Atezolizumab Combo Shows Potential in Advanced NSCLC With Brain Metastases

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The combination of atezolizumab (Tecentriq) with carboplatin and pemetrexed appears to be active and shows an acceptable safety profile in patients with advanced nonsquamous non–small cell lung cancer (NSCLC) with untreated brain metastases, according to a single-arm, phase 2 trial.¹

Among the 40 patients enrolled in the study, the overall 12-week progression-free survival (PFS) rate was 62.2% (95% credibility interval [CrI], 47.1-76.2). With a median follow-up of 31 months, the intracranial median PFS was 6.9 months, and the response rate was 42.7% (95% CrI, 28.1-57.9). The systemic median PFS was 8.9 months, and the response rate was 45% (95% CrI, 28.1-57.9). Additionally, the median overall survival (OS) observed was 11.8 months (95% CI, 7.6-16.9) and at 2 years, the OS rate was 27.5% (95% CI, 16.6-45.5).

For safety, the rate of grade 3/4 adverse events (AEs) during the first 9 weeks was 27.5%. Though the majority of neurologic events were grade 1 and 2, 5 patients (12.5%) had grade 3 or 4 neurologic events, including grade 4 hallucinations in 1 patient, grade 3 seizure in 2 patients, and grade 3 sciatica and spinal cord compression in 1 patient each.

The open-label, phase 2 trial enrolled patients with advanced nonsquamous NSCLC with untreated brain metastases who did not have neurologic symptoms or were asymptomatic with medical treatment. Patients were aged 18 years and older, had to have an ECOG performance status of 0-1, adequate bone marrow, liver, and renal function, and at least 1 measurable lesion with a minimum size of 10 mm.

Patients were administered treatment with atezolizumab 1,200 mg via intravenous infusion once every 3 weeks in combination with carboplatin and pemetrexed 500 mg per square meter. All patients were given premedication with folic acid, vitamin B12, and dexamethasone according to guidelines for pemetrexed use. After giving for 4-6 cycles, patients continued treatment with pemetrexed and atezolizumab as maintenance until unacceptable toxicity, disease progression, patient decision, completion of 2 years of therapy, or patient withdrawal of consent.

Investigators assessed the primary end points of PFS at 12 weeks and the incidence of grade ≥3 AEs during the first 9 weeks. Secondary end points were the intracranial and systemic response rate, duration of response (DOR), and OS.

Forty patients met eligibility criteria and were enrolled at 13 sites in Spain. The median age of patients enrolled in the study was 62.5 years, 29 (72.5%) patients were male, all were Caucasian, the majority had a history of smoking (85%), and in most patients, brain metastases were diagnosed concurrently with lung cancer (92.5%). For PD-L1 expression, it was ≥1% in 20 patients (50%), negative in 18 patients (45%), and unknown in 2 patients (5%). Twenty-six (65%) patients had an ECOG performance status of 1 and the rest has a status of 0, the median total number of brain metastases per patient was 5 (range, 1-20), and the median size of the sum of all target lesions per patient was 13 mm (range, 10-42 mm).

In 17 patients (42.7%), there was a confirmed intracranial response (95% CrI, 28.1-57.9) consisting of 12 (70.6%) partial responses (PRs) and 5 (29.4%) complete responses (CRs). Another 17 patients had stable disease (SD) in the brain and 5 had progressive disease (PD). The median time to intracranial response was 82 days. For patients with CNS response, the median DOR in the brain was 14 months (95% CI, 10 to not reached [NR].

Systemic response was reached in 18 patients (45%; 95% CrI, 28.1-57.9). This included 17 (94%) PRs, 1 (6%) CR, 16 with SD, and 4 patients with PD. Except for 6 (15%) patients, most responses were concordant in the brain and in the body.

Looking at an exploratory analysis, the intracranial overall response rate (ORR) was similar between patients given corticosteroids (50%) and patients who did not receive them (38.9%), as were the systemic ORRs (52.6% v 44.4%). There were no differences observed in the intracranial or systemic ORR according to PD-L1 expression.

Further safety data showed that 28 (70%) patients had grade 3-4 treatment-related AEs. However, only 7 (17.5%) were deemed serious. Additionally, 1 patient had a grade 5 AE, which was febrile neutropenia and sepsis, and this was considered related to chemotherapy.

Additional studies moving forward will focus on targeting additional immune checkpoints or integrating systemic therapies with stereotactic radiotherapy to improve the control rate and minimize the risk of brain toxicity are warranted.

REFERENCE:

Nadal E, Rodríguez-Abreu D, Simó M, et al. Phase II trial of atezolizumab combined with carboplatin and pemetrexed for patients with advanced nonsquamous non-small-cell lung cancer with untreated brain metastases (Atezo-Brain, GECP17/05) [published online ahead of print, 2023 Aug 21]. J Clin Oncol. 2023;JCO2202561. doi:10.1200/JCO.22.02561