Atezolizumab Plus Bevacizumab as First-line Treatment for Patients With Metastatic Nonsquamous Non–Small Cell Lung Cancer With High Tumor Mutation Burden

Abstract

ImportanceAntiangiogenic drug combinations with anti–programmed cell death 1 protein and anti–programmed cell death 1 ligand 1 (PD-L1) agents are a novel treatment option for lung cancer. However, survival remains limited, and the activity of these combinations for tumors with high tumor mutation burden (TMB) is unknown.ObjectiveTo assess the clinical benefits and safety of atezolizumab plus bevacizumab for patients with high-TMB advanced nonsquamous non–small cell lung cancer (NSCLC).Design, Setting, and ParticipantsThis multicenter, single-arm, open-label, phase 2 nonrandomized controlled trial (Atezolizumab Plus Bevacizumab in First-Line NSCLC Patients [TELMA]) included treatment-naive patients aged 18 years or older with confirmed stage IIIB-IV nonsquamous NSCLC with TMB of 10 or more mutations/megabase and no EGFR, ALK, STK11, MDM2, or ROS1 alterations. From May 2019 through January 2021, patients were assessed at 13 sites in Spain, with follow-up until February 28, 2022.InterventionsParticipants were given atezolizumab, 1200 mg, plus bevacizumab, 15 mg/kg, on day 1 of each 21-day cycle. Treatment was continued until documented disease progression, unacceptable toxic effects, patient withdrawal, investigator decision, or death.Main Outcomes and MeasuresThe primary end point was 12-month progression-free survival (PFS) rate (according to Response Evaluation Criteria in Solid Tumours, version 1.1 criteria); PFS was defined as the time from enrollment to disease progression or death. Adverse events were monitored according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.ResultsA total of 307 patients were assessed for trial eligibility, of whom 266 were ineligible for enrollment. Of the 41 patients enrolled, 3 did not fulfill all inclusion criteria and were excluded. The remaining 38 patients (28 [73.7%] male; mean [SD] age, 63.7 [8.3] years) constituted the per-protocol population. The 12-month PFS rate was 51.3% (95% CI, 34.2%-66.0%), which met the primary end point. The 12-month overall survival (OS) rate was 72.0% (95% CI, 54.1%-83.9%). The median PFS was 13.0 months (95% CI, 7.9-18.0 months), and the median OS was not reached. Of the 38 patients, 16 (42.1%) achieved an objective response and 30 (78.9%) achieved disease control. The median time to response was 2.8 months (IQR, 2.8-3.58 months), with a median duration of response of 11.7 months (range, 3.57-22.4 months; the response was ongoing at cutoff). Of 16 responses, 8 (50.0%) were ongoing. Most adverse events were grade 1 or 2. For atezolizumab, the most common adverse events were fatigue (6 [15.8%]) and pruritus (6 [15.8%]). For bevacizumab, they were hypertension (10 [26.3%]) and proteinuria (4 [10.5%]). Drug discontinuation occurred in 2 patients receiving atezolizumab (5.3%) and 3 patients receiving bevacizumab (7.9%). PD-L1 levels were not associated with response, PFS, or OS.Conclusions and RelevanceThese findings suggest that atezolizumab with bevacizumab is a potential treatment for high-TMB nonsquamous NSCLC.Trial RegistrationClinicalTrials.gov Identifier: NCT03836066

Atezolizumab Plus Bevacizumab in TMB-High Non−Small Cell Lung Cancers—The Hunt for Predictive Biomarkers to Optimize Treatment Selection

“…For instance, the first-line phase 2 @Be study of atezolizumab plus bevacizumab among 39 patients with nonsquamous NSCLC and PD-L1 expression levels of 50% or more reported a promising ORR of 64.1%, with a 12-month PFS and overall survival rates of 54.9% and 70.6%, respectively. The activity of atezolizumab plus bevacizumab in a PD-L1 unselected population in the TEMLA study also appears encouraging with an ORR of 42.1%, a median PFS of 13.0 months, and a 1-year overall survival rate of 72%.…”

“…These findings from the TEMLA study should be interpreted in the context of the trial’s particular enrollment criteria. As in other immunotherapy trials, the TEMLA study excluded cancers with genomic alterations in EGFR , ALK , and ROS1 , but TEMLA also uniquely excluded NSCLCs with STK11 and MDM2 amplification, as these have been associated with resistance to PD-1 blockade in NSCLC.…”

“…Recent evidence indicates that NSCLCs with a very high TMB of approximately 19 mut/Mb (approximately the 90th percentile for TMB) derive the greatest survival benefit from immunotherapy, suggesting that a TMB level of 10 mut/Mb may not be a high enough cut point to identify patients who are most likely to respond to PD-L1 inhibition. Indeed, among the NSCLCs with 10 mut/Mb or more in the TEMLA study, those that responded to atezolizumab plus bevacizumab had a significantly higher TMB than nonresponders.…”

“…To tackle these unmet needs, in this issue of JAMA Oncology , Dr Provencio and colleagues present the results of the Atezolizumab Plus Bevacizumab in First-Line NSCLC Patients (TELMA) study, an open label, phase 2, multicenter clinical trial evaluating a novel first-line combination of atezolizumab (a PD-L1 inhibitor) in combination with bevacizumab (a vascular endothelial growth factor inhibitor) in 38 patients with advanced nonsquamous NSCLC. In this study, enrollment was restricted to patients with NSCLCs with a high tumor mutation burden (TMB), which is a measure of somatic coding mutations in the cancer’s genome.…”

“…With several approved first-line immunotherapy plus or minus chemotherapy regimens available for patients with advanced NSCLC, another important question raised by the TEMLA study is whether the addition of bevacizumab to PD-L1 inhibition improves clinical outcomes compared with PD-L1 monotherapy alone in patients with lung cancer and high TMB. Combining PD-L1 inhibitors with antiangiogenic therapies, such as bevacizumab or ramucirumab, has been the subject of intense clinical investigation, both in patients with NSCLCs who have progressed through prior PD-L1 inhibitors (eg, the Lung-MAP S1800A trial) as well as in treatment-naïve patients with NSCLC.…”