The addition of the programmed death-ligand 1 inhibitor atezolizumab to an obinutuzumab-bendamustine chemoimmunotherapy regimen does not further improve progression-free survival (PFS) relative to that previously reported for obinutuzumab-bendamustine and carries an increased risk of adverse events (AEs) in patients with previously untreated follicular lymphoma (FL), according to research published in Blood Advances.
Researchers conducted a phase 1b/2 trial to evaluated the safety and efficacy of atezolizumab-obinutuzumab-bendamustine in adult patients with previously untreated FL (ClinicalTrials.gov Identifier: NCT02596971).
The primary endpoint was complete response (CR) rate on positron emission
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tomography-computed tomography at the end of induction (by independent review committee [IRC] using modified Lugano 2014 criteria). Secondary endpoints included
investigator-assessed PFS and overall survival (OS), and minimal residual disease (MRD) status was an exploratory endpoint.
The investigators included a safety run-in phase followed by an expansion phase with atezolizumab-obinutuzumab-bendamustine. The induction treatment comprised intravenous infusions of atezolizumab (840 mg on days 1 and 15 of cycles 2 to 6), obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1 and day 1 of cycles 2 to 6), and bendamustine (90 mg/m2 on days 1 and 2 of cycles 1 to 6), on 28-day cycles.
Patients who achieved CR or partial response (PR) at the end of induction were administered maintenance therapy (atezolizumab, 840 mg on days 1 and 2 of each month, and obinutuzumab, 1000 mg on day 1 of every other month) for up to 24 months or until disease progression or unacceptable toxicity.
A total of 40 patients with previously untreated FL (mean age, 56.5 years; range, 29-75; 50% male and 50% female) were enrolled in the study and treated with atezolizumab-obinutuzumab-bendamustine. Most patients were less than 65 years of age (85.0%), White (87.5%), and had advanced-stage disease (Ann Arbor stage III-IV, 92.5%).
The team reported an IRC-assessed CR rate of 75.0% (95% confidence interval [CI], 61.3-85.8%) and 3-year investigator-assessed PFS and OS rates of 80.9% (95% CI, 63.9-90.5%) and 89.3% (95% CI, 73.9-95.9%), respectively.
Of 21 patients who had circulating lymphoma-specific clonotypes at baseline, the investigators found that all these patients were MRD-negative (10-5 sensitivity) at the end of induction, with 76.2% in CR, 14.3% in PR, and 9.5% with stable disease (IRC assessed).
In the phase III GALLIUM trial, obinutuzumab demonstrated a significant improvement in PFS when compared with rituximab-based chemoimmunotherapy (hazard ratio [HR], 0.66; 3-year PFS, 80.0% vs 73.3%; P =.001). Also in this study, a benefit was observed with obinutuzumab over rituximab for all 3 of the assessed chemotherapy regimens, including obinutuzumab-bendamustine (HR, 0.63; 3-year PFS, 84.0% obinutuzumab-bendamustine vs 76.0% rituximab-bendamustine; P =.0062, the researchers explained in their report.
In the present study, the investigators reported grade 3-5 AEs in 32 patients (80%) grade 5 AEs in 5 patients (12.5%). The addition of atezolizumab to obinutuzumab-bendamustine was associated with an increased risk of AEs, with AEs of special interest related to atezolizumab including pneumonitis, colitis, endocrinopathies, hepatitis, systemic lupus erythematosus, neurological disorders, hypersensitivity reactions, nephritis, ocular toxicities, myositis, myopathies, vasculitis, grade ≥2 cardiac disorders, and severe cutaneous reactions.
“Although effective in the first-line treatment of FL, the combination of [atezolizumab-obinutuzumab-bendamustine] does not appear to offer a significant clinical benefit over that achievable with [obinutuzumab-bendamustine] alone,” the researchers wrote in their report. “Furthermore, the addition of [atezolizumab] to [obinutuzumab-bendamustine] appears to carry an increased risk of clinically significant AEs, particularly immune-related AEs. Therefore, due to the unfavorable safety profile, [atezolizumab-obinutuzumab-bendamustine] should not be recommended in patients with previously untreated FL,” concluded the investigators.
Limitations of the study included the modest number of patients with untreated FL, lack of a control group, and limited follow-up duration.
Disclosure: This research was supported by F. Hoffmann-La Roche Ltd. Please see the original reference for a full list of disclosures.
Reference
Younes A, Burke JM, Diefenbach C, et al. Safety and efficacy of atezolizumab with obinutuzumab and bendamustine in previously untreated follicular lymphoma. Blood Adv. 2022;6(20):5659-5667. doi:10.1182/bloodadvances.2021006131
