The results of a phase II Atezo-Brain study show that patients with treatment-naïve advanced non-squamous non-small cell lung cancer (NSCLC) with untreated brain metastases can benefit from initiating systemic treatment with atezolizumab combined with carboplatin and pemetrexed. It is the first study centred on this special population that evaluates the activity and safety of a PD-L1 inhibitor combined with platinum-based chemotherapy in patients with NSCLC with untreated brain metastases. This phase II study has a Bayesian sequential design to minimise the risk of harm or futility on this vulnerable population.
Systemic and intracranial efficacy was similar. The findings are published by Dr. Ernest Nadal of the Department of Medical Oncology, Catalan Institute of Oncology in Barcelona, Spain, and colleagues on 21 August 2023 in the JCO.
About one quarter of patients diagnosed with stage IV NSCLC have brain metastases at diagnosis. Historically, whole-brain radiotherapy (WBRT) had been the cornerstone of treatment for brain metastases in patients with advanced NSCLC, especially when stereotactic radiosurgery (SRS) and surgery were not feasible or indicated. However, the use of WBRT has diminished because of modest survival benefit and its negative impact on cognitive function and quality of life (QoL), and because of emerging evidence that SRS may benefit patients with higher disease burden in the brain metastases.
The incorporation of highly CNS-penetrant targeted therapies in oncogene-addicted NSCLC modified the clinical management of patients with asymptomatic brain metastases harbouring EGFR and ALK positive tumours such that local therapy could be deferred.
The authors wrote in the background that although most clinical studies exclude or under-represent patients with NSCLC who have previously untreated brain metastases, immunotherapy has shown encouraging intracranial efficacy in patients with oncogene driver–negative PD-L1–positive NSCLC who have brain metastases that are untreated or progressing after previous radiotherapy.
Several post hoc exploratory analyses of phase III clinical studies showed that chemotherapy combined with immunotherapy improved overall survival (OS) compared with chemotherapy alone regardless of the presence of brain metastases. However, these studies were not specifically designed to evaluate the intracranial efficacy of chemo-immunotherapy and excluded patients receiving corticosteroids at doses higher than 10 mg daily of prednisone or equivalent.
The study team designed this single-arm, multicentre phase II study to evaluate the safety and the efficacy of atezolizumab combined with carboplatin and pemetrexed in patients with advanced non-squamous NSCLC with untreated brain metastases without neurologic symptoms or asymptomatic with medical treatment. Dexamethasone was allowed up to 4 mg once daily. Atezolizumab plus carboplatin and pemetrexed was given for four to six cycles followed by atezolizumab plus pemetrexed until progression for a maximum of 2 years.
The primary endpoints were to determine the progression-free survival (PFS) rate at 12 weeks and the incidence of grade ≥3 adverse events during the first 9 weeks. Intracranial outcomes were assessed using response assessment in neuro-oncology brain metastases criteria. In the latest JCO article, the authors published the results from the final study analysis.
A total, 40 patients were enroled and 22 (55%) were receiving corticosteroids at baseline. The overall 12-week PFS rate was 62.2% (95% credibility interval [CrI] 47.1 to 76.2). The rate of grade 3/4 adverse events during the first 9 weeks was 27.5%. Most neurologic events were grade 1 and 2, but five patients (12.5%) experienced grade 3-4 neurologic events.
With a median follow-up of 31 months, intracranial median PFS was 6.9 months and response rate was 42.7% (95% CrI 28.1 to 57.9). Systemic median PFS was 8.9 months and response rate was 45% (95% CrI 28.1 to 57.9). The median OS was 11.8 months (95% CI 7.6 to 16.9) and the 2-year OS rate was 27.5% (95% CI 16.6 to 45.5).
The major limitation of this study is the single-arm design, which precludes establishing the optimal treatment strategy for patients with NSCLC and synchronous brain metastases. Randomised studies would help to understand how to integrate brain local therapy with immunotherapy or chemo-immunotherapy in this patient population. Another limitation is the relatively small sample size, which reduces the statistical power to conduct subgroup analyses.
The authors commented that future studies targeting additional immune checkpoints or integrating systemic therapies with stereotactic radiotherapy to improve the control rate and minimise the risk of brain toxicity are warranted.
In an accompanied editorial, drs. Benjamin Y. Lu and Sarah B. Goldberg of the Department of Medicine (Medical Oncology), Yale School of Medicine in New Haven, CT, US wrote that the Atezo-Brain investigators should be commended for designing and executing the study in a safe and inclusive manner, which closely mirrors real-world practices.
In addition to demonstrating the intracranial safety and efficacy of chemo-immunotherapy, even in patients with a considerable burden of intracranial disease, the results from this study suggest that the use of systemic therapy before local therapy allows for the delay of WBRT while preserving the QoL and function of patients with clinically stable brain metastases. Additional prospective studies are needed to identify the optimal regimen and sequence of therapies to manage patients with brain metastases.
The findings were previously pesented in part at the World Congress of Lung Cancer (virtual, 8-14 September 2021) and the ASCO Annual Meeting (Chicago, IL, US, 3-7 June 2022).
The study was supported by Roche, sponsored and conducted through the Spanish Lung Cancer Group (GECP).
