Summary
Rituximab monotherapy has proven efficacy in treatment-naïve, asymptomatic advanced-stage follicular lymphoma (FL). Ofatumumab is a fully humanized anti-CD20 monoclonal antibody with increased CD20 affinity and complement-dependent cytotoxicity. This phase 2 trial (NCT01190449) evaluated ofatumumab in patients with untreated, low/intermediate-riskFL International Prognostic Index (FLIPI), advanced-stage FL to determine single-agent efficacy. Patients with measurable disease in stages III/IV or bulky stage II, regardless of Groupe d’Etude des Lymphomes Folliculaires criteria, received 4 weekly 1000 mg doses followed by 4 extended induction doses once every 8 weeks. Primary endpoint was overall response rate (ORR) to 1000 mg; secondary endpoints were progression-free survival (PFS) and safety. Fifty-one patients were enrolled. Fifteen patients were randomized to 500 mg prior to discontinuing that arm for slow accrual. Among 36 patients on the 1000 mg arm, ORR was 84%, median PFS was 1.9 years and median response duration was 23.7 months. All patients remain alive. No grade 4 infusion reactions or grade 3/4 infections occurred. Grade 3 infusion reactions occurred in 25% in the 1000 mg arm only (all first infusion); all but 2 patients continued on study. Discontinuation was 6% for the total study population. Ofatumumab monotherapy administered by extended induction in untreated, low/intermediate-risk FLIPI, advanced-stage FL is well tolerated and active. Activity appears similar to that reported with single-agent rituximab.
Keywords: follicular lymphoma, previously untreated, immunotherapy, monoclonal antibody, ofatumumab
Introduction
Despite high rates of response to initial chemoimmunotherapy, most patients with advanced-stage follicular lymphoma (FL) will develop recurrent or refractory disease and many ultimately die from lymphoma or treatment-related complications (Johnson et al, 1995). In patients with previously untreated indolent non-Hodgkin lymphoma (NHL), overall response rates (ORR) to a single course of rituximab range from 46–73% with complete remission (CR) rates of 9–31%; repeated dosing schedules yield an increased ORR of 67–78% with CR rates rising to 37–52% and a doubling of median event-free survival and progression-free survival (PFS) to 34–36 months (Colombat et al, 2001; Ghielmini et al, 2004, 2009; Martinelli et al, 2010; Hainsworth et al, 2002; Taverna et al, 2016).
Ofatumumab, a second generation, humanized, IgG1 kappa type I monoclonal antibody (mAb) binds to a distinct epitope of CD20 compared to rituximab, resulting in higher affinity and possibly greater activity in cases of low CD20 surface expression (Cheson, 2010). Both antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) occur, but CDC is increased compared to rituximab (Cheson, 2010). This enhanced CDC and apoptosis may be the result of a slower off rate from CD20 given the closer cell membrane binding as well as a significant increase of C1q binding and activation (Bologna et al, 2013). Preclinical studies demonstrate that higher ofatumumab plasma concentrations may be required to deplete CD20+ B cells residing in lymph nodes compared to peripheral blood and that maximal engagement of CDC occurs at 100% target saturation of the tumour cell compared to only 50% target saturation required for ADCC (Bleeker et al, 2008).
Ofatumumab is approved for treatment of chronic lymphocytic leukaemia (CLL) refractory to fludarabine and alemtuzumab (Kipps et al, 2009). Ofatumumab has shown activity in combination with chemotherapy in frontline FL, with ORR and CR rates comparable to similar rituximab-containing regimens (Czuczman et al, 2012a, 2015), and as a single agent in low grade, rituximab-naïve or sensitive relapsed/refractory (R/R) FL (Hagenbeek et al, 2008). In the latter dose escalation trial, patients received 4 weekly doses of ofatumumab in cohorts ranging from 300 to 1000 mg with ORR of 43% and acceptable toxicity profiles (Hagenbeek et al, 2008). In rituximab-refractory FL, however, ofatumumab monotherapy has yielded a much lower ORR of 22% and thus has limited value in this setting as a single agent (Czuczman et al, 2012b). A phase 3 trial comparing ofatumumab vs rituximab monotherapy in patients whose FL had relapsed at least 6 months after completion of a rituximab-containing regimen, however, showed equivalent PFS in a previously treated population (Maloney et al, 2016).
We hypothesized that ofatumumab may have significant efficacy in rituximab-naïve, previously untreated FL and prolong remission duration in low tumour burden, advanced-stage patients who are appropriate candidates for a chemotherapy-free treatment regimen. Given previously described pharmacokinetic studies of ofatumumab showing variable efficacy based on disease compartment and CD20 receptor target occupancy, the Alliance for Clinical Trials in Oncology conducted a phase 2, multicentre study to evaluate single-agent efficacy and tolerability of two different doses of ofatumumab in previously untreated, low-risk or intermediate-risk (int-risk), advanced-stage FL. The main objective when we designed this study was to determine if there was a dose effect, one of the criticisms of the activity of this antibody. The study was therefore planned to evaluate both 500 and 1000 mg flat doses on two different treatment arms to compare efficacy and safety.
Methods
Patients
Patients aged ≥ 18 years had previously untreated FL grades 1, 2, or 3a that was stage III, IV or bulky stage II, defined as a single mass ≥ 7 cm. Patients were required to have low or int-risk disease by the Follicular Lymphoma International Prognostic Index (FLIPI score 0–2) (Solal-Céligny et al, 2004) and Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. At least one site of measurable disease ≥ 1cm in diameter must have been present by physical examination or imaging studies. No corticosteroids within two weeks prior to study entry except for maintenance therapy for a non-malignant disease were allowed. Patients may have received involved field radiation therapy. Other eligibility criteria included: absolute neutrophil count ≥ 1.0 × 109/l, platelet count ≥75 × 109/l, creatinine clearance ≥ 30 ml/min, total bilirubin ≤ 2x institutional upper limit of normal (absent a history of Gilbert’s syndrome or hepatic involvement of NHL) and no active hepatitis B or C infection. No indications were specified for treatment initiation; all patients with measurable disease were eligible who otherwise met study eligibility. All patients required treatment according to the judgement of the treating physician. The Groupe d’Etude des Lymphomes Folliculaires (GELF) recommended criteria were not used to determine study eligibility.
Each patient provided written informed consent. Consent forms, protocol and amendments were approved by National Cancer Institutes (NCI)/Cancer Therapy Evaluation Program and local independent review boards. The study was conducted in accordance with the Guidelines for Good Clinical Practice and the Declaration of Helsinki, and registered at ClinicalTrials.gov (NCT01190449).
Treatment
At study initiation, patients were randomized to the ofatumumab 500 or 1000 mg dose arm. Induction consisted of 4 weekly doses per dose arm followed by an extended induction schedule with dosing every 8 weeks for 4 additional doses for a planned duration of 9 months total or until progression of disease and/or unacceptable adverse events (AEs). Due to slower than anticipated accrual, the study was amended to a single-arm design and randomization to the 500 mg arm was discontinued. Patients previously randomized to the 500 mg arm continued to receive that dose for the remainder of study treatment.
On each treatment day, premedication administered to reduce infusion related reactions (IRR) consisted of diphenhydramine 50–100 mg orally/intravenously (IV), glucocorticoid (equivalent to 20 mg dexamethasone) IV and acetaminophen 650 mg. If no grade 3 or 4 IRRs occurred during the first or second weeks’ infusions, steroids could be omitted prior to the third and/or fourth weekly infusion but readministered prior to the extended induction infusions in weeks 12, 20, 28 and 36. Routine supportive measures were allowed per institutional standards, including erythropoietin, blood transfusions and haematopoietic colony-stimulating factors for cytopenias.
Assessments
Response assessments were obtained by CT scan at month 3 and repeated every 4 months for 2 years, followed by every 6 months until disease progression or for a maximum of 10 years from study entry. The 2007 revised response criteria for malignant lymphoma were used for response assessment (Cheson et al, 2007). Bone marrow biopsy was performed at baseline and repeated if positive to confirm a CR.
Safety evaluations
Adverse events and their potential relationships to the study drug were reported by investigators. The severity of AEs was graded by investigators according to NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0 (https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf). Patients were evaluable for toxicity if at least one partial dose or more of study drug had been administered. Blood chemistry and haematology values were assessed at screening and at all visits.
Study design and statistical analysis
The primary endpoint was ORR (ORR=CR + partial remission [PR]) to 1000 mg of ofatumumab. The response outcome was defined as the best response observed during the first 12 months on study. Secondary endpoints included PFS and safety. PFS was calculated as the time from study entry until progression or death, whichever occurred first. Patients were censored at the time last known alive and progression-free. Duration of response was calculated as the time from first response (PR/CR) until disease progression. PFS and duration of response were estimated using the Kaplan–Meier method (Kaplan & Meier, 1958). Data from all patients who received any therapy were included in the safety analyses.
The study was initially designed as a randomized phase 2 study with 1:1 randomization to either 500 or 1000 mg of ofatumumab. Each arm would be independently compared to a historical control for efficacy and toxicity in a similar patient population receiving rituximab monotherapy. By single-stage design, accrual of 45 patients to each arm was planned with an ORR of 60% or lower at 12 months set as the null hypothesis and an ORR of 80% or higher to be reached for the therapy to be accepted for further study. After accruing for 24 months at a slower than anticipated rate, enrolment to the 500 mg arm was discontinued and the study design changed to single-arm, enrolling all patients at 1000 mg. Patients accrued to the 500 mg arm prior to the amendment continued to receive that dose until all induction and extended induction therapy was complete. Under the amended study design, we accrued 36 patients to achieve over 90% power for an ORR of 80% with a one-sided α level of 0.05 for an ORR of 60%.
Data were collected and analysed by the Alliance Statistics and Data Center according to Alliance policies and procedures. Data quality was assured through data manager, study chair and statistician review. Data were analysed using SAS version 9.4 (SAS Institute, Cary, NC). This report reflects all data collected to 24 July 2017.
