Chemoimmunotherapy Safe, Effective for Untreated Lung Cancer Brain Metastases

Chemoimmunotherapy for untreated lung cancer brain metastases delayed progression and use of whole-brain radiation, a prospective phase II study showed.

Atezolizumab (Tecentriq) plus carboplatin and pemetrexed led to a 12-week progression-free survival (PFS) of 62.2%, an intracranial media PFS of 6.9 months, and systemic median PFS of 8.9 months. About a fourth of patients had grade 3/4 adverse events (AEs) during the first 9 weeks, but most neurologic events were grade 1/2 severity.

Given the similarity of intracranial and systemic efficacy, the findings suggest the chemoimmunotherapy combination could be an option for a highly vulnerable patient population, concluded Ernest Nadal, MD, PhD, of L’Hospitalet de Llobregat in Barcelona, and co-authors in the Journal of Clinical Oncology.

“To our knowledge, this is the first study centered on this special population that evaluates the activity and safety of a PD-L1 inhibitor combined with platinum-based chemotherapy in patients with NSCLC [non-small cell lung cancer] and untreated brain metastases,” the authors stated. “Some patients had significant disease burden on the basis of the total number of brain metastases and half of the patients were receiving corticosteroids at baseline.

“The patients received atezolizumab combined with carboplatin and pemetrexed, which was previously evaluated in the IMpower132 trial in advanced nonsquamous NSCLC; however, this study excluded patients with untreated brain metastases and those requiring corticosteroids.”

Most patents who had progression in the brain were considered candidates for salvage brain radiotherapy, they added.

The report added to a limited body of evidence about the safety and efficacy of chemoimmunotherapy for untreated NSCLC brain metastases, noted Benjamin Y. Lu, MD, and Sarah B. Goldberg, MD, of the Yale School of Medicine in New Haven, Connecticut, in an accompanying editorial. The overall systemic median PFS was similar to that of previous studies, but the intracranial PFS was numerically longer. “Impressively, the intracranial overall response rate was 42.7%.”

“Despite these results, the median overall survival was only 11.8 months, which is considerably shorter than those observed in subgroup analyses of patients with brain metastases treated with chemoimmunotherapy regimens,” Lu and Goldberg pointed out. “This observation may be reflective of the concurrent use of corticosteroids … which is known to diminish the overall efficacy of immunotherapies. In addition, almost half of the patients had PD-L1 <1% disease, which is also associated with a shorter survival in patients with NSCLC.”

Despite adding to the existing evidence base, “we do not have randomized data to determine whether upfront systemic or local therapy is preferred,” Lu and Goldberg continued. “It is likely that the answer varies on the basis of specific patient- and disease-related characteristics … We also do not yet know whether chemoimmunotherapy is superior to single-agent immunotherapy for patients with brain metastases.”

“Additional prospective studies are needed to identify the optimal regimen and sequence of therapies to manage patients with brain metastases, but in the meantime, we can add chemoimmunotherapy to our armamentarium of tools to treat lung cancer brain metastases,” they added.

Most clinical trials of advanced NSCLC have excluded or under-represented patients with untreated brain metastases, despite encouraging intracranial efficacy in patients without driver mutations, Nadal and coauthors noted in their introduction. Post hoc exploratory analyses of phase III clinical trials have shown that chemoimmunotherapy improved overall survival versus chemotherapy alone, regardless of the presence of brain metastases. However, the trials were not designed to evaluate intracranial efficacy.

Investigators designed a phase II trial to investigate the safety and efficacy of chemoimmunotherapy in patients with advanced nonsquamous NSCLC and untreated brain metastases. Conducted at 15 hospitals in Spain, the trial included patients with stage IV nonsquamous NSCLC, untreated asymptomatic brain metastases, and ECOG performance status 0-1. The primary endpoints were safety (grade ≥3 AEs during the first 9 weeks) and PFS.

Data analysis encompassed 40 evaluable patients who had a median age of 62.5. Men accounted for 72.5% of the cohort, and 85% of the patients had a history of smoking. Median number of brain metastases was five and the median size of the sum of all target lesions per patient was 13 mm, ranging from 10 mm to 42 mm. Twenty patients had tumors with PD-L1 expression ≥1%. A majority (22 of 40) of patients were receiving corticosteroids at enrollment.

Grade 3/4 AEs occurred within the first 9 weeks in 27.5% of patients. Five patients had grade 3/4 neurologic events. In addition to a 42.7% overall intracranial response rate, 42.5% of patients had stable disease. The systemic overall response rate was 45%, and 40% patients achieved stable disease as best response.

After a median follow-up of 31 months (minimum of 27 months), the cohort had an intracranial median PFS of 6.9 months, systemic median PFS of 8.9 months, median OS of 11.8 months, and 2-year OS of 27.5%. An exploratory analysis showed that intracranial response was 50% among patients receiving corticosteroids at enrollment and 38.9% among those who were not. The systemic response rate was 52.6% with corticosteroids and 44.4% without.

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