Prognostic and Immune-Related Factors for Response to Duvelisib in the Phase 2 DYNAMO^TM Clinical Trial in iNHL

Introduction:

Indolent NHL (iNHL) remains largely incurable, with the majority of patients (pts) eventually becoming refractory to standard therapies, necessitating new effective and tolerable treatments. Duvelisib is an oral dual PI3K-δ,γ inhibitor being developed for the treatment of hematologic malignancies, including CLL/SLL and follicular lymphoma (FL). In the Phase 2 DYNAMO trial of duvelisib monotherapy for relapsed/refractory iNHL(NCT01882803), the FL subgroup (n=83) had a median progression-free survival (mPFS) of 8.3 months (mo) and an overall response rate (ORR) of 43%. Although adverse events (AEs) observed with other PI3K-inhibitors also occurred with duvelisib, they infrequently led to discontinuation of treatment. An understanding of prognostic factors that can inform duvelisib responsiveness would be valuable for guiding patient selection treatment options. This study presents updated data on prognostic factors potentially associated with duvelisib efficacy and safety.

Methods:

To identify FL risk subgroups, clinical parameters were assessed according to the FL Prognostic Index (FLIPI). Incidences of AEs (per combined preferred term: neutropenia, diarrhea, colitis, pneumonia, pneumonitis, transaminase elevation, rash, and infections) were also evaluated for associations with clinical responses. Blood collected at baseline (Cycle1 Day1) was analyzed by a central laboratory for a 7 gene expression signature to generate the combined M7-FLIPI, and biopsies were evaluated at screening for del(6q) cytogenetics. In addition, baseline immune cell counts (subgrouped low [^L] or high [^H] by flow cytometry), and levels of key chemokines, cytokines, and serum factors were centrally assessed. Multivariate regression models were developed via a stepwise procedure from a selection of these parameters identified by individual univariate analysis for the efficacy endpoints of mPFS and ORR.

Results:

In the DYNAMO study, there were no significant differences in mPFS, ORR, or lymph node response rate (LNRR) identified for FL pts between high and low risk subgroups stratified by prognostic indexes. Efficacy responses were similar using the FLIPI (FLIPI <3: mPFS, 11.9 mo; ORR, 42.9%; LNRR, 42.9%; n=28) vs (FLIPI ≥3: mPFS, 8.3 mo; ORR, 42.6%; LNRR, 46.3%; n=54) and the M7-FLIPI algorithm (M7-FLIPI ≥0.8: mPFS, 9.0 mo; ORR, 63.6%; LNRR, 72.7%; n=11) vs (M7-FLIPI <0.8: mPFS, 10.0 mo; ORR, 40%; LNRR, 40%; n= 30). Patients with del(6q13-q15) or del(6q23.3-q24.1) had an mPFS of 11.8 mo (n=17) compared to 8.3 mo (n=23) for those without either deletion, with an ORR of 52.9% vs 43.5%, respectively. For immune cell subpopulations, mPFS was similar between high and low baseline levels (CD3 T, CD8 T, T-reg, TH17 T), whereas higher monocyte cell counts (5.6 mo^H vs 9.0 mo^L) and a higher CD8/T-reg (5.4 mo^H vs 11.0 mo^L) correlated with lower mPFS. The ORR for CD3^H was 56% (n=25) vs 34.9% (n=43) for CD3^L. Chemokine and cytokine levels generally did not correlate with mPFS and ORR (CCL22, CCL3, CCL4, CCL17, IL12P40, CXCL10, CXCL9, CXCL13, and TNFα); however, shorter mPFS was associated with higher levels of CXCL11 (9.0 mo^L, n=39 vs 5.6 mo^H, n=32) and IL2RA (9.0 mo^L, n=36 vs 5.6 mo^H, n=35).

Prognostic factors selected via univariate analyses for mPFS or ORR were advanced into multivariate models. None of these factors reached significance in a multivariate mPFS model, and only CD3^H was significant in a stepwise ORR model (odds ratio H/L=2.69, 95% CI [1.20,6.06]).

The FL pt subgroups having AEs were evaluated for mPFS (mo [95% CI] as follows: neutropenia, 8.3 mo [3.5,11.8], n=25; diarrhea 11.0 mo [8.3,16.4], n=40; colitis 10.0 mo [8.3,24.0], n=5; rash 8.3 mo [1.9,28.0], n=26; transaminase elevation, 11.8 mo [1.4,24.0], n=12; pneumonitis 13.0 mo [9.5,16.4], n=4; pneumonia 12.0 [4.2,28.0], n=8; and infection 9.0 [3.7,12.0], n=38.

Conclusion

In the Phase 2 DYNAMO study, mPFS and ORR were similar for duvelisib-treated FL pts regardless of poor prognostic indicators, including FLIPI, M7-FLIPI, and chromosome 6q deletions. Elevated levels of CXCL11 and IL2RA correlated with shorter mPFS. This analysis also shows that AEs, when managed, allow continued treatment with duvelisib and increased benefit as demonstrated by mPFS. Overall, these data suggest that duvelisib as a single-agent is effective in FL patients, including pts with poor prognostic factors.