Results
Patient characteristics
Between 15 July 2011 and 28 March 2014, 51 previously untreated FL patients were enrolled at 15 Alliance participating institutions; 36 patients were either randomized to or enrolled in the 1000 mg arm and 15 patients were randomized to the 500 mg arm prior to protocol update 2 on 15 August 2013 (Fig 1). Baseline patient characteristics of the entire study population are summarized in Table I. The median age was 60 years (range 40–85); 86% were Caucasian and 55% were male. The majority had FL grade 1 (45%) or grade 2 (41%); 14% had grade 3a. Nearly all were modified Ann Arbor stage III-IVA (96%). Five patients had B-symptoms (night sweats; all stage III disease). The majority of patients were low-risk (21%) or int-risk (75%) by FLIPI. Nearly all of the patients (98%) had ECOG performance status 0–1. In the 1000 mg arm, 97% were Stage III-IV; 92% were grade 1–2 and 8% grade 3A with low-risk (25%) or int-risk (69%) FLIPI in the majority. Two patients in the 1000 mg arm had bulky disease, defined as largest diameter ≥ 7cm. In the 500mg arm, 93% were stage III-IV and 80% grade 1–2; 20% had grade 3A disease. Two patients in the 500 mg arm had bulky disease with stages of IIA and IVA, respectively. In the total study population, 24% of patients enrolled needed treatment per GELF criteria (Brice et al, 1997), 25% in the 1000 mg arm and 20% in the 500 mg arm, respectively.
Fig 1. CONSORT diagram showing the flow of patients from registration to analysis.
*Patients enrolled prior to protocol update 2 (15 August 2013) were randomised to either 500 mg or 1000 mg ofatumumab.
CALGB: Cancer and Leukemia Group B
Table I.
Baseline Patient Characteristics (all patients enrolled)
| Characteristic | Treatment Arm | Overall N=51 (%) | |
|---|---|---|---|
| 500 mg N=15 (%) | 1000 mg N=36 (%) | ||
| Age (years) | |||
| Median Range (min, max) | 63 (43, 85) | 58 (40, 85) | 60 (40, 85) |
| Sex | |||
| Female | 4 (27%) | 19 (53%) | 23 (45%) |
| Male | 11 (73%) | 17 (47%) | 28 (55%) |
| Race | |||
| White | 13 (87%) | 31 (86%) | 44 (86%) |
| Black or African American | 1 (7%) | 5 (14%) | 6 (12%) |
| Not reported | 1 (7%) | 0 | 1 (2%) |
| Ethnicity | |||
| Not Hispanic or Latino | 14 (93%) | 36 (100%) | 50 (98%) |
| Not reported | 1 (7%) | 0 | 1 (2%) |
| ECOG Performance Status | |||
| 0 | 11 (73%) | 29 (80%) | 40 (78%) |
| 1 | 4 (27%) | 6 (17%) | 10 (20%) |
| 2 | 0 | 1 (3%) | 1 (2%) |
| WHO Classification Grade | |||
| Follicular lymphoma grade I | 8 (53%) | 15 (42%) | 23 (45%) |
| Follicular lymphoma grade II | 3 (20%) | 18 (50%) | 21 (41%) |
| Follicular lymphoma grade IIIa | 4 (27%) | 3 (8%) | 7 (14%) |
| Modified Ann Arbor Stage | |||
| IIA | 1 (7%) | 1 (3%) | 2 (4%) |
| IIIA | 8 (53%) | 15 (41%) | 23 (45%) |
| IIIB | 1 (7%) | 2 (6%) | 3 (6%) |
| IIIE | 0 | 2 (6%) | 2 (4%) |
| IVA | 5 (33%) | 16 (44%) | 21 (41%) |
| B-Symptoms | |||
| No | 14 (93%) | 32 (89%) | 46 (90%) |
| Yes | 1 (7%) | 4 (11%) | 5 (10%) |
| Night Sweats | 1 | 4 | 5 |
| Extent of Involvement | |||
| Number of Nodal sites | |||
| ≤ 4 | 12 (80%) | 22 (61%) | 34 (67%) |
| > 4 | 3 (20%) | 14 (39%) | 17 (33%) |
| Longest diameter of lesion (cm) | |||
| Median | 5.3 | 3.75 | 4.1 |
| Range (min, max) | 2.3 – 13.0 | 1.4 – 8.1 | 1.4 – 13.0 |
| CNS involvement | |||
| No | 15 (100%) | 36 (100%) | 51 (100%) |
| Extranodal involvement | |||
| No | 9 (60%) | 19 (53%) | 28 (55%) |
| Yes | 6 (40%) | 17 (47%) | 23 (45%) |
| FLIPI | |||
| FLIPI score | |||
| 0–1 (low risk) | 2 (13%) | 9 (25%) | 11(21%) |
| 2 (intermediate risk) | 13 (87%) | 25 (69%) | 38 (75%) |
| 3 (high risk) | 0 | 2 (6%) | 2 (4%) |
| FLIPI2 score | |||
| 0–1 (low risk) | 6 (40%) | 22 (61%) | 28 (55%) |
| 2 (intermediate risk) | 5 (33%) | 13 (36%) | 18 (35%) |
| 3 (high risk) | 4 (27%) | 1 (3%) | 5 (10%) |
CNS: central nervous system; ECOG: Eastern Cooperative Oncology Group; FLIPI: Follicular Lymphoma International Prognostic Index; WHO: World Health Organization.
