Similar Intracranial Responses Seen With Trastuzumab Deruxtecan in HER2-Mutated NSCLC With Brain Metastases
In an exploratory analysis, different doses of fam-trastuzumab deruxtecan-nxki revealed consistent intracranial responses in HER2-mutated non–small cell lung cancer with treated or untreated brain metastases at baseline.
David Planchard, MD, PhD
When given at varying doses, fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) elicited consistent intracranial responses in patients with HER2-mutated non–small cell lung cancer (NSCLC) with treated or untreated brain metastases at baseline, according to pooled findings from exploratory analyses of the phase 2 DESTINY-Lung01 (NCT03505710) and DESTINY-Lung02 (NCT04644237) trials. Further, the antibody-drug conjugate (ADC) generated systemic responses that were similar in patients with or without baseline brain metastases.1
Findings from the pooled analyses presented at the 2023 ESMO Congress showed that patients with any baseline brain metastases treated with 5.4 mg/kg of T-DXd during the DESTINY-Lung02 study (n = 14) experienced a confirmed intracranial overall response rate (IC-ORR) of 50% (95% CI, 23.0%-77.0%), including a complete response (CR) rate of 21.4%, a partial response (PR) rate of 28.6%, a stable disease (SD) rate of 42.9%, and progressive disease (PD) rate of 7.1%. Moreover, the confirmed intracranial disease control rate (IC-DCR) was 92.9% (95% CI, 66.1%-99.8%), and the median intracranial duration of response (IC-DOR) was 9.5 months (95%, 3.6–not evaluable [NE]).
Patients with baseline brain metastases treated with 6.4 mg/kg of T-DXd in DESTINY-Lung01 or DESTINY-Lung02 (n = 30) achieved a confirmed IC-ORR of 30% (95% CI, 14.7%-49.4%); 30.0% had a PR, 43.3% had SD, 13.3% had PD, and 6.7% were NE. Notably, data were missing for 6.7% of patients. The IC-DCR was 73.3% (95% CI, 51.4%-87.7%) in this patient group, and the median IC-DOR was 4.4 months (95%, 2.9-10.2).
It was also noted that 86% of patients who had measurable brain metastasis and received T-DXd at 5.4 mg/kg and 78% of patients treated with 6.4 mg/kg of the ADC experienced a reduction in the baseline size of their brain lesion as their best overall response.
“Limitations of this post-hoc analysis include the small number of patients and the lack of a comparator arm,” said lead study author David Planchard, MD, PhD, a thoracic-oncologist and head of the Thoracic Cancer Group in the Department of Medicine at Gustave Roussy, in Villejuif, France.
In August 2022, the FDA granted accelerated approval to T-DXd for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 mutations, as detected by an FDA-approved test, and who have received previous systemic therapy. The regulatory decision was supported by data from DESTINY-Lung02.2
DESTINY-Lung01 enrolled patients with unresectable/metastatic nonsquamous NSCLC that was relapsed from or refractory to standard treatment. Patients in cohort 2 had to have locally reported HER2 mutations. DESTINY-Lung02 included patients with metastatic HER2-mutant NSCLC who received at least 1 prior lines of systemic therapy, including platinum-based chemotherapy. Furthermore, patients on both trials were required to have measurable disease per RECIST v1.1 criteria and an ECOG performance status of 0 or 1. Those with asymptomatic brain metastasis were allowed to participate in both studies.1
In DESTINY-Lung01, patients treated in cohort 2 and the expansion of cohort 2 (n = 91) received T-DXd at 6.4 mg/kg once every 3 weeks. In DESTINY-Lung02, patients were randomly assigned in a 2:1 fashion to receive T-DXd at 5.4 mg/kg once every 3 weeks (n = 102) vs T-DXd at 6.4 mg/kg once every 3 weeks (n = 50).
The pooled exploratory analyses included patients received T-DXd at 6.4 mg/kg with baseline brain metastases (n = 54) and without brain metastases (n = 87), as well as patients from DESTINY-Lung02 treated with T-DXd at 5.4 mg/kg who had baseline brain metastases (n = 32) or did not have brain metastases (n = 70).
Patients with baseline brain metastases treated with 6.4 mg/kg of T-DXd had a median age of 62.5 years (range, 29.0-88.0); 59.3% were female; the median time from NSCLC diagnosis to randomization was 17.9 months (range, 1.7-125.9); 75.9% had an ECOG performance status of 1; 83.3% had a history of prior brain metastases; 38.9% had more than 2 prior regimens in the metastatic setting; 44.4% of patients had prior treatment for brain metastasis; and the median time since prior radiotherapy was 1.6 months (range, 0.5-17.2).
This population achieved a confirmed systemic ORR of 50.0% (95%, 36.1%-63.9%), a DCR of 92.6% (95% CI, 82.1%-97.9%), and a median DOR of 7.2 months (95% CI, 5.3-NE). Sites of progression included intracranial (14.8%), extracranial (16.7%), and missing. The median progression-free survival (PFS) was 7.1 months (95% CI, 4.5-9.6), and the median overall survival (OS) was 13.8 months (95% CI, 11.1-19.5). Additionally, 75.9% of patients had grade 3 or higher treatment-emergent adverse effects (TEAEs), including 59.3% who experienced drug-related grade 3 or higher TEAEs..
Patients without brain metastases treated with 6.4 mg/kg of T-DXd had a median age of 59.0 years (range, 27.0-83.0); 71.3% were female; the time from NSCLC diagnosis to randomization was 16.2 months (range, 3.3-151.9); 66.7% of patients had an ECOG performance status of 1; 17.2% had a history of prior brain metastases; 31.0% had more than 2 prior regimens in the metastatic setting; 6.9% of patients had prior brain metastases treatment; and the median time since prior radiotherapy is 13.6 months (range, 3.0-21.0).
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This population experienced a confirmed systemic ORR of 58.6% (95%, 47.6%-69.1%), a DCR of 80.0% (95% CI, 84.1%-96.7%), and a median DOR of 14.1 months (95% CI, 9.3-NE). Sits of progression included extracranial (26.4%), both intracranial and extracranial (2.3%), and missing (11.5%). The median PFS was 11.9 months (95% CI, 7.2-16.1) and the median OS was 27.9 months (95% CI, 17.8-NE). Notably, 63.2% of patients had grade 3 or higher TEAEs, and 44.8% had grade 3 or higher drug-related TEAEs.
Patients with brain metastasis treated with 5.4 mg/kg of T-DXd on DESTINY-Lung02 had a median age of 57.5 years (range, 37.0.0-83.0); 59.4% were female; the median time from NSCLC diagnosis to randomization was 22.4 months (range, 3.2-63.0); 81.3% had an ECOG performance status of 1; 90.6% had a history of prior brain metastases; 28.1% had more than 2 prior regimens in the metastatic setting; 53.1% of patients had prior treatment for brain metastasis; and the median time since prior radiotherapy was 8.5 months (range, 1.0-38.5).
These patients achieved a confirmed systemic ORR of 46.9% (95%, 29.1%-65.3%), a DCR of 90.6% (95% CI, 75.0%-98.0%), and a median DOR of 4.6 months (95% CI, 4.2-9.5). Sites of progression included intracranial (9.4%), extracranial (18.8%), both intracranial and extracranial (9.4%), and missing (3.1%). The median PFS was 7.1 months (95% CI, 5.5-9.7), and the median OS was 13.6 months (95% CI, 9.4-NE). Grade 3 or higher TEAEs occurred in 64.5% of patients, including 38.7% who had grade 3 or higher drug-related TEAEs.
Patients with no baseline brain metastases treated with 5.4 mg/kg of T-DXd had a median age of 59.5 years (range, 30.0-79.0); 65.7% were female; the time from NSCLC diagnosis to randomization was 17.9 months (range, 3.3-149.6); 67.1% of patients had an ECOG performance status of 1; 21.4% had a history of prior brain metastases; 34.3% had more than 2 prior regimens in the metastatic setting; 17.1% of patients had prior brain metastases treatment; and the median time since prior radiotherapy was 6.8 months (range, 0.1-80.1).
This patient population experienced a confirmed systemic ORR of 50.0% (95%, 37.8%-62.2%), a DCR of 94.3% (95% CI, 86.0%-98.4%), and a median DOR of 16.8 months (95% CI, 8.7-NE). Sites of progression included extracranial (20.0%) and missing (1.4%). The median PFS was 18.0 months (95% CI, 8.5-NE), and the median OS was 19.5 months (95% CI, 14.9-NE). Grade 3 or higher TEAEs occurred in 47.1% of patients, and 38.6% had grade 3 or higher drug-related TEAEs..
Additional data showed that for patients with treated baseline brain metastases and received 5.4 mg/kg of T-DXd (n = 8) achieved a confirmed IC-ORR of 50.0% (95% CI, 15.7%-84.3%), and those with untreated baseline brain metastases who received the same dosage of T-DXd (n = 6) had a confirmed IC-ORR of 50%( 95% CI, 11.8%-88.2%).
Patients with previously treated brain metastases treatment who received 6.4 mg/kg of T-DXd (n = 14) achieved a confirmed IC-ORR of 21.4% (95% CI, 4.7%-50.8%) vs 37.5% (95% CI, 15.2%-64.6%) in patients who had untreated brain metastases (n = 16).
