FLIPI Score Is Applicable and Predictive of Response to Upfront Immunotherapy in CALGB 50402: Phase II Trial of Extended Induction Galiximab ([G] anti-CD80 monoclonal antibody) Plus Rituximab [R].

The majority of indolent B-cell lymphoma patients [pts] receive R, either as a single agent or in combination with chemotherapy. Recently, “biologic” agents (e.g. GM-CSF, Interferon-alpha, other monoclonal antibodies [mAbs]) are being combined with R in an attempt to increase its anti-tumor activity. Compared to R-chemo, these “purely” immuno-therapies avoid chemotherapy-associated non-specific toxicities while introducing unique mechanisms-of-action [MOA] against drug-resistant cells. G is a primatized anti-CD80 mAb with single-agent activity and excellent safety profile in prior psoriasis and previously treated FL trials. CD80 (i.e. B7.1) is a transmembrane glycoprotein present on the surface of various lymphoma subtypes, but also on a number of immuno-effector cells (e.g. activated macrophages, activated B-cells, dendritic cells). MOA of G includes the ability to induce ADCC on targeted malignant B-cells, but also possible immunomodulatory effects by altering cellular composition and/or cytokine profile within the tumor microenvironment. Objectives of CALGB 50402 were to determine ORR and time-to-progression [TTP] from an “extended” induction schedule of G + R (i.e. G + R weekly x 4, then every 2 months x 4) in previously untreated FL pts (WHO grades 1–3a). The base-line characteristics of 61 evaluable pts are: 61% M: 39% F; median age = 57 years (range: 22–85) with 48% of pts >60; 23% with elevated LDH; FLIPI: good risk = 20.3%, intermediate-risk = 42%, high-risk = 37%; histology: 44% grade 1, 46% grade 2, 10% grade 3a; 93% stage III/IV; 24% bulky (>7 cm) disease. Therapy was very well tolerated with only 13% grade 3 adverse events. ORR is 70% (95% CI: 57% – 81.5%) and includes 44% CR/CRu, 26% PR. Greater than 10% of pts had “delayed” initial responses (i.e. 8–14 months after starting therapy) and more than 15% of pts converted from PR to CR after at least 9 months or more of therapy. Of particular interest is an apparent association of FLIPI score to ORR and CR rate: | | | ORR (p=0.059) | CR (p=0.03) | |:-----------:| --- | ------------- | ----------- | | FLIPI Score | 0–1 | 11 (92%) | 9 (75%) | | | 2 | 20 (80%) | 12 (48%) | | | 3–5 | 12 (55%) | 6 (27%) | In further analyses, ORR was not associated with stage, gender, bulky disease, marrow involvement or age > 60. At a median follow-up of 2.17 years, 41 of 61 (67%) pts remain progression-free. Notably, PFS also is impacted by FLIPI score (p=0.0012): | | | % Progressed | Median PFS | |:-----------:| --- | ------------ | ----------- | | FLIPI Score | 0–1 | | Not reached | | | 2 | 24% | Not reached | | | 3–5 | 59% | 1.62 years | In conclusion, upfront extended induction G + R immunotherapy was well tolerated and achieved a current (i.e. continue to monitor for “late” responders) ORR of 70% (44% CR/ Cru). Although the FLIPI was originally developed in pts receiving chemotherapy alone, our data strongly suggest that it has applicability to a purely upfront immunotherapy (i.e. G + R) treated group of FL pts. G + R combination immunotherapy is an extremely well-tolerated and promising regimen in previously untreated FL pts with low- and intermediate-risk FLIPI status. An update, including “delayed” response rate, durability of therapeutic response, TTP, and analysis of Fc receptor polymorphisms versus response to dual monoclonal antibody therapy will be presented at the annual meeting.