Treatment exposure
In total, 80% (n=12) and 75% (n=27) of patients in the 500 and 1000 mg arms, respectively, completed the planned 8 ofatumumab infusions. Of the 9 patients on the 1000 mg arm who did not complete all 8 infusions, 2 (6%) discontinued study therapy due to progressive disease (PD), 1 switched to alternative systemic therapy, 1 withdrew consent, 1 discontinued without a specified reason who was later deemed ineligible and 4 were taken off due to AEs/complications (1 for grade 4 pneumonitis, 1 who received local radiotherapy for pain and 2 due to grade 3 IRRs during the first infusion of which 1 patient was later deemed ineligible). Of the 3 patients on the 500 mg arm who did not complete all infusions, PD occurred in 2 (13%) patients and one discontinued treatment due to lack of response without disease progression. During follow-up, 3 patients withdrew from the study for reasons other than PD. On the 1000 mg arm, a patient who achieved CR at month 11 withdrew consent at month 15 for follow-up. On the 500 mg arm, one patient withdrew consent for monitoring after month 19 but agreed to survival follow-up and another lost insurance and had no subsequent monitoring after month 23.
Efficacy
Of the 36 patients randomized to the 1000 mg arm, 32 (88%) were included in response analysis. Four patients were excluded due to ineligibility (Fig 1). One patient randomized to the 1000 mg arm, who received a partial amount of the first dose, did not have response evaluated as consent was withdrawn before response assessment, but is included per intention to treat analysis as a non-responder (treatment failure). The ORR was 84% (95% confidence interval [CI], 67–95%). The observed best response achieved by month 12 was CR=3 (9%), PR=24 (75%) and stable disease (SD)=3 (9%) (Fig 2a). Two patients achieving PR by 12 months subsequently reached CR at months 22 and 27, respectively, yielding an overall CR rate of 16% (n=5). At the 3-month time point from start of treatment and 1 month following completion of induction therapy, 58% of evaluable patients (18 of 31) had achieved a reduction in tumour size of 50% or greater (i.e., ≥ PR) and all but 1 patient had achieved at least some reduction in tumour size (Fig 2b). Of patients who achieved a PR or CR as best response, 18 (66%) responded by month 3. The ORR was 88% in the low-risk (n=8) and 83% in the int-risk FLIPI patients (n=24). Of the 3 eligible study patients not achieving a response, 2 had discontinued treatment early. One patient had received <100 mg of the initial 1000 mg dose before withdrawal from the study without response assessment. The other patient received 2 induction doses before study removal due to grade 4 pneumonitis; response evaluation at week 6 instead of month 3 per study protocol revealed SD. Only one patient of the 3 non-responders completed the entire 4 induction doses.
Fig 2a. Response depicted as change in tumour size from baseline for 500 mg and 1000 mg dose arms.
Maximal change in tumour size from baseline over 12 months.
Fig 2b. Response depicted as change in tumour size from baseline for 500 mg and 1000 mg dose arms.
Change in tumour size from baseline at months 3, 7 and 11 restaging time points.
Of 15 patients randomized to the 500 mg arm, the ORR was 60% (95% CI, 32–84%). The best response achieved by month 12 was CR 7% (n=1), PR 53% (n=8) and SD 33% (n=5) (Fig 2a). One patient who achieved PR later achieved CR at month 18. Both patients with bulky disease at baseline had SD as best response at month 3 and progressed during and shortly after completing extended induction therapy at months 7 and 12, respectively. The ORR was 50% in the low-risk (n=2) and 61% in the int-risk (n=13) patients.
At the time of this analysis, 22 (69%) patients have progressed in the 1000 mg arm and 12 (80%) in the 500 mg arm (Fig 3). The median follow-up is 30.7 months (<1– 55.4). In the 1000 mg arm, the median PFS is 1.9 years (95% CI, 1.5–3.0), 1-year PFS is 90% (95% CI, 73–97%) and 2-year PFS 48% (95% CI, 29–64%). The median duration of response in the 1000 mg arm is 23.7 months (95% CI, 16.6–36.2). In the 500 mg arm, the median PFS is 1.9 years (95% CI, 1.0–1.9), 1-year PFS is 80% (95% CI, 50–93%) and 2-year PFS 22% (95% CI, 5–46%). Median duration of response is 16.5 months (95% CI, 11.6–50.6). In both arms, the majority of patients who progressed had int-risk FLIPI at baseline. No low-risk patient progressed in the first year and only 1 progressed by 2 years. All patients who participated in this study remain alive.
Fig 3. Kaplan-Meier curve of progression-free survival (PFS) by dose arm.
