Exposure-Response of Idelalisib Administered in Combination with Ofatumumab for the Treatment of Relapsed Chronic Lymphocytic Leukemia

Background:  

Idelalisib (ZydeligŪ) is a potent and selective PI3Kd inhibitor approved for the treatment of relapsed CLL (in combination with rituximab) and relapsed iNHL subtypes, FL and SLL. Relationship between plasma exposures to idelalisib or its inactive circulating metabolite, GS-563117, and clinical efficacy and safