Atezolizumab plus Chemotherapy Displays Efficacy, Tolerability in NSCLC with Untreated Brain Metastases

Ernest Nadal, MD

Atezolizumab (Tecentriq) plus carboplatin and pemetrexed yielded a favorable safety and efficacy profile in patients with advanced non-squamous non-small cell lung cancer (NSCLC) with untreated brain metastases, according to results from the phase 2 ATEZO-BRAIN trial (NCT03526900) presented by Ernest Nadal, MD, at the International Association for the Study of Lung Cancer 2021 World Conference on Lung Cancer.

At a median follow-up of 17.3 months, the combination elicited a median systemic progression-free survival (PFS) of 8.9 months (95% CI, 6.7-13.8) in the 40-patient population. The median intracranial PFS was 6.9 months (95% CI, 4.7-12.1). The 18-month PFS rate was 24.9% and 10.4% systemically and intracranially, respectively.

“Brain metastases are the most frequent cancer-related neurological complication and are associated with a negative impact in quality of life and neurocognitive function, as well as being associated with poor prognosis,” explained Nadal, a medical oncologist at the Catalan Institute of Oncology and an assistant professor at the Universitat de Barcelona in L'Hospitalet de Llobregat, Spain. “Patients with untreated brain metastases and those who have received corticosteroids have been excluded or underrepresented in many [previous] trials evaluating chemotherapy plus immunotherapy in the first-line setting. We have data from previous studies demonstrating that immunotherapy and chemotherapy could yield promising intracranial efficacy and safety results in NSCLC.”

Eligible patients had untreated stage IV non-squamous NSCLC with untreated brain metastases and were EGFR/ALK negative, regardless of PD-L1 expression. To be included in the study, patients also needed to register an ECOG performance status of 0 to 1 and have measurable lesions systemically and in the brain. Anticonvulsivants and dexamethasone ≤4 mg daily was allowed.

The primary end points of the study were safety and investigator-based PFS by RECIST v1.1 in and RANO-BM. Secondary end points included overall response rate (ORR), overall survival (OS), quality of life, and time to brain radiotherapy. The exploratory end point was to identify neuroimaging and blood biomarkers that could potentially predict response or resistance.

Atezolizumab, a monoclonal antibody, was administered intravenously at a dose of 1200 mg once every 3 weeks for 4 to 6 cycles. Carboplatin (5 AUCs) and pemetrexed (500 mg/m²) were given over the same dosing schedule. Afterwards, pemetrexed 500 mg/m² and atezolizumab 1200 mg were administered once every 3 weeks for maintenance until tumor progression or unacceptable toxicity for a maximum of 2 years. Tumor evaluation was performed via body CT scan and brain MRI every 6-weeks until week 12, then every 9-weeks until disease progression.

The study, conducted at 11 cancer centers across Spain, utilized a Multc Lean Bayesian statistical design to monitor safety and efficacy. Investigators determined that a sample size of 40 patients was necessary, assuming a PFS rate of 50% at 12 weeks and a maximum grade 3/4 toxicity of 35%. Safety and efficacy were assessed every 5 patients.

The median age of the study population was 62.6 (IQR 11.5) and 72.5% of patients were male. All patients were Caucasian, 75% were smokers or former smokers and 15% never smoked. Most participants were patients with lung adenocarcinoma histology (97.5%) and an ECOG performance status of 1 (65%).

Investigators concluded the 12-week PFS rate was 60%, exceeding the expected rate of 50%. The grade 3/4 toxicity rate was 27.5%, falling into the acceptable range of 0%-35%. Median OS was 13.6 months (95% CI, 9.7-not reached) and the 2-year OS rate was 32%

The intracranial ORR per RANO-BM was 40%. Four (10%) patients achieved a complete response and 47.5% experienced stable disease (SD). The systemic ORR, made up of all partial responses (PRs), was 47.5% according RECIST v1.1 and 40% of patients had SD. Only 4 patients had discordance among systemic and central nervous system response, 2 with disease progression in the body and SD in the brain and 2 with disease progression in the brain and a PR in the body.

In terms of safety, most treatment-related adverse events (TRAEs) were grade 1/2. Investigators observed grade 4 thrombocytopenia, neutropenia, and hallucinations in 1 patient each. No fatal TRAEs occurred.

Common AEs of any grade included fatigue (60%), anemia (45%), dyspnea (28%), and nausea (28%). Grade 3 AEs included anemia (20%), back pain (10%), thrombocytopenia (5%), and dyspnea (3%). Immune-related AEs of any grade mostly consisted of skin rash (20%), anorexia (20%), alanine transaminase increase (13%), and aspartate transaminase increase (13%). Two patients had grade 3 immune-related AEs, 1 with increased ALT and 1 with pneumonitis.

“The safety profile and efficacy of atezolizumab with chemotherapy was favorable in patients with NSCLC with untreated brain metastases, including those receiving corticosteroids. Most responses were concordant in the body and brain,” concluded Nadal. “Currently, we are conducting correlative studies with brain imaging and blood samples to identify markers predicting response or lack of benefit of this combination.”

Reference

1. Nadal E, Rodriguez-Abreu D, Massuti B, et al. Single arm phase II study of atezolizumab plus chemotherapy in stage IV NSCLC with untreated brain metastases. Presented at: International Association for the Study of Lung Cancer 2021 World Conference on Lung Cancer; September 10-13, 2021; Virtual. Abstr OA09.02.