Exploratory Analyses Show Trastuzumab Deruxtecan Elicits Consistent Intracranial Responses in HER2-Mutated NSCLC With Brain Metastases

David Planchard, MD, PhD

Pooled findings from exploratory analyses of the phase 2 DESTINY-Lung01 (NCT03505710) and DESTINY-Lung02 (NCT04644237) trials showed that different doses of fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) elicited similar intracranial responses in patients with HER2-mutated non–small cell lung cancer (NSCLC) who had treated or untreated brain metastases at baseline, and the antibody-drug conjugate (ADC) produced similar systemic responses 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).

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).

References

1. Li BT, Planchard D, Goto K, et al. 1321MO trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2 (ERBB2)-mutant (HER2m) metastatic non–small cell lung cancer (NSCLC) with and without brain metastases (BMs): Pooled analyses from DESTINY-Lung01 and DESTINY-Lung02. Ann Oncol. 2023;34(suppl 2):S762-S763. doi:10.1016/j.annonc.2023.09.2354
2. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. News release. FDA. August 11, 2022. Accessed October 27, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-her2-mutant-non-small-cell-lung