Atezolizumab regimen active in NSCLC with untreated brain metastases
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The combination of atezolizumab, carboplatin and pemetrexed demonstrated encouraging activity among patients with nonsquamous non-small cell lung cancer and untreated, asymptomatic brain metastases, according to phase 2 study results.
Researchers, who presented the results at International Association for the Study of Lung Cancer World Conference on Lung Cancer, reported promising PFS results and determined the combination was safe.
“Brain metastases are the most frequent cancer-related neurological complication and are associated with a negative impact in neurocognitive function, quality of life deterioration and poor prognosis,” Ernest Nadal, MD, of Catalan Institute of Oncology and Bellvitge Biomedical Research Institute in Barcelona, said during a presentation. “Brain local therapy— such as surgery and radiation — can add toxicity and delay systemic treatment, which may have significant impact.”
Immune checkpoint inhibitors, either alone or in combination with chemotherapy, have appeared safe and demonstrated promising intracranial efficacy. However, clinical trials designed to evaluate the combination of chemotherapy and immune checkpoint inhibitors in the first-line setting often exclude patients with untreated brain metastases, Nadal said.
Nadal and colleagues conducted their study to assess the efficacy and safety of atezolizumab (Tecentriq, Genentech/Roche), an anti-PD-L1 monoclonal antibody, for patients with advanced NSCLC and untreated, asymptomatic brain metastases.
Researchers enrolled 40 patients (median age, 62.6 years; interquartile range [IQR], 11.5; 72.5% men; 100% white) with stage IV nonsquamous NSCLC and untreated brain metastases. All patients had ECOG performance status 0 or 1; 75% either were current or former smokers; 97.5% had lung adenocarcinoma; and 43% had received baseline corticosteroids. Study participants had no EGFR or ALK genetic alterations, and they had not received prior chemotherapy.
Patients received carboplatin (area under the curve, 5), 500 mg/m2 pemetrexed and 1,200 mg atezolizumab every 3 weeks for four to six cycles. They then received maintenance therapy with 500 mg/m2 pemetrexed and 1,200 mg atezolizumab every 3 weeks for 2 years, or until disease progression or unacceptable toxicity.
Safety and investigator-assessed PFS served as co-primary endpoints. Secondary endpoints included response rate, duration of response, OS, quality of life, neurocognitive function and time to brain radiotherapy.
Patients received a median four cycles (IQR, 2.2) of carboplatin, 8.5 cycles (IQR, 13) of pemetrexed and 8.5 cycles (IQR, 13) of atezolizumab.
Slightly more than one-quarter (27.5%) of patients experienced grade 3 or grade 4 toxicities.
The most common adverse events included fatigue (any grade, 60%; grade 3, 0%), anemia (45%; 20%), dyspnea (28%; 3%), nausea (28%; 0%), back pain (23%; 10%), cough (23%; 0%), anorexia (20%; 0%), headache (20%; 0%), mucositis (20%; 0%), thrombocytopenia (20%; 5%) and vomiting (20%; 0%).
The most common immune-related adverse events included skin rash (any grade, 20%; grade 3, 0%), alanine transaminase increase (13%; 3%), aspartate transaminase increase (13%, 0%) and hypothyroidism (5%; 0%).
Three patients experienced grade four treatment-related adverse events (thrombocytopenia, neutropenia and hallucinations).
Median follow-up for PFS was 17.3 months.
Researchers reported a 12-week PFS rate of 60%.
Median systemic PFS was 8.9 months (95% CI, 6.7-13.8), with an 18-month PFS rate of 24.9%.
Median intracranial PFS was 6.9 months (95% CI, 4.7-12.1), with an 18-month PFS rate of 10.4%.
Median OS was 13.6 months (95% CI, 9.7-not reached). About one-third (32%) of patients remained alive at 2 years.
Only four patients had discordance between systemic responses and central nervous systemic responses. Two had progressive disease in the brain and partial response in the body, and two had stable disease in the brain and progressive disease in the body.
Correlative studies with blood samples and brain imaging are underway, Nadal said.
Perspective
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Heather A. Wakelee, MD
If we go back in time, there was a lot of concern that immune checkpoint inhibitors could lead to poor outcomes in the brain because of the potential for swelling. Early on, patients with brain metastases often were excluded from trials and this made me quite irate, because excluding a group of patients perhaps most in need of therapy doesn’t make any sense.
Fortunately, there was some work done early on looking at the use of checkpoint inhibitors in the brain — with Sarah Goldberg, MD, MPH, at Yale School of Medicine being one of the people who pioneered this — that showed there actually were no safety concerns. Later studies showed efficacy.
The study by Nadal and colleagues is a beautiful work designed to look at this treatment regimen specifically in the population of patients with brain metastases, and pemetrexed is a good partner because we know it has great activity in the brain. The study results add to the evidence that we shouldn’t exclude patients with brain metastases who otherwise are appropriate for immune checkpoint inhibitors from getting this treatment along with chemotherapy.
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Nadal E, et al. Abstract OA09.02. Presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer (virtual meeting); Sept. 8-14, 2021.
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