This article is more than 5 years old. Information may no longer be current.
Atezolizumab-based triplet effective, but toxic, for follicular lymphoma
Click Here to Manage Email Alerts
ATLANTA — A combination of atezolizumab, obinutuzumab and bendamustine demonstrated first-line activity among previously untreated patients with follicular lymphoma, but also resulted in widespread adverse events and one treatment-related death, according to an interim analysis presented at the ASH Annual Meeting and Exposition.
“The aims of this study were to evaluate the safety and preliminary efficacy of the novel combination of atezolizumab [Tecentriq, Genentech] plus obinutuzumab [Gazyva, Genentech] plus bendamustine in patients with newly diagnosed follicular lymphoma,” Anas Younes, MD, chief of lymphoma service at Memorial Sloan Kettering Cancer Center, said during his presentation. “We also had a safety arm to confirm the safety of combining the three therapies for frontline treatment.”
In a phase 3 Gallium study, researchers reported that induction with the anti-CD20 monoclonal antibody obinutuzumab plus chemotherapy, followed by maintenance with obinutuzumab alone, significantly prolonged PFS among previously untreated patients with follicular lymphoma compared with a regimen containing rituximab (Rituxan; Genentech, Biogen).
However, follicular lymphoma remains incurable and most patients eventually relapse. Researchers assessed whether atezolizumab, which targets PD-L1, would improve outcomes when added to obinutuzumab and bendamustine chemotherapy, followed by maintenance with atezolizumab and obinutuzumab.
Researchers assigned 42 patients (median age, 57 years; range, 29-75; 52% men) with follicular lymphoma (93% Ann Arbor stage III or IV; 49% grade 2) to infusions of 1,000 mg obinutuzumab (days 1, 8 and 15 of cycle 1; day 1 of cycles 2-6), 90 mg/m2 bendamustine (days 1 and 2 of cycles 1-6) and 840 mg atezolizumab (days 1 and 15 of cycles 2 -6) in 28-day cycles.
Patients with complete or partial response received maintenance therapy with 1,000 mg obinutuzumab (day 1 every other month) and 840 mg atezolizumab (days 1 and 2 of each month for 24 months or less).
Complete response at the conclusion of induction served as the primary endpoint. Researchers also assessed safety and tolerability.
At end of induction, 40 patients were evaluable and two had died. Of those evaluable, 34 patients (85%) had an overall response and 30 patients (75%) had a complete response. Sixteen patients with a positive circulating tumor DNA at baseline had a repeat testing at end of induction and all were MRD negative.
All patients in the study experienced at least one adverse event, and 57% (n = 24) experienced grade 3 or grade 4 adverse events that led to interruption of therapy. Twelve patients (29%) had severe adverse events.
The most common toxicities included infusion-related reaction, fatigue, nausea and constipation. Neutropenia (14%) was the most common hematologic toxicity.
Two patients died during treatment — one death was sudden and unrelated to treatment, and the other, a 52-year-old woman, died of cardiac arrest related to atezolizumab 19 days after receiving her first dose. The patient had grade 4 myocarditis and bronchiolitis obliterans.
“Myocarditis is a known rare side effect with checkpoint inhibitors,” Younes said. “The toxicity profile is always a concern. Having said that, it’s unfortunate that one patient died of this. That’s why we looked back on the database and found [grade 3 myocarditis] only happened in one other patient [with renal cell carcinoma] who received atezolizumab and bevacizumab [Avastin, Genentech] out of 11,000. It’s unfortunate it happened.”
Longer follow-up is needed for a more comprehensive benefit-risk evaluation of the triplet combination and analysis of biomarkers, including PD-L1 expression and CD8 tumor infiltration, is ongoing, according to Younes.
“No one really knows if this will be a consistent outcome with these combination immune checkpoint inhibitors, and that’s why we’re looking at these to see the response rates,” Younes said. “As an investigator, I don’t think we expect a difference during induction. The potential of this combination is whether it will make responses longer.” – by Chuck Gormley
Reference:
Younes A, et al. Abstract 481. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
Disclosures: Younes reports honoraria from Incyte, Janssen, Roche, Sanofi and Takeda/Millennium, as well as research funding from Curis and Johnson & Johnson. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
Back to Top
Ann S. LaCasce, MD
It’s very hard to get a lot of information from this very preliminary report. There were only 15 patients for whom researchers reported response evaluation. There is a definite move in follicular lymphoma away from chemotherapies toward using novel agents but, in some ways, I wish this study had been a combination of atezolizumab and obinutuzumab in the relapsed setting as opposed to immediately upfront with bendamustine, which is an old chemotherapy that works well. I’m not entirely certain what the goal of this study is.
The activity looks good, but if you compare it with the Gallium study of obinutuzumab and bendamustine, this study comprised a significantly lower-risk group of patients, with only about 20% of patients in the highest-risk group. We need longer-term follow-up to assess the impact of adding atezolizumab in an already active combination.
It’s also disconcerting that a patient in the study died during treatment. This is a disease for which, in general, the median survival is 20 years, and to have someone die of treatment-related complications upfront requires careful consideration. The toxicity — 48% grade 3 or grade 4 adverse events — looked significant. Overall, we are going to need a lot more follow-up on this to see both the activity and the toxicity, and it’s going to need to be compared in a prospective study to really assess the benefit in terms of PFS and response rates.
Granted, heavily treated patients may be a more beaten-up group of patients. If they receive a drug like bendamustine, they are more likely to have cytopenias and more adverse effects. Personally, I would love to see bendamustine go away and provide patients a nonchemotherapy-containing regimen. I’d also love to see more safety data of the combination of obinutuzumab and atezolizumab in the relapsed setting. We have some data looking at pembrolizumab (Keytruda, Merck) and rituximab coming out that look interesting, but when you have relapsed patients it would be nice to have a randomized phase 2 study such as atezolizumab plus obinutuzumab vs. obinutuzumab alone so that we can really understand the added benefit of atezolizumab among patients who may respond to obinutuzumab. Although this is an interesting study, we need a lot more information before we can really understand the role of PD-L1 inhibition in this particular disease.
Reference:
Marcus RE, et al. Abstract 6. Presented at: ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.
Click Here to Manage Email Alerts