Improved Survival in Patients with NSCLC and Brain Metastases

Sharon Worcester

September 17, 2021

A single-arm, phase 2 clinical trial of atezolizumab with chemotherapy for patients with nonsquamous non-small cell lung cancer (NSCLC) and brain metastases shows promise for improving progression-free survival, according to a study presented at the 2021 World Congress on Lung Cancer.

The trial is noteworthy because to date, few patients with nonsquamous NSCLC and untreated asymptomatic brain metastases (or those treated with corticosteroids), were ever included in clinical trials that examine the efficacy and safety of chemotherapy and immunotherapy together as first-line treatment, said Ernest Nadal, MD, PhD, of the University of Barcelona Catalan Institute of Oncology at L'Hospitalet de Llobregat. He and his colleagues presented their findings at the meeting, which was organized by the International Association for the Study of Lung Cancer (IASLC).

With only 40 patients, the clinical trial was small, but the safety profile of atezolizumab combined with carboplatin and pemetrexed was favorable in patients with untreated brain metastases and those receiving corticosteroids (dexamethasone of 4 mg once a day or less).

At a median follow-up of 17.3 months, median intracranial and systemic progression-free survival – the co-primary study endpoints, along with safety – were 6.9 months and 8.9 months in 40 patients treated with the immune checkpoint inhibitor and chemotherapy combination, and the 18-month progression-free survival rates were 10.4% and 24.9%, respectively, Nadal said.

Secondary study endpoints included response rate and overall survival rate. The overall response rate was 40% at 12 weeks; 19 patients (47.5%) had stable disease in the central nervous system, and 19 (47.5%) had a systemic response. The median overall survival was 13.6 months, and 2-year overall survival was 32%.

"The 12-week progression-free survival rate was 60%, [which was] above the expected rate of 50%, and the grade 2-4 toxicity rate was 27.5%, [which was] below the threshold of 35%," Nadal said.

Four patients achieved complete response in the brain, and four patients had discordance between systemic and central nervous system response: two with progressive disease in the body and stable disease in the brain, and two with progressive disease in the brain and stable disease in the body.

Study subjects were chemotherapy-naive patients with stage IV non-squamous NSCLC without estimated glomerular filtration rate (EGFR) or anaplastic lymphoma kinase (ALK) genetic alterations and with untreated brain metastases. They were enrolled from 11 clinical sites and treated with carboplatin (5 AUCs) and pemetrexed (500 mg/m2) plus atezolizumab (1,200 mg) every 3 weeks for four to six cycles, followed by maintenance with pemetrexed plus atezolizumab for 2 years or until disease progression or unacceptable toxicity.

Grade 3 treatment-related adverse events occurring in at least 5% of patients were anemia (eight patients), back pain (four patients), thrombocytopenia (two patients) and dyspnea, pneumonitis, and elevated alanine transaminase (one patient each). Grade 4 treatment-related adverse events occurred in three patients and included thrombocytopenia, neutropenia, and hallucinations.

"Brain metastases are the most frequent cancer-related neurological complication and have a major impact on the neurocognitive function, quality of life, and the patient's prognosis," Nadal said, adding that local therapy could add toxicity and delay systemic treatment.

The progression-free survival findings in this study are similar to those reported in the KEYNOTE-189 clinical trial in patients with brain metastases, which showed improved outcomes with pembrolizumab plus chemotherapy in patients with previously untreated metastatic nonsquamous NSCLC, Nadal said.

The safety profile was also favorable – even in the 17 patients receiving corticosteroids at baseline.

"This combination can result in clinical benefit in terms of overall survival in this population "Correlative studies with brain imaging and blood samples are currently ongoing," he said.

Charu Aggarwal, MD, MPH, an oncologist with Penn Medicine who specializes in lung cancer, said the findings help address how patients with untreated, asymptomatic brain metastases should be treated.

Taken together with findings from other prospective and retrospective trials in this population, the outcomes demonstrate that "in patients with asymptomatic brain metastases, upfront immunochemotherapy is associated with intracranial response rates," she said. Patients with asymptomatic brain metastases can be safely treated with chemoimmunotherapy, but "proper patient selection is going to be key."

Unanswered questions from this study include the size of brain metastases at trial enrollment, whether programmed death-ligand 1 status matters, and whether there is an optimal dose of steroids that should be mandated for inclusion into trials, Aggarwal added, noting that several trials enrolling patients with lung cancer are seeking to answer these questions.

Nadal reported receiving research support, speaker bureau fees, and/or honoraria from multiple pharmaceutical companies. Aggarwal reported serving on an advisory board for multiple pharmaceutical companies. She also reported clinical trial funding to her institution from multiple companies.

This article originally appeared on, part of the Medscape Professional Network.


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