Ofatumumab was both active and well-tolerated at 2 different dose levels in treatment-naïve patients with advanced follicular lymphoma who had low tumor burden, according to findings from a phase II, multicenter study recently published in the <em>British Journal of Haematology</em>.
Cara A. Rosenbaum, MD
Ofatumumab was both active and well tolerated at 2 different dose levels in treatment-naïve patients with advanced follicular lymphoma (FL) who had low tumor burden, according to findings from a phase II, multicenter study recently published in theBritish Journal of Haematology.
“We show that 1000 mg of ofatumumab is well-tolerated and active as upfront treatment, resulting in an objective response rate (ORR) of 84% (evaluable patients 87%) to meet the primary endpoint of the study,” wrote the study authors, led by Cara A. Rosenbaum, MD, Meyer Cancer Center, Weill Medical College of Cornell University and New York-Presbyterian Hospital. “The majority of responses were partial responses (PRs) with a 16% complete response (CR) rate. The safety profile was favorable with minimal grade 3 or 4 hematological or infectious adverse events (AEs).”
Initially, the authors, operating under the Alliance for Clinical Trials in Oncology, planned to focus on determining whether the dose of ofatumumab affected its performance. They intended to evaluate 2 doses of the drug500 mg and 1000 mg—head-to-head. However, they changed the protocol when the 500 mg trial arm accrued patients too slowly.
The authors recruited patients with previously untreated FL that was grade 1, 2, or 3a and stage III or IV. They also enrolled patients with bulky stage II disease, which they defined as a single mass ≥7 cm. Patients were required to have low- or intermediate-risk disease (Follicular Lymphoma International Prognostic Index [FLIPI] score 02) and an ECOG performance status (PS) of 0 to 2. Other eligibility criteria included an absolute neutrophil count ≥1.0 x 109/l, platelet count ≥75 x 109/l, creatinine clearance ≥30 ml/min, and total bilirubin ≤2 x institutional upper limit of normal.
Patients were randomized to either the ofatumumab 500 mg or 1000 mg dose arm. All patients received 4 weekly doses followed by dosing every 8 weeks for 4 additional cycles. The planned treatment duration was a total of 9 months or until progression of disease and/or unacceptable AEs. Patients who were randomized to the 500 mg arm continued to receive that dose for the duration of the study.
The primary endpoint was the ORR among patients who had received 1000 mg dosing. Secondary endpoints were progression-free survival (PFS) and safety. Ultimately, the trial accrued 51 patients (1000 mg, n = 36; 500 mg, n = 15).
Among the patients, the median age was 60 (range, 40-85) and just over half were male (55%). Nearly equal numbers had grade 1 (45%) or grade 2 (41%) disease, while just 14% of patients had grade 3a disease. Nearly all were modified Ann Arbor stage III-IVA (96%). Nearly all of the patients (98%) had ECOG PS of 0 or 1 and a clear majority (75%) were FLIPI intermediate risk.
The ORR was 84% (95% CI, 67%-95%). At month 12, the observed best response was 3 patients with CR (9%), 24 patients with PR (75%), and 3 patients with stable disease (SD; 9%). Notably, 2 patients who had PRs at 1 year later reached CRs (1 each at months 22 and 27), for an overall CR rate of 16% (n = 5).
When the investigators assessed patient response at 3 months on treatment and 1 month after completing treatment, they found that more than half of patients (18 of 31 evaluable patients, 58%) had experienced at least a 50% reduction in tumor size. Only 1 patient did not achieve any reduction in tumor size at these time intervals.
Among partial or complete responders, two-thirds showed improvement by month 3 (n = 18, 66%). The low-risk FLIPI patients had an ORR of 88% (n = 8), while intermediate-risk patients had an ORR of 83% (n = 24).
In the 500 mg group, the ORR was 60% (95% CI, 3284%). One patient (7%) achieved a CR at month 12, while about half the group achieved PR (53%, n = 8). One of the PR patients at 12 months had achieved a CR at month 18. When stratified by risk, the ORR was 50% (n = 2) among low-risk and 61% (n = 13) among intermediate-risk patients.
All study patients were still alive at the time of analysis, with a median follow-up of 30.7 months (range, <1 to 55.4).
In the higher-dose group, the median PFS was 1.9 years (95% CI, 1.5-3.0), 1-year PFS was 90% (95% CI, 73%-97%) and 2-year PFS was 48% (95% CI, 29%-64%). The median duration of response in this arm was 23.7 months (95% CI, 16.6-36.2).
Among patients who received 500 mg, the median PFS was 1.9 years (95% CI, 1.0-1.9), 1-year PFS was 80% (95% CI, 5093%) and 2-year PFS was 22% (95% CI, 5-46%). The median duration of response among these patients is 16.5 months (95% CI, 11.6-50.6).
The authors noted that the majority of patients who progressed had baseline intermediate-risk FLIPI. Additionally, no low-risk patient progressed in the first year and only 1 had progressed by the 2-year mark.
The entire study population experienced only minimal hematological grade 3 AEs (all <10%) and no grade 4 AEs at all. In the higher-dose group, lymphopenia (28%), anemia (17%), and neutropenia (14%) were the most common grade 1 and 2 hematological AEs. One patient had grade 3 neutropenia and two patients had grade 3 lymphopenia.
Rosenbaum et al characterized the durability of response to extended induction ofatumumab in their study as “inferior to that reported for similar extended dosing regimens of rituximab monotherapy in chemotherapy-naïve, low tumor burden FL.”
In contextualizing ofatumumab’s clinical potential, they wrote, “[T]his antibody does not appear superior to either rituximab or obinutuzumab at the doses and extended dosing schedule used in this study and, therefore, its future in FL remains questionable.”
Rosenbaum CA, Jung SH, Pitcher B, et al. Phase 2 multicentre study of single-agent ofatumumab in previously untreated follicular lymphoma: CALGB 50901 (Alliance).Br J Haematol. 2019 Feb 5. doi: 10.1111/bjh.15768. [Epub ahead of print]