Clinical and Biological Indicators of Duvelisib Efficacy in CLL from the Phase 3 DUOTM Study
Authors: Brown Jennifer R. , Flinn Ian W. , Davids Matthew S. , Hillmen Peter , Montillo Marco , Nagy Zsolt , Delgado Julio , Kuss Bryone J. , Tam Constantine S. , Jaeger Ulrich , Ghia Paolo , Stilgenbauer Stephan , Moreno Carol , Le NgocDiep , Lustgarten Stephanie , Sprott Kam , Pachter Jonathan A. , Weaver David T. , Cymbalista Florence 
Published: October 2019

Abstract
Introduction
In CLL, the timing and selection of therapy is largely informed by disease stage, prognostic molecular features, tumor load, and patient (pt) performance status. Duvelisib (DUV) is a novel, oral, dual PI3K-δ,γ inhibitor in clinical development for the treatment of CLL/SLL, FL, and other hematologic malignancies. Results from the Phase 3 DUO study (NCT02004522) for relapsed/refractory CLL/SLL showed that DUV monotherapy resulted in statistically significant improvement over ofatumumab (OFA) monotherapy for median progression-free survival (mPFS; 13.3 vs 9.9 months (mo); p<0.0001), overall response rate (ORR; 73.8% vs 45.3%; p<0.0001), and lymph node response rate (85.0% vs 15.7%; p<0.0001) per IRC assessments, with a median overall follow-up of 22.4 mo for both arms (Flinn et al., 2018). In order to identify pts from DUO who were more likely to respond to DUV, multiple markers, including tumor burden, cytogenetics, immune cell profiles, and serum factors were correlated with clinical responses in an exploratory analysis.
Methods
Of the 319 pts enrolled in the DUO study, 158 were treated with DUV and 155 with OFA. Tumor burden was assessed at baseline using target lymph node diameter and absolute lymphocyte count. Baseline blood samples from Cycle1 Day1 were analyzed for cytogenetic abnormalities (17p, 11q, 6q deletions; trisomy 12); immune cell counts by flow cytometry; and serum chemokine, cytokine, and serum factor levels. Univariate analysis of these markers was conducted for PFS and ORR. The statistically significant univariate markers were tested in a stepwise multivariate regression (MVR) model using binary high [H] or low [L] thresholds based on the median.
Results
Tumor Burden: The mPFS (in mo) for DUV monotherapy did not appear to be impacted by baseline tumor burden: high (n=20), 16.6; medium (n=88), 12.7; and low (n=47), 15.1. Across these tumor burden levels, DUV maintained its PFS advantage over OFA.
Cytogenetics: DUV-treated pts with del(11q), a marker associated with poor CLL outcomes, had a longer mPFS (in mo) and ORR compared to pts without del(11q) (mPFS: 24.8, n=25 vs 12.7, n=81; HR 0.56, 95% CI [0.30,1.06]; ORR: 80.0% vs 69.1%, odds ratio, 0.56). In contrast, mPFS was shorter in OFA-treated del(11q) pts relative to those without this deletion (5.3, n=24 vs 11.3, n=71). Median PFS was significantly extended in the del(17p) subgroup for DUV vs OFA (16.6, n=27 vs 9.2, n=27; HR 0.42, [0.21,0.85]), and, to a lesser degree, in pts without del(17p) (13.1, n=83 vs 11.1, n=74; HR 0.55 [0.37,0.83]). For the 6 DUV pts with del(11q/17p), mPFS was 17.4 mo. A shorter mPFS was observed for DUV-treated pts with trisomy 12 compared with trisomy 12-negative pts (9.1, n=16 vs 16.5, n=73). For the 10 DUV pts with trisomy 12 as well as del(11q/17p), mPFS was more similar to the trisomy 12 group, at 9.1 mo.
