Patients with advanced non–small cell lung cancer (NSCLC) and brain metastases derived benefit from treatment with atezolizumab plus chemotherapy, according to findings from the multicenter phase II ATEZO-BRAIN/GECP 17/05 trial. The study was presented at the International Association for the Study of Lung Cancer (IASLC) 2021 World Conference on Lung Cancer by Ernest Nadal, MD, Head of the Thoracic Tumors Section at the Catalan Institute of Oncology and University of Barcelona in Spain, and colleagues (Abstract OA09.02).

“The safety profile and efficacy of atezolizumab combined with carboplatin and pemetrexed is favorable in [patients with] NSCLC with untreated brain metastases, including those receiving corticosteroids,” Dr. Nadal said. “This combination yielded a 12-week progression-free survival rate of 60% and median progression-free survival of 6.9 months… It can result in clinical benefit in terms of overall survival, with 32% of patients alive at 2 years.”

Ernest Nadal, MD

Heather Wakerlee, MD

At a press briefing, IASLC President Heather Wakerlee, MD, Professor of Medicine at Stanford University, praised the study and called the results important.

Dr. Nadal’s study supports emerging data showing patients with NSCLC and brain metastases should not be excluded from clinical trials or from treatment with an immune checkpoint inhibitor, she said, adding, “This is a very good regimen.”

Brain Metastases: An Unmet Need

Brain metastases are the most frequent cancer-related neurological complication of NSCLC and are associated with a negative impact in neurocognitive function, quality of life, and prognosis. Local therapy to the brain can add toxicity and delay systemic treatment and can also have negative consequences for patients with significant tumor burdens. Furthermore, patients with untreated brain metastases and those who received corticosteroids have been excluded or under-represented in clinical trials evaluating chemotherapy plus immunotherapy in the first-line setting, Dr. Nadal noted.

ATEZO-BRAIN Details

Immune checkpoint inhibitors alone or in combination with chemotherapy have shown promising intracranial efficacy and safety results in NSCLC. This formed the basis of the current nonrandomized phase II trial that aimed to examine the efficacy and safety of atezolizumab combined with chemotherapy in patients with NSCLC and untreated brain metastases. Safety and efficacy were co-primary endpoints.

Dr. Nadal and his co-researchers at 11 clinical sites enrolled 40 patients with stage IV NSCLC and asymptomatic brain metastases who did not have EGFR or ALK genetic alterations and were previously untreated with chemotherapy for advanced disease. Patients received carboplatin and pemetrexed plus atezolizumab every 3 weeks for four to six cycles, followed by maintenance therapy with pemetrexed plus atezolizumab until disease progression or for a maximum of 2 years.

The study had a Bayesian design that allowed for close monitoring of safety and efficacy. Historical data has shown a 12-week progression-free survival rate in this population of 40% with chemotherapy and a grade 3 and 4 toxicity rate of 35% when atezolizumab is given with platinum-based chemotherapy. The study’s goal was a progression-free survival rate of ≥ 50% and grade 3 or 4 toxicity limited to 35%.

In the study population of 40 patients, 75% were smokers, 37% had an Eastern Cooperative Oncology Group performance status of 1, and 43% had received corticosteroids.

The median number of treatment cycles was 4 for carboplatin, 8.5 for pemetrexed, and 8.5 for atezolizumab. Most patients with progression of brain metastasis received radiotherapy; many of those who did not experience disease progression elsewhere are continuing on study treatment.

Results

“The study was completed, as the boundaries for futility or unacceptable toxicity were not reached,” Dr. Nadal reported.

At a median follow-up of 17.2 months, the 12-week progression-free survival rate was 60% and the grade 3 or 4 toxicity rate was 27.5%. Systemic progression-free survival was 8.8 months, and the 18-month progression-free survival was 24.9%. Median intracranial progression-free survival was 6.9 months, with an 18-month progression-free survival rate of 10.4%, Dr. Nadal reported.

The objective response rate was 47.5% systemically (no complete responses) and 40% intracranially (complete responses in 4 patients, 10%).

“Only four patients had discordance between their systemic and intracranial response,” he said. “Two had progression in the body and stable disease in the brain, and two had progression in the brain and partial response in the body.”

Median overall survival was 13.6 months and 2-year overall survival was 32%.

As Dr. Nadal noted, these results are similar to the reported progression-free survival in the KEYNOTE-189 trial in patients who had brain metastases; pembrolizumab plus pemetrexed and platinum-based chemotherapy reduced the risk of disease progression by 58% over control treatment.

Safety Profile

Most treatment-related adverse events were grade 1 and 2. Grade 3 events included anemia (20%), dyspnea (3%), back pain (10%), thrombocytopenia (5%), increased alanine aminotransferase (3%), and pneumonitis (3%). Three patients had grade 4 events, including thrombocytopenia, neutropenia, and hallucinations. No fatal treatment-related adverse events were reported.

Correlative studies with brain imaging and blood samples are ongoing to help identify patients best suited for this treatment.

Disclosure: Dr. Nadal has served on speaker bureaus and has received honoraria from Roche, Bristol Myers Squibb, Pfizer, AstraZeneca, Amgen, Lilly, Bayer, Takeda, and Boehringer Ingelheim.