Rezivertinib Generates Promising CNS Efficacy in NSCLC With an EGFR T790M Mutation

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Rezivertinib (BPI-7711) showed promising clinical central nervous system (CNS) efficacy among patients with advanced non–small cell lung cancer (NSCLC) with EGFR T790M mutation and CNS metastases.​​

The study included individual data from 2 different single-arm, phase 1 (NCT03386955) and phase 2b studies (NCT03812809) to assess the CNS response of rezivertinib in advanced NSCLC patients with an EGFR T790M mutation who had progressed following prior treatment including first- or second-generation EGFR TKIs.

Findings showed that in the CNS full analysis set (cFAS), the CNS objective response rate (CNS-ORR) was 32.0% (95% CI, 24.6%-40.1%) and the CNS disease control rate (CNS-DCR) was 42.0% (95% CI, 34.0%-50.3%), while in the CNS evaluable for response set(cEFR), these rates were 68.9% (95% CI, 53.4%-81.8%) and 100% (95% CI, 92.1%-100.0%).

Patients were eligible for enrollment if aged 18 years or older with a histologically or cytologically confirmed locally advanced or metastatic NSCLC with an EGFR mutation, radiologically confirmed disease progression after their latest treatment with a first- or second-generation EGFR TKI, and a centrally confirmed EGFR T790M mutation with either tumor tissue or plasma samples.

In the phase 1 study, rezivertinib was administered orally once a day from 30 to 300 mg, and in the phase 2b study all patients received 180 mg until disease progression, unacceptable toxicity, or withdrawal of consent. If a patient reported a grade 3 or greater treatment-related adverse event (TRAE) or intolerable toxicity caused by rezivertinib, dose interruption was implemented.

The full analysis set (FAS) included post-progressive patients who received a prescribed dosage (≥180 mg) of rezivertinib orally once daily, while those with stable, asymptomatic CNS lesions, including measurable and non-measurable ones at baseline were included in cFAS.

Investigators evaluated the end points of blinded independent central review-assessed CNS-ORR, CNS-DCR, CNS duration of response (CNS-DoR), CNS progression-free survival (CNS-PFS), and CNS depth of response (CNS-DepOR).

A total of 355 patients were included in the FAS with 150 included in the cFAS, and 45 patients in cEFR. Baseline demographic and disease characteristics were similar between the FAS and cFAS populations with patients having a median target CNS lesion size of 20.8 (range, 10.0-99.6) mm. In the FAS and cFAS populations, the median age was 59 (range, 30-81), and 58 (range, 30-81), most patients were female (69% and 68.7%), and had an ECOG performance status of 1 (70.1% and 70.0%).

Twenty-six patients were confirmed EGFR T790M-positive with both baseline tissue and plasma samples, 154 patients were confirmed with tissue EGFR T790M-positive only, and 175 patients were confirmed with plasma EGFR T790M-positive only in the FAS populations while in the cFAS population, 13 patients were confirmed EGFR T790M-positive with both baseline tissue and plasma samples, 47 patients were confirmed with tissue EGFR T790M-positive only, and 90 patients were confirmed with plasma EGFR T790M-positive only.

At the data cutoff date of December 23, 2021 in the phase 1 study and January 24, 2022 in the phase 2b study, the median duration of rezivertinib exposure was 8.3 (range, 0.2–28.8) months in cFAS.

Additional efficacy findings showed that the median CNS-DepOR and the mean of CNS-DepOR were -52.0% (range, 100.0%-16.1%) and -46.8% (95% CI, –55.5% to -38.1%) in the cEFR population. Then in the cFAS population, the median CNS-DoR and CNS-PFS were 13.8 (95% CI, 9.6-not calculable [NC]) and 16.5 (95% CI, 13.7-NC) months.

The safety profile of rezivertinib was favorable with 98.3% of patients in FAS having at least 1 treatment-emergent adverse event (TEAE) and 83.9% with a treatment-related adverse event (TRAE). The safety profile in cFAS was consistent with that seen in the FAS population.

A total of 98.7% of patients in the cFAS population had TEAEs and 85.3% had TRAEs. Grade 3 of higher TEAEs were reported by 36.3% in FAS and 37.3% in cFAS, and 3.1% and 1.3% patients experienced serious TRAEs, respectively. In FAS and cFAS, 0.3% and no patients died due to TRAEs, and dose interruptions caused by TRAEs occurred in 10.7% and 6.7%. Dose reductions due to TRAEs occurred in 4.8% and 4.0% patients in FAS and cFAS, respectively. Finally, 3.9% and 4.0% patients discontinued treatment from their TRAEs in FAS and cFAS, respectively.

Overall, data from this pooled analysis showed that rezivertinib generated promising clinical CNS efficacy in patients with advanced NSCLC with an EGFR T790M mutation and CNS metastases. In addition to promising CNS efficacy findings with favorable CNS-ORR, CNS-DepOR, CNS-DoR, CNS-PFS data, the safety profile was consistent with previously published findings, warranting further evaluation of the CNS efficacy of rezivertinib in future studies.

REFERENCES:

Yang S, Wu S, Zhao Y, et al. Central nervous system efficacy of rezivertinib (BPI-7711) in advanced NSCLC patients with EGFR T790M mutation: A pooled analysis of two clinical studies. Lung Cancer. 2023;180:107194. doi:10.1016/j.lungcan.2023.107194

BPI-7711 capsule in patients with EGFR mutation T790M positive non-small cell lung cancer. ClinicalTrials.gov. Updated May 16, 2022. Accessed June 16, 2023. https://clinicaltrials.gov/ct2/show/NCT03386955

A phase IIb study of BPI-7711 capsule in non-small cell lung cancer patients with T790M mutation positive. ClinicalTrials.gov. Updated May 19, 2022. Accessed June 16, 2023. https://clinicaltrials.gov/ct2/show/NCT03812809