Patients with non–small cell lung cancer (NSCLC) and brain metastasis derived significant benefit from treatment with the monoclonal antibody atezolizumab plus chemotherapy, according to the multicenter phase II Atezo-Brain trial.1 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, of the Institut Català d’Oncologia, L’Hospitalet, Spain.
“This combination [atezolizumab plus chemotherapy] resulted in clinical benefit in terms of overall survival, with 32% of patients alive at 2 years….”— Ernest Nadal, MD
Tweet this quote
“The safety profile and efficacy of atezolizumab combined with carboplatin and pemetrexed are favorable in patients with NSCLC and untreated brain metastases, including those receiving corticosteroids,” Dr. Nadal said. “This combination yielded a 12-week progression-free survival rate of 60% and a 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…. We were expecting a 10% increase in progression-free survival over historical data, and we reached 20%. I think this is the kind of research we need to continue, as it benefits patients. Medical oncologists will now feel safer knowing this combination is an option for patients with brain metastases.”
Brain metastases are the most frequent cancer-related neurologic complication of NSCLC and are associated with a negative impact in neurocognitive function, quality of life, and prognosis. Local therapy to the brain can result in toxicity, delay systemic treatment, and have negative consequences for patients with significant tumor burdens. Furthermore, patients with untreated brain metastases and those who have received corticosteroids have been excluded or underrepresented in clinical trials evaluating chemotherapy plus immunotherapy in the first-line setting.
Immune checkpoint inhibitors alone or in combination with chemotherapy have shown promising intracranial efficacy and safety results in the treatment of NSCLC. This formed the basis of the current nonrandomized phase II trial that examined the efficacy and safety of atezolizumab combined with chemotherapy in NSCLC with untreated brain metastases. Safety and efficacy were co-primary endpoints.
Dr. Nadal and his colleagues at 11 clinical sites enrolled 40 patients with brain metastases related to previously untreated stage IV nonsquamous NSCLC without EGFR or ALK genetic alteration. They received carboplatin and pemetrexed plus atezolizumab every 3 weeks for four to six cycles, followed by maintenance with pemetrexed plus atezolizumab until progressive disease or a maximum of 2 years.
The study had a Bayesian design to closely monitor safety and efficacy. Historical data have shown a 12-week progression-free survival rate in this population of 40% with chemotherapy and a grade 3 or 4 toxicity rate of 35% when atezolizumab is given with platinum-based chemotherapy. The study’s goal was a progression-free survival rate of at least 50% and a rate of grade 3 or 4 toxicity limited to 35%.
In the 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 patients without systemic disease progression have remained on study treatment.
“The study was completed, as the boundaries for futility or unacceptable toxicity were not reached,” Dr. Nadal reported. “The regimen yielded promising systemic and intracranial progression-free survival, as well as promising overall survival, in this population of patients, who can have a dismal prognosis.”
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 by Response Evaluation Criteria in Solid Tumors version 1.1 criteria was 8.8 months, and the 18-month progression-free survival was 24.9%. Median intracranial progression-free survival by Response Assessment in Neuro-Oncology Brain Metastases criteria was 6.9 months, with an 18-month progression-free survival rate of 10.4%. Median overall survival was 13.6 months, and 2-year overall survival was 32%.
The objective response rate was 47.5% systemically (no complete responses) and 40% intracranially (complete response in four patients, 10%). “Four patients had discordance between their systemic and intracranial responses,” added Dr. Nadal. “Two had disease progression in the body and stable disease in the brain, and two had disease progression in the brain and a partial response in the body.”
As Dr. Nadal noted, these results are similar to the reported progression-free survival among patients with brain metastases in KEYNOTE-189.2 In that study, treatment with pembrolizumab plus pemetrexed and platinum-based chemotherapy reduced the risk of disease progression by 58% over control treatment.
Most treatment-related adverse events were grade 1 or 2. Grade 3 events included anemia (20%), dyspnea (3%), back pain (10%), thrombocytopenia (5%), alanine aminotransferase increases (3%), and pneumonitis (3%). Three patients had grade 4 events, including thrombocytopenia, neutropenia, and hallucinations. No treatment-related adverse event was fatal.
Dr. Nadal acknowledged that this study did not address an important question: Can this regimen delay the need for whole-brain radiotherapy, which can have deleterious effects on quality of life and cognitive function?
The question also remains as to the optimal regimen for this heterogeneous patient population, and whether some patients can be identified who will benefit more than others. Correlative studies with brain imaging and blood samples are ongoing.
DISCLOSURE: The Atezo-Brain trial was sponsored by the Spanish Lung Cancer Group and funded by Roche. Dr. Nadal has served on speakers bureaus and has received honoraria from Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pfizer, -AstraZeneca, Amgen, Lilly, Bayer, Takeda, and Boehringer Ingelheim.
1. Nadal E, Rodriguez-Abreu D, Massuti B, et al: Atezo-Brain: Single arm phase II study of atezolizumab plus chemotherapy in stage IV NSCLCL with untreated brain metastases. 2021 World Conference on Lung Cancer. Abstract OA09.02. Presented September 9, 2021.
2. Rodríguez-Abreu D, Powell SF, Hochmair MJ, et al: Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: Protocol-specified final analysis from KEYNOTE-189. Ann Oncol 32:881-895, 2021.
Heather A. Wakelee, MD, FASCO
Heather A. Wakelee, MD, FASCO, President of the International Association for the Study of Lung Cancer (IASLC), who moderated a press briefing where the results of the Atezo-Brain trial were presented, called the study “beautiful work designed specifically” for...