Frontline Atezolizumab Triplet Shows Promising Response Rates in Follicular Lymphoma

Anas Younes, MD

According to results of a phase Ib/II trial presented at the 2017 ASH Annual Meeting, the frontline triplet regimen of atezolizumab (Tecentriq), obinutuzumab (Gazyva), and bendamustine was associated with an overall response rate (ORR) of 85% (Modified Lugano criteria; independent review) in patients with follicular lymphoma.

The findings also included a complete response (CR) in 75% and a 10% partial response (PR) rate. 

“Atezolizumab, obinutuzumab, and bendamustine demonstrated encouraging end of induction activity in previously untreated patients with follicular lymphoma,” lead study author Anas Younes, MD, professor of medicine and chief of the Lymphoma Service at Memorial Sloan Kettering Cancer Center, said when presenting the data at ASH.

The study included a 6-month induction period, follow by 2-years of maintenance. Induction cycle 1 included only obinutuzumab (Gazyva) and bendamustine (Treanda), then induction cycles 2 through 6 included the triplet. Each cycle was 28 days. In the maintenance phase, patients received only atezolizumab (Tecentriq) and obinutuzumab.

Obinutuzumab was administered at 1000 mg IV on days 1, 8, and 15 of induction cycle 1; day 1 of induction cycles 2 through 6; and during maintenance once on day 1 every 2 months. Bendamustine was administered at 90 mg/m²IV on days 1 and 2 of each induction cycle. Patients received atezolizumab at 840 mg IV on days 1 and 15 of induction cycles 2 through 6, and on days 1 and 2 every month during the maintenance phase.

The safety population for the study included 42 patients, 6 from the safety run-in phase, which included treatment-naive (n = 4) and previously treated patients (n = 2), and 36 in the expansion phase, all of whom were previously untreated. The efficacy population was limited to the 40 patients who were receiving the triplet as frontline therapy.

At the data cutoff, 35 of the overall 42-patient population remained on maintenance, with a median duration of 5.5 months (range, 1-15). Eight patients received at least 12 months of therapy. 

Among all 42 patients, the median patient age was 57 years (range, 29-75), 52% of were male, and 93% of patients had Ann Arbor stage III/IV disease. Twenty-one percent of patients had bulky disease (>7 cm) and 48% had bone marrow infiltration. Seventy-one percent of patients had grade 2 or 3a disease. Across the population, 24% of patients were FLIPI low risk, 43% were intermediate risk, and 33% were high risk.

End of induction response rates in the frontline population were measured by both Modified Lugano (2014) criteria and Cheson (2007) criteria. Using Modified Lugano, the ORR was 85% per independent review, including a CR rate of 75% and PR rate of 10%. Ten percent of patients had stable disease (SD). By investigator review, the ORR was 95%, comprising a CR rate of 85% and a PR rate of 10%.

Using Cheson criteria, the ORR per independent review was 90%, with a CR rate of 75% and a PR rate of 15%. Five percent of patients had SD. Investigator-assessed ORR was 95%, with a CR rate of 80% and a PR rate of 15%.

Younes also noted that 16 patients who had positive circulating tumor DNA (minimal-residual disease [MRD]) at baseline were all MRD-negative at the end of induction.

All patients experienced adverse events (AEs). The rate of grade 3/4 AEs was 57%, with a serious AE rate of 29%. AEs led to discontinuation in 10% of patients, dose reduction (bendamustine only) in 10%, and dose interruption in 57%.

The most common grade 3/4 hematologic AEs in the induction population were neutropenia (n = 11) and thrombocytopenia (n = 2). Also in the induction group, 3 patients experienced grade 3/4 increased lipase, which also occurred in 2 of the 38 patients in the maintenance group.

Younes also noted that 17% of patients experienced 12 AEs of special interest. In the induction group, these included grade 1/2 infusion-related reaction (n = 3), grade 4 lipase increase (n = 1), grade 2 rash (n = 1), grade 4 myocarditis (n = 1), and grade 1 bronchiolitis (n = 1). In the maintenance group, 2 patients had grade 4 lipase increase, 1 patient had grade 2 eczema, and 1 patient had grade 3 colitis.

There were 2 patient deaths: cardiac arrest in a patient with severe myocarditis and bronchiolitis (related), and a sudden death at home of an unknown cause.  

“Long follow-up is needed for a more comprehensive benefit/risk evaluation of this treatment combination,” said Younes, adding, “Analysis of biomarkers including PD-L1 expression and CD8 tumor infiltration is ongoing.”

Reference:

Younes A, Burke JM, Diefenbach CS, et al. Safety and Efficacy of Atezolizumab in Combination with Obinutuzumab and Bendamustine in Patients with Previously Untreated Follicular Lymphoma: An Interim Analysis. Presented at: 2017 ASH annual meeting; December 9-12, 2017; Atlanta, GA. Abstract 481.