Obinutuzumab Plus Lenalidomide Shows Promise in High Tumor Burden Follicular Lymphoma

Loretta J. Nastoupil, MD

Obinutuzumab (Gazyva) combined with lenalidomide (Revlimid) resulted in early and very high complete response (CR) rates in previously untreated patients with follicular lymphoma (FL) in a single-center phase II study. At a median follow-up of 25 months, the 2-year progression-free survival (PFS) was 96%.

Despite high initial response rates to chemotherapy combined with anti-CD20 antibodies, patients with FL will experience relapse and succumb to their disease. Therefore, the search for effective, well-tolerated therapies continues.

“There is still an unmet need, in my opinion, to develop highly effective but also well-tolerated frontline therapies that can challenge chemotherapy for the treatment of untreated follicular lymphoma,” said Loretta J. Nastoupil, MD, Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, who presented the results at the 2019 American Society of Hematology Annual Meeting.¹

This study evaluated the efficacy and safety of obinutuzumab combined with lenalidomide in patients with stage II, III, or IV, high tumor burden (defined by Groupe d'Etude des Lymphomes Folliculaires criteria) FL (grade 1, 2 or 3A). Patients (N = 90) received 1000 mg of obinutuzumab on days 1, 8, and 15 of cycle 1, day 1 of cycles 2 to 6, and day 1 of even numbered cycles, cycle 8 to 30. Cycle length was 28 days. Lenalidomide was administered at 20 mg on days 1 to 21 of cycles 1 to 6. Patients with a CR after 6 cycles received reduced dose lenalidomide (10 mg on days 1 to 21) for cycles 7 to 18. Among patients with a partial response (PR) after 6 cycles, lenalidomide was continued at 20 mg for the next 3 to 6 cycles or until CR, whichever occurred first. The lenalidomide dose was then reduced to 10 mg on days 1 to 21 for the remainder of 18 cycles.

Patients at low risk for thromboembolic events received aspirin prophylaxis; those at high risk received anticoagulants. The primary end point was progression-free survival (PFS) at 2 years (according to Lugano 2014 criteria). Secondary end points included safety, CR, PR, overall response (ORR), and overall survival (OS).

Median age was 58 years, 52% were male, most had stage III (24%), or IV (64%) disease, and the majority (80%) had grade 1-2 FL. Twenty-one percent had low risk, 37% intermediate risk, and 42% high risk as determined by Follicular Lymphoma International Prognostic Index scores. Approximately, a third of patients (34%) had bulky disease.

With a median follow-up of 25 months (range 6-35 months), at the first response assessment 87% of patients experienced CRs, and the best CR rate was 94%. ORR was 94% at the first response assessment and 96% at the best response. The 2-year PFS estimate is 96% (95% CI, 92%-100%).

Nastoupil reported no deaths. Common grade 1 and 2 adverse events (AE) included fatigue and gastrointestinal events. Common grade 3 and 4 AEs included neutropenia (17%, requiring growth factor support in 13%), rash (12%), fatigue (7%, all grade 3), and diarrhea (3%, all grade 3). There were 2 thromboembolic events, 1 of which was life-threatening, and the other was asymptomatic. There were 2 secondary malignancies, including non-invasive bladder cancer and non-melanoma skin cancer. Of the 18 (20%) of patients who discontinued therapy, 13 (14%) were because of toxicity, 3 (3%) because of progression, and 2 (2%) for financial reasons.

Nastoupil noted that the median number of cycles completed before discontinuation was 13 (range 3-24), and 12 of the 13 patients were experiencing CR at the time of discontinuation. She suggested that the 30 cycles in the treatment protocol might not be necessary.

In an attempt to understand the mechanism of action, 4 paired pretreatment and on-treatment biopsies were examined by scRNA-seq and compared with a reference cohort of 11 FL tumors. At day 8 of the first cycle of treatment there is an increase in the fraction of cycling T-cells compared with baseline and the reference cohort. Although additional correlative studies are planned, these results support the hypothesis that lenalidomide-based treatment is enhancing immune synapse formation in FL.

Obinutuzumab plus lenalidomide was associated with very early and high CR rates and the 2-year PFS estimates at a short follow-up in untreated, high tumor burden FL are very promising. The toxicity profile was manageable. Nastoupil concluded that the combination of obinutuzumab and lenalidomide is a highly active and tolerable therapy, and that future study is warranted. She noted that as a single -center study with no comparator, this study is hypothesis-generating. Longer follow-up is also desirable in this patient population.

Reference:

Nastoupil LJ, Westin JR, Hagemeister FB, et al. Results of a phase II study of obinutuzumab in combination with lenalidomide in previously untreated, high tumor burden follicular lymphoma (FL). Presented at: American Society of Hematology Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 125. https://bit.ly/2LyWnzJ.