Immune cell profiles and serum factors: Several immune cell profiles correlated with longer mPFS (in mo) for DUV, including Treg (16.4H vs 12.9L, HR 0.69 [0.43,1.12]) and monocytes (15.1L vs 12.7H, HR 0.82 [0.54,1.24]). Baseline chemokine and serum factor levels associated with longer mPFS with DUV included CCL3 (22.1L vs 12.2H, HR 0.60 [0.37,0.99]), IL2RA (16.3L vs 11.6H, HR 0.73 [0.47,1.14]), and TNFα (16.6L vs 12.2H, HR 0.78 [0.49,1.24]).
Multivariate regression model: The MVR model showed that the biomarker profile of trisomy 12-negative (HR -/+, 0.15), CCL22L (HR H/L, 2.23), TNFαL (HR H/L, 3.66), TregH (HR H/L, 0.31), and monocytesL (HR H/L, 2.45), was associated with longer PFS; TNFαL and TregH were the largest associations, with estimated 73% and 69% reductions in risk of progression or death, respectively. Similarly, stepwise models yielded TNFαL (odds ratio H/L, 0.37) and CXCL11H (odds ratio H/L, 2.99) as biomarkers for improvement in ORR. Based on these analyses, pts with TNFαL tend to have better efficacy profiles for PFS and/or ORR.
Conclusions: DUV monotherapy was highly efficacious in CLL/SLL pts with markers of poor response, including high tumor burden, del(17p), and del(11q) as shown by univariate analyses of tumor burden, cytogenetics, immune cell profiles, and serum factors. Multivariate analyses revealed a biomarker profile of CCL22L, TNFαL, TregH, monocytesL, and trisomy 12-negative that correlated with improved mPFS and/or ORR. Additional analyses are underway to characterize the predicted PFS for the biomarker profile.

Disclosures
Brown: Verastem: Consultancy, Research Funding; Janssen: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy; Sun Pharmaceutical Industries: Research Funding; TG Therapeutics: Consultancy; Sunesis: Consultancy; Gilead: Consultancy, Research Funding; Roche/Genentech: Consultancy; Genentech: Consultancy; Celgene: Consultancy; Boehringer: Consultancy; Beigene: Membership on an entity's Board of Directors or advisory committees; Acerta / Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Invectys: Membership on an entity's Board of Directors or advisory committees; Loxo: Consultancy. Flinn:Novartis: Research Funding; Merck: Research Funding; Infinity: Research Funding; Forty Seven: Research Funding; Janssen: Research Funding; Trillium: Research Funding; Pharmacyclics: Research Funding; Verastem: Research Funding; Pfizer: Research Funding; Kite: Research Funding; Takeda: Research Funding; Forma: Research Funding; BeiGene: Research Funding; Curis: Research Funding; Seattle Genetics: Research Funding; TG Therapeutics: Research Funding; Verastem: Consultancy, Research Funding; Portola: Research Funding; Calithera: Research Funding; ArQule: Research Funding; Celgene: Research Funding; Constellation: Research Funding; Genentech: Research Funding; Incyte: Research Funding; Gilead: Research Funding; Agios: Research Funding. Davids:Surface Oncology: Research Funding; Merck: Consultancy; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Consultancy, Research Funding; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hillmen:F. Hoffmann-La Roche Ltd: Research Funding; Celgene: Research Funding; Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Pharmacyclics: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees. Montillo:Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Speakers Bureau. Tam:Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jaeger:GSK: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria; Infinity: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding. Ghia:Sunesis: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; AbbVie, Inc: Honoraria, Research Funding. Stilgenbauer:Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmcyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffmann La-Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Moreno:Janssen: Consultancy; AbbVie: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy. Le:Verastem Oncology: Employment. Lustgarten:Verastem Oncology: Employment. Sprott:Verastem Oncology: Employment. Pachter:Verastem Inc: Employment, Other: Stockholder. Weaver:Agios Pharmaceuticals: Employment; Verastem Oncology: Employment, Other: Stockholder; Femto Dx: Equity Ownership.