the median age was 58 and 63, respectively. The majority were women (53% versus 65%, respectively), Asian (55% versus 58%), had an ECOG performance score of 1 (64% versus 69%) and were never smokers (55% versus 56%).

Further, of those with and without baseline brain metastases, most had an EGFR mutation (55% versus 58%, respectively) or ALK rearrangement (28% versus 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%).

Overall Response to Dato-DXd

In an analysis, at the data cutoff of Dec. 14, 2022, 53 patients with baseline brain metastases (tumor spread to the brain) demonstrated an overall response rate (ORR; percentage of patients whose tumors shrunk or disappeared) of 28%. This included no complete responses (CRs; complete tumor disappearance), 28% with partial responses (PRs; tumor shrinkage), 40% with stable disease (SD) and 19% with progressive disease (PD).

In the group of 84 patients without baseline brain metastases, the ORR was 40%, including 5% with CRs, 36% with PRs, 42% with SD and 11% with PD.

In addition, the disease control rate (DCR; stopping the growth of tumors) for those with baseline brain metastases was 72% and 83% for those without. Similarly, clinical benefit rates (CBR; includes CR, PR and SD) were 40% and 51%, respectively.

Median progression-free survival (PFS; time patients live until disease worsening) was 5.4 months for patients with baseline brain metastases and 5.6 months for those without.

Intracranial Efficacy

When evaluating intracranial efficacy, the ORR for the 18 evaluable patients with baseline brain metastases was 22%, including 18% for 11 patients in the subgroup with EGFR mutations, 29% for seven patients in the subgroup with non-EGFR mutations and 20% for five patients in the subgroup with ALK rearrangements.

Of note, among the three patients with brain metastasis target lesions who did not undergo previous local therapy, one patient experienced central nervous system response with an ORR of 33%.

Among these 18 patients, the DCR was 72% and CBR was 44%. Lastly, intracranial PFS was 6.9 months.

Dato-DXd Safety

Treatment-related side effects of any severity occurred in 91% of patients with brain metastases at baseline, compared with 96% of those without, with grade 3 (severe) or higher treatment-related side effects occurring in 23% and 32% of patients in the respective groups.

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

Further Investigation

The median duration of treatment for those with baseline brain metastases was 3.2 months and 4.9 months 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 researchers concluded, adding that additional studies of the intracranial activity of the agent are ongoing, including the phase 2 TUXEDO-2 trial and the phase 2 DATO-BASE trial.

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