Pembrolizumab Plus Rituximab Promising in Follicular Lymphoma

Loretta J. Nastoupil, MD

Combining pembrolizumab (Keytruda) with rituximab (Rituxan) induced a high response rate in patients with relapsed follicular lymphoma.

Half of the treated patients experienced complete disease remission, according to findings from a phase II trial presented at the 2017 International Conference on Malignant Lymphoma biennial meeting in Lugano, Switzerland.

At the preplanned interim analysis, 20 patients treated with the pembrolizumab combination had evaluable efficacy data and 30 were evaluable for safety. The overall response rate (ORR) was 65%, including a complete response rate of 50%. The best response was stable disease in 3 patients and 4 patients had progressive disease. The median follow-up was 8.2 months.

“The combination was expected to improve ORR to 60% as compared with historical controls demonstrating ORR of 40% with rituximab retreatment,” said Loretta J. Nastoupil, MD, associate professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center.

Nastoupil explained the trial’s rationale: “Follicular lymphoma tumors are infiltrated with antitumor T cells, but their function is impaired by immune checkpoints, such as PD-1; blocking PD-1 could enhance antitumor T cells’ activity that could be further enhanced by inducing ADCC using an anti-CD20 antibody. Therefore, we reasoned that the combination of pembrolizumab, an anti­—PD-1 antibody, and rituximab, an anti-CD20 antibody, would likely be synergistic through activation of both the innate and adaptive immune systems and result in enhanced clinical activity in follicular lymphoma.”

Adult patients with follicular lymphoma grades 1 to 3a that relapsed following at least 1 prior therapy were enrolled in this open-label, nonrandomized, single institution, phase II trial. Patients had ECOG performance status of 0 to 1 and rituximab-sensitive disease, defined as a having a complete or partial response lasting at least 6 months after the most recent rituximab-containing therapy.

The median patient age was 64 years (range, 43-84), 57% of patients were male, 73% had intermediate- or high-risk FLIPI, and 50% met GELF criteria. The patients had received a median of 2 prior therapies (range, 1-4) and 73% had received prior chemotherapy.

Rituximab was administered at 375 mg/m² IV on days 1, 8, 15, and 22 of cycle 1 plus pembrolizumab at 200 mg IV every 3 weeks for up to 16 cycles starting on day 2 of cycle 1.

The primary endpoint of the trial was ORR and secondary endpoints included progression-free survival (PFS), duration of response (DOR), and safety.

At the time of this analysis, median DOR, PFS, and overall survival had not been reached.

Grade 1/2 adverse events (AEs) occurring in ≥10% of patients included fatigue (53%), eye pain/blurry vision (43%), nausea/vomiting and diarrhea (30% each), rash (23%) and dyspnea (13%). Two (7%) patients experienced grade 3 nausea/vomiting, and 1 (3%) patient had grade lymphopenia.

Four patients discontinued treatment due to grade 2 IR-AEs that included diarrhea in 2 patients and 1 patient each stopped treatment due to rash and pneumonia.

PD-L1 expression testing of 8 baseline tumor samples using PD-L1 22C3 immunohistochemistry pharmDx revealed PD-L1 expression on histiocytes in all 8 tumors, but PD-L1 was expressed in only 1% to 8% of tumor cells out of the 5 tumors evaluated.

This led to an evaluation of T cells done in 12 biopsies taken prior to treatment to explain the response observed, where levels of CD8+ T effector cells were detected.

An evaluation of response by CD8+ T effector score showed ORR was 83% in patients with CD8+ high scores versus 67% in patients with CD8+ low scores, and CR rates were 83% versus 33% in the respective cohorts.

“These interim results warrant further investigation of this combination in patients with follicular lymphoma,” said Nastoupil, “An expansion is planned to include patients with refractory follicular lymphoma.”

Nastoupil LJ, Westin J, Fowler N, at al. High response rates with pembrolizumab in combination with rituximab in patients with relapsed follicular lymphoma: interim results of an on open-label, phase II study. Hematological Oncology, 35(S2): 120-121. doi:10.1002/hon.2437_108.

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Immune related AEs (IR-AEs) included grade 1 diarrhea (20%), rash (10%), transaminitis (10%), and hypothyroidism (3%). Grade 2 IR-AEs of diarrhea (10%), rash (13%), pneumonitis (3%), and esophagitis (3%) were reported. One (3%) grade 3 case of aseptic meningitis occurred.