Safety
Haematological and nonhaematological AEs are displayed in Table II. There were minimal haematological grade 3 AEs (all <10%) and no grade 4 AEs in the entire study population. In the 1000 mg arm, the most common grade 1 and 2 haematological AEs were 28% lymphopenia (grade 2, 6%), 17% anaemia and 14% neutropenia (grade 2, 11%). One patient had grade 3 neutropenia and 2 patients grade 3 lymphopenia. Haematological toxicity rates were equivalent in induction compared to extended induction except for low-grade neutropenia (12% vs 3%, respectively; Table III). Nonhaematological AEs in the 1000 mg arm included grade 3 IRRs (25%), all of which occurred during the first infusion, and grade 2 IRRs (56%), which all occurred during the first infusion as well except for one during infusion 2 and one during infusion 4. There were no grade 4 IRRs (Fig 4). Steroid-induced AEs included grade 3 hypertension (8%) and grade 3 hyperglycaemia (11%). There were no grade 3 or 4 infections. Additional grade 3 AEs occurring in <10% of patients included fatigue and dyspnea; those occurring in <5% of patients included syncope, small bowel obstruction, hyponataremia, hypokalaemia and hyperkaleamia (each in 1 patient, respectively). The only grade 4 AE reported was acute respiratory distress syndrome with acute coronary syndrome occurring after the second dose. The patient withdrew from the study and made a full recovery.
Table II.
Most commonly reported adverse events (>10% or ≥ 1 grade 3+ event).
Highest grade reported per patient per event regardless of attribution
Number of evaluable patients: 500 mg=15 1000 mg=36
| Haematological Adverse Events | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| All Grades | Grade1 | Grade 2 | Grade 3 | Grade 4 | ||||||
| Arm (mg) | 500 | 1000 | 500 | 1000 | 500 | 1000 | 500 | 1000 | 500 | 1000 |
| Lymphopenia | 20% | 34% | 7% | 22% | 13% | 6% | 0% | 6% | 0% | 0% |
| Anaemia | 13% | 17% | 13% | 14% | 0% | 3% | 0% | 0% | 0% | 0% |
| Thrombocytopenia | 13% | 6% | 13% | 6% | 0% | 0% | 0% | 0% | 0% | 0% |
| Neutropenia | 0% | 17% | 0% | 3% | 0% | 11% | 0% | 3% | 0% | 0% |
| Leucocytosis | 7% | 0% | 0% | 0% | 0% | 0% | 7% | 0% | 0% | 0% |
| Nonhaematological Adverse Events | ||||||||||
| All Grades | Grade1 | Grade 2 | Grade 3 | Grade 4 | ||||||
| Arm (mg) | 500 | 1000 | 500 | 1000 | 500 | 1000 | 500 | 1000 | 500 | 1000 |
| Infusion-related reaction | 87% | 89% | 7% | 8% | 80% | 56% | 0% | 25% | 0% | 0% |
| Pain | 73% | 64% | 53% | 50% | 20% | 14% | 0% | 0% | 0% | 0% |
| Fatigue | 74% | 64% | 67% | 47% | 7% | 11% | 0% | 6% | 0% | 0% |
| Dyspneoa | 40% | 34% | 33% | 25% | 7% | 3% | 0% | 6% | 0% | 0% |
| Insomnia | 27% | 30% | 20% | 19% | 7% | 11% | 0% | 0% | 0% | 0% |
| Nausea | 20% | 36% | 13% | 33% | 7% | 3% | 0% | 0% | 0% | 0% |
| Hyperglycaemia | 33% | 33% | 20% | 14% | 13% | 8% | 0% | 11% | 0% | 0% |
| Cough | 27% | 20% | 27% | 14% | 0% | 6% | 0% | 0% | 0% | 0% |
| Hyponatraemia | 27% | 17% | 27% | 14% | 0% | 0% | 0% | 3% | 0% | 0% |
| Infection | 27% | 28% | 0% | 3% | 7% | 25% | 20% | 0% | 0% | 0% |
| Hypertension | 21% | 30% | 7% | 8% | 7% | 14% | 7% | 8% | 0% | 0% |
| Diarrheoa | 14% | 20% | 7% | 17% | 7% | 3% | 0% | 0% | 0% | 0% |
| Pruritus | 13% | 19% | 13% | 19% | 0% | 0% | 0% | 0% | 0% | 0% |
| Hypoalbuminaemia | 20% | 8% | 20% | 8% | 0% | 0% | 0% | 0% | 0% | 0% |
| Hypophosphataemia | 14% | 14% | 7% | 3% | 7% | 11% | 0% | 0% | 0% | 0% |
