Atezolizumab Plus Chemotherapy Demonstrates Intracranial Activity in Advanced Nonsquamous NSCLC

Combination treatment with atezolizumab (Tecentriq), carboplatin, and pemetrexed showed activity in patients with advanced nonsquamous non–small cell lung cancer (NSCLC) and untreated brain metastases without neurologic symptoms or asymptomatic with medical treatment, according to data from the phase 2 ATEZO-BRAIN trial (NCT03526900) published in the Journal of Clinical Oncology.

Following 12 weeks of therapy with the immunotherapy and chemotherapy combination, patients (n = 40) experienced an overall progression-free survival (PFS) rate of 62.2% (95% credibility interval [CrI], 47.1%-76.2%), which investigators noted was above the expected rate of 50%. Additionally, with a minimum follow-up of 27 months, the median intracranial PFS was 6.9 months (95% CI, 4.7-11.9) with a 12-week PFS rate of 62.2% (95% CrI, 47.1%-76.2%).

The overall intracranial response rate was 42.7% (95% CrI, 28.1%-57.9%). Among those 17 responders, a confirmed intracranial partial response (PR) was reported in 70.6%, and 29.4% of responders had complete responses (CRs) per response assessment in neuro-oncology brain metastases (RANO-BM) criteria.

Among all patients, the best intracranial overall responses assessed using RANO-BM criteria included CR (12.5%), PR (30.0%), stable disease (SD; 42.5%), progressive disease (PD; 13.0%), and not evaluable (NE; 2.5%). The median duration of response (DOR) was 14 months (95% CI, 10–not reached [NR]).

Systemic outcomes were assessed per RECIST 1.1 criteria and showed patients achieved a median PFS of 8.9 months (95% CI, 6.7-13.8) and a systemic overall response rate (ORR) of 45.0% (95% Crl, 28.1%-57.9%). Most responses were PRs (42.5%). The best systemic overall responses were CR (2.5%), SD (40.0%), PD (10.0%), and NE (5.0%). The median DOR was 11.9 months (95% CI, 8.9-NR).

The open-label study, single-arm study enrolled patients across 13 sites in Spain who were 18 years of age or older with stage IV nonsquamous NSCLC and untreated brain metastases. Patients with brain metastases could not exhibit neurologic symptoms or were controlled via anticonvulsants or dexamethasone at a maximum dose of 4 mg daily. Patients had an ECOG performance score of 0 (35%) or 1 (65%) and 1 or more measurable lesions at least 10 mm in size.

Patients were not included if they had EGFR mutations or ALK rearrangements; leptomeningeal carcinomatosis or metastases in the brainstem, medulla, or lesions causing obstructive hydrocephalus; previous malignancies occurring within 3 years of study entry; hepatitis B or C infection; HIV positivity; or had received prior treatment with immune checkpoint inhibitors.

In accordance with pemetrexed treatment guidelines, patients were given premedication with folic acid, vitamin B12, and dexamethasone, before receiving atezolizumab at 1200 mg intravenously once every 3 weeks in combination with carboplatin and pemetrexed for 4 to 6 cycles. Following therapy, maintenance atezolizumab and pemetrexed were administered until completion of 2 years of therapy or unacceptable toxicity, disease progression, patient decision, or patient withdrawal of consent. Three patients completed the planned 2 years of therapy; the median number of carboplatin cycles received was 4 and the median atezolizumab and pemetrexed cycles was 8.

Safety as well as PFS comprised the primary end points and secondary end points included ORR, DOR, time from first documented CR/PR to disease progression or death, and overall survival (OS).

The median age was 62.6 years (IQR, 11.5), most patients were men (72.5%), and all were White. The primary histology was lung adenocarcinoma (97.5%) and patients had never smoked (15.0%) or were former (27.5%) or current (57.5%) smokers. PD-L1 was expressed at 50% or greater (25.0%), 1% to 49% (25.0%), 0% (45.0%), or unknown (5.0%) in the study. Most patients had received baseline corticosteroids (55.0%) and had synchronous brain metastases (92.5%). Metachronous metastases (7.5%) were present as well. The median number of brain lesions per patient was 5 (range, 1-20) and the median number of target brain lesions per patient was 1 (range, 1-4).

Most neurologic toxicities were grade 1, but headache, insomnia, anxiety, and edema cerebral all occurred at grade 2 in 1 patient each. Common grade 1 neurologic events included headache (20.0%), dizziness (10.0%), as well as central nervous system (CNS) disorders (7.5%) and grade 3 toxicities included CNS disorders (5.0%) as well as seizure (5.0%). One patient experienced grade 4 hallucinations.

Further, 1 patient experienced grade 5 febrile neutropenia and sepsis that was associated with chemotherapy. Treatment-related grade 3/4 AEs occurred in 70% of patients and 17.5% were considered serious including acute kidney injury (n = 2), pneumonitis (n = 2), and nephritis (n = 1), pulmonary embolism (n = 1), and febrile neutropenia (n = 1).

The median OS was 11.8 months (95% CI, 7.6-16.9) and the estimated 1- and 2-year OS rates were 50% (95% CI, 36.7%-68.2%) and 27.5% (95% CI, 16.6%-45.5%), respectively. At intracranial progression, 60% of patients received brain radiotherapy; 16 patients were given whole brain radiotherapy and 8 stereotactic radiosurgery with a median time to brain radiotherapy of 10.9 months (95% CI, 7.8-15.9). The median event-free survival was 7.6 months (95% CI, 5.5-10.9) from the time of trial commencement to brain radiotherapy or death.

An exploratory analysis demonstrated that the intracranial and systemic ORRs were 50.0% and 52.6%, respectively, for patients who received corticosteroids vs 38.9% and 44.4% for those who did not, revealing consistent results regardless of corticosteroid treatment according to the investigators. Further, investigators noted there were no differences observed in ORR relating to PD-L1 expression.

Further, there were no significant differences in OS observed based on PD-L1 expression; however, investigators reported that patients with PD-L1 expression of 1% or higher (n = 20) had a 2-year OS rate of 40.0% (95% CI, 23.4%-68.4%) vs 16.7% (95% CI, 5.9%-46.8%) for those with PD-L1 expression less than 1% (n = 18).

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). J Clin Oncol. Published online August 21, 2023. doi:10.1200/JCO.22.02561