The combination of atezolizumab plus bevacizumab could become a standard first-line treatment for patients with metastatic nonsquamous NSCLC with high tumour mutation burden (TMB), reports a study published in JAMA Oncology.

Among the 38 adults in the single-arm, open-label TELMA trial, median PFS with the combination was 13 months, and OS at 12 months was 72%.

The combination was "associated with encouraging survival rates and durable responses, with a favorable safety profile," say the investigators, led by Mariano Provencio, MD, PhD, a medical oncologist at Puerta de Hierro-Majadahonda University Hospital in Madrid.

It "may become a standard treatment in this population," they suggest.

Antiangiogenic drugs, such as bevacizumab, and anti-programmed cell death-1 (PD-1) and anti-programmed cell death-ligand 1 (PD-L1) inhibitors, such as atezolizumab, seem to have synergistic effects for patients with NSCLC, but even among patients with high PD-L1 expression, only a minority respond, note the authors of an accompanying editorial.

As a result, there is a "pressing need" to identify predictive biomarkers for patient selection, explained research fellow Biagio Ricciuti, MD, and thoracic oncologist Mark Awad, MD, PhD, both of Dana-Farber Cancer Institute, Boston.

Echoing earlier investigations, the trial suggests that high TMB might be that biomarker. The editorialists agree that the results are "encouraging," but they were doubtful of drawing conclusions from the trial.

Without head-to-head comparisons and with several first-line immunotherapies―including atezolizumab―already available for metastatic NSCLC with or without chemotherapy, "the TELMA regimen should not yet be incorporated into clinical practice for the initial treatment of advanced NSCLC, particularly given the added toxic effects associated with bevacizumab," they say.

The 38 patients in the trial had stage IIIB-IV nonsquamous NSCLC and were treatment-naive. They had high TMBs, defined as 10 or more somatic coding mutations per megabase (mut/Mb) in tumour samples as per the FoundationOne CDx assay.

As in other immunotherapy trials, patients with tumours with EGFR, ALK, and ROS1 alterations were excluded; the TELMA investigators also excluded patients with tumours with STK11 and MDM2 amplifications, which have been associated with resistance to PD-1 blockade in NSCLC.

All patients received atezolizumab 1200 mg plus bevacizumab 15 mg/kg on the first day of 3-week cycles. Treatment continued until disease progression, intolerable toxicity, or death.

Additional outcomes included a 12-month PFS of 51.3%, an objective response rate of 42.1%, and a median response duration of 11.7 months. Median OS was not reached over a median follow-up of 22.1 months.

Outcomes tended to be better among patients with higher TMBs, which led the editorialists to suggest that the cutoff point of 10 mut/Mb in TELMA "may not be high enough" to identify patients most likely to respond to treatment.

PD-L1 levels were not associated with outcomes in the trial, indicating "that PD-L1 levels have no added value in estimating response or survival in the population with high TMB," the investigators say. However, given the small sample sizes in the different PD-L1 expression groups, the editorialists suggest that this "finding should be regarded with caution."

The median PFS of 13 months in TELMA compares favourably to the PFS of 12.6 months among patients with high PD-L1 expression in a previous trial of atezolizumab plus bevacizumab on a background of carboplatin and paclitaxel, but without the toxicity of chemotherapy, the researchers note.

No new safety signals were identified. The most common adverse events with atezolizumab were fatigue and pruritus, both of which occurred in 16% of patients. For bevacizumab, the most common events were hypertension in a quarter of patients and proteinuria in 10.5% of patients.

The article was adapted from its original form, written by M. Alexander Otto, which appeared on Medscape.com, part of the Medscape Professional Network.

Lung cancer: combination of atezolizumab plus bevacizumab improves outcomes

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