| Anorexia | 20% | 6% | 13% | 3% | 7% | 3% | 0% | 0% | 0% | 0% |
| Dizziness | 7% | 14% | 7% | 11% | 0% | 3% | 0% | 0% | 0% | 0% |
| Allergic rhinitis | 13% | 8% | 13% | 8% | 0% | 0% | 0% | 0% | 0% | 0% |
| Transaminitis | 0% | 20% | 7% | 20% | 0% | 0% | 0% | 0% | 0% | 0% |
| Gastroesophageal reflux | 7% | 12% | 7% | 6% | 0% | 6% | 0% | 0% | 0% | 0% |
| Constipation | 7% | 11% | 7% | 11% | 0% | 0% | 0% | 0% | 0% | 0% |
| Hypotension | 13% | 6% | 13% | 3% | 0% | 3% | 0% | 0% | 0% | 0% |
| Hyperhidrosis | 13% | 6% | 13% | 6% | 0% | 0% | 0% | 0% | 0% | 0% |
| Hyperkalaemia | 7% | 6% | 7% | 3% | 0% | 0% | 0% | 3% | 0% | 0% |
| Hypokalaemia | 7% | 6% | 7% | 3% | 0% | 0% | 0% | 3% | 0% | 0% |
| Aortic valve disease | 7% | 0% | 0% | 0% | 0% | 0% | 7% | 0% | 0% | 0% |
| Acute coronary syndrome | 0% | 3% | 0% | 0% | 0% | 0% | 0% | 0% | 0% | 3% |
| ARDS | 0% | 3% | 0% | 0% | 0% | 0% | 0% | 0% | 0% | 3% |
| Syncope | 0% | 3% | 0% | 0% | 0% | 0% | 0% | 3% | 0% | 0% |
| Small bowel obstruction | 0% | 3% | 0% | 0% | 0% | 0% | 0% | 3% | 0% | 0% |
ARDS, Acute Respiratory Distress Syndrome
Table III.
Most commonly reported haematological adverse events in induction vs extended induction (>10% or ≥ 1 grade 3+ event).
Highest grade reported per patient per event regardless of attribution
Number of evaluable patients: 500 mg=15 1000 mg=36
| Induction | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| All grades | Grade 1 | Grade 2 | Grade 3 | Grade 4 | ||||||
| Arm (mg) | 500 | 1000 | 500 | 1000 | 500 | 1000 | 500 | 1000 | 500 | 1000 |
| Lymphopenia | 20% | 26% | 7% | 14% | 13% | 6% | 0% | 6% | 0% | 0% |
| Anaemia | 7% | 14% | 7% | 11% | 0% | 3% | 0% | 0% | 0% | 0% |
| Thrombocytopenia | 13% | 6% | 13% | 6% | 0% | 0% | 0% | 0% | 0% | 0% |
| Neutropenia | 0% | 15% | 0% | 3% | 0% | 9% | 0% | 3% | 0% | 0% |
| Leucocytosis | 7% | 0% | 0% | 0% | 0% | 0% | 7% | 0% | 0% | 0% |
| Extended Induction | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| All grades | Grade 1 | Grade 2 | Grade 3 | Grade 4 | ||||||
| Arm (mg) | 500 | 1000 | 500 | 1000 | 500 | 1000 | 500 | 1000 | 500 | 1000 |
| Lymphopenia | 20% | 25% | 20% | 19% | 0% | 3% | 0% | 3% | 0% | 0% |
| Anaemia | 13% | 14% | 13% | 14% | 0% | 0% | 0% | 0% | 0% | 0% |
| Thrombocytopenia | 6% | 6% | 6% | 6% | 0% | 0% | 0% | 0% | 0% | 0% |
| Neutropenia | 0% | 6% | 0% | 0% | 0% | 3% | 0% | 3% | 0% | 0% |
| Leucocytosis | 0% | 0% | 0% | 0% | 0% | 0% | 0% | 0% | 0% | 0% |
Fig 4. Bar graph of infusion-related reactions reported per infusion by dose arm.
CI: confidence interval; PFS: progression-free survival
In the 500 mg arm, the most common haematological AEs included grade 2 lymphopenia (13%) and grade 3 leucocytosis (7%). Nonhaematological AEs included grade 2 IRRs (80%) which all occurred during the first infusion except for one during dose 2 infusion. There were no grade 3 or 4 IRRs (Fig 4). Grade 2 and 3 infections were 7% and 20%, respectively. Steroid-induced AEs included grade 3 hypertension (7%). No grade 4 nonhaematological AEs were reported.
The discontinuation rate due to toxicity alone in the overall study population was 6% (n=3). All 3 of these patients were in the 1000 mg arm. Of note, 2 of the 3 patients discontinued the study for grade 3 IRRs which occurred after receiving only 25 mg and 63 mg of the first 1000 mg dose, respectively, without attempt at rechallenge.
Discussion
This trial is the first to report the outcomes of ofatumumab monotherapy in previously untreated, advanced-stage FL. We show that 1000 mg of ofatumumab is well-tolerated and active as upfront treatment, resulting in an ORR of 84% (evaluable patients 87%) to meet the primary endpoint of the study. The majority of responses were PRs with a 16% CR rate. The safety profile was favourable with minimal grade 3 or 4 haematological or infectious AEs. Grade 2/3 infusion reactions with the first dose, however, were more common than previously reported in R/R FL patients receiving single-agent ofatumumab (Czuczman et al, 2015; Hagenbeek et al, 2008). This may be explained by the greater immunocompromised state in the R/R setting with significant peripheral blood lymphopenia and B-cell depletion prior to receiving ofatumumab compared to our frontline, low/int-risk patients with normal baseline peripheral B-lymphocyte counts. There also appears to be a relationship between dose and severity of infusion reaction, as more grade 3 reactions occurred with the 1000 mg dose. Despite the higher rate observed with the first infusion, only 3 patients (6%) of the overall study population discontinued treatment due to infusion reactions.
The study was initially designed to evaluate whether a dose-response relationship for ofatumumab exists in previously untreated FL. In a prior study from our group evaluating ofatumumab monotherapy in rituximab-refractory FL, no difference in response was observed between the 500 and 1000 mg flat doses in heavily pretreated patients (Czuczman et al, 2012b). Similarly, no dose response relationship was observed in the initial phase 1 trial in R/R FL evaluating ofatumumab doses ranging from 300 to 1000 mg (Hagenbeek et al, 2008). Although our trial was not statistically designed for comparison between the two dose arms, an ORR of 84% was observed in the 1000 mg arm compared to an ORR of 60% in the 500 mg arm. The 1-year PFS was also higher in the 1000 mg dose arm compared to the 500 mg arm, 90% vs 80%, respectively. One possible explanation for these trends observed in dose response is the FcRIIIa receptor (FCGR3A) may not be fully saturated at the 500 mg dose and that higher ofatumumab plasma concentrations and full receptor target occupancy may be needed to maximally deplete CD20+ B cells residing in lymph nodes and achieve the highest degree of ADCC. In addition to FCGR3A target occupancy, Fc-gamma receptor (FCGR) and/or complement protein polymorphisms may play a role in the efficacy of ofatumumab in FL as well. FCGR3A and FCGR2A genotypes were not predictive of initial response to rituximab or response duration with maintenance treatment in treatment-naïve, low tumour burden FL (Kenkre et al, 2016). The CFHR3 complement protein polymorphism, however, was found to be a candidate biomarker for obinutuzumab response in FL, suggesting that response to other anti-CD20 mAbs may vary based on the genotype of complement regulatory proteins (Rogers et al, 2017). Given the greater dependence of ofatumumab on CDC over ADCC for overall activity, complement protein C1QA genotyping remains of particular interest.
Durability of response to extended induction ofatumumab in this study appears inferior to that reported for similar extended dosing regimens of rituximab monotherapy in chemotherapy-naïve, low tumour burden FL. At median follow-up of 30.7 months in the 1000 mg arm, 31% of patients remain in remission yielding a 1-year PFS of 90% and median PFS of 22.8 months. Prolonged median event-free/PFS durations of 34–42 months were comparatively observed in studies of rituximab extended induction dosing (Ghielmini et al, 2004, 2009; Martinelli et al, 2010; Hainsworth et al, 2002; Taverna et al, 2016; Kahl et al, 2014). In our study, many patients who achieved PR subsequently relapsed within 4 to 14 months of the last extended induction dose given at month 9. The 2-year PFS dropped to 48% from 90% at 1-year, suggesting that either continued extended dosing of ofatumumab beyond month 9 may improve duration of response or retreatment with 4 weekly doses ofatumumab at relapse may result in a similar time to treatment failure. The gradual rise in ORR over the first 12 months favours extended induction and ongoing maintenance therapy (i.e., month 3 ORR 56%, month 7 ORR 78%, month 12 ORR 84% after 4 extended induction doses). Deepening in quality of response over time with PR to CR conversions occurred in both dose arms after month 12 and completion of extended induction therapy. Three of the 7 patients achieved CRs at months 18, 22 and 27, respectively, suggesting that maintenance dosing with ofatumumab may not only improve ORR, but potentially the quality and duration of response. Analysis of B-cell depletion kinetics to better understand response, response duration and relapse patterns on the extended induction schedule utilized in this study may also shed light on optimal maintenance schedules, such as continuation of ofatumumab for up to 2 years or longer, to prolong remission duration and time to treatment failure compared to retreatment strategies.
Although the initial study goal was to compare two ofatumumab doses in previously untreated, advanced-stage FL, the role of ofatumumab in this population comes into question given the demonstrated efficacy of rituximab in this setting and the improved PFS compared to rituximab of the next generation anti-CD20 mAb obinutuzumab. In previously untreated, symptomatic FL, combination regimens of ofatumumab with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and bendamustine, respectively, are highly active with comparable efficacy to rituximab-based immunochemotherapy regimens (Czuczman et al, 2012a, 2015). In the R/R setting, however, poor single-agent efficacy in rituximab-refractory FL is evident and the outcomes of an immunochemotherapy trial with ofatumumab in rituximab-refractory disease have not yet been reported. Subsequent to the design of our study, the phase 3 trial in relapsed, rituximab-sensitive FL comparing ofatumumab vs rituximab was halted early with no superior response difference observed (Maloney et al, 2016). The finding that up to 60% of rituximab-sensitive patients fail to respond to retreatment may make this population less likely to respond to relative doses of other anti-CD20 mAbs including ofatumumab (McLaughlin et al, 1998; Davis et al, 2000). Whether there is clinical benefit of single-agent ofatumumab or obinutuzumab over rituximab in treatment-naive patients with lower tumour burden remains unanswered. Partial supporting evidence for this hypothesis is provided by the GALLIUM study, in which previously untreated, symptomatic, advanced-stage FL patients were randomized to obinutuzumab 1000 mg vs standard rituximab-based immunochemotherapy and maintenance (Marcus et al, 2017). Despite a similar ORR and lower CR rate, a prolonged 3-year PFS was observed with obinutuzumab vs rituximab maintenance therapy following immunochemotherapy induction, postulated to result from the higher relative dose of obinutuzumab vs rituximab when given in the maintenance setting with low tumour burden. Obinutuzumab has not been studied as a single agent in a similar population to that of our study and no randomized studies have been done to investigate whether novel anti-CD20 mAbs may be superior to either rituximab or a watch-and-wait strategy in patients with asymptomatic or minimally symptomatic, low tumour burden, advanced-stage FL.
Given the dose response relationship observed between 500 and 1000 mg in terms of ORR, despite similar PFS curves, a limitation to the study is that we did not test doses higher than 1000 mg as maximal engagement of CDC with ofatumumab is known to occur at 100% target saturation of the tumour cell. In addition, higher ofatumumab plasma concentrations may more effectively target tumour cells residing in lymph nodes compared to peripheral blood (Bleeker et al, 2008). Doses, such as 2000 mg, approved in CLL have not been studied in FL. This potential for dose modulation affords an advantage to ofatumumab in FL. As ADCC-dependent drugs, such as obinutuzumab and rituximab, require only partial target saturation of the tumour cell for maximal effect, there is less of a role for dose escalation to improve response. In addition, as obinutuzumab is engineered to have greater ADCC than rituximab but lower CDC, high drug concentrations are already required to recruit CDC.
In summary, ofatumumab monotherapy given in an extended induction dosing schedule was well tolerated and active as upfront treatment in low/int-risk, advanced-stage FL. However, this 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.
Acknowledgements
The authors acknowledge the investigators from the participating Alliance institutions for their participation, the Cancer Therapy Evaluation Program and Novartis Corporation.
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821 and U10CA180882 (to the Alliance for Clinical Trials in Oncology), U10CA180833, U10CA180836, U10CA180857, and UG1CA189830. Ofatumumab was provided by GlaxoSmithKline.
The following institutional networks participated in this study:
Dana-Farber/Partners Cancer Care LAPS, Boston, MA, Harold Burstein, U10CA180867; Delaware/Christiana Care NCI Community Oncology Research Program, Newark, DE, Gregory Masters, UG1CA189819; Heartland Cancer Research NCORP, Decatur, IL, James Wade, UG1CA189830; MedStar Georgetown University Hospital, Washington, DC, Chaitra Ujjani; New Hampshire Oncology Hematology PA-Hooksett, Hooksett, NH, Douglas Weckstein; The Ohio State University Comprehensive Cancer Center LAPS, Columbus, OH, Clara Bloomfield, U10CA180850; UNC Lineberger Comprehensive Cancer Center LAPS, Chapel Hill, NC, Thomas Shea, U10CA180838; University of Chicago Comprehensive Cancer Center LAPS, Chicago, IL, Hedy Kindler, U10CA180836; University of Iowa/Holden Comprehensive Cancer Center, Iowa City, IA, Laith Abushahin; VCU Massey Cancer Center Minority Underserved NCORP, Richmond, VA, Steven Grossman, UG1CA189869; Wake Forest University Health Sciences, Winston-Salem, NC, Heidi Klepin; Washington University - Siteman Cancer Center LAPS, Saint Louis, MO, Nancy Bartlett, U10CA180833; and Weill Medical College of Cornell University, New York, NY, Scott Tagawa.
Footnotes
Conflict of Interest
The authors declare no conflict of interest in relation to the work described. C.A.R. has received institutional research funding for industry-sponsored clinical trials from Bristol-Myers Squibb, Novartis, GlaxoSmithKline and Millennium, and has consulted for Celgene and Bristol-Myers Squibb. E.H. has received research funding from Abbvie, Cellerant Therapeutics and Eli Lilly, and has consulted for Seattle Genetics and Mundi. N.W-J. has received research funding from Merck, Regeneron and Novartis and honoraria from JUNO, ADC Therapeutics and Janssen. S.P.T. has received research funding from Celgene, BMS, Genentech, Astellis and Janssen and honoraria from Abbvie, Exelixis and Roche. B.D.C. has received research funding from Abbvie, Roche-Genentech, Gilead, Pharmacyclics and Acerta, and has consulted for Abbvie, Acerta, Roche-Genentech, Pharmacyclics/Janssen, TG Therapeutics, Bayer, Celgene and Sunesis. The remaining authors declare no competing financial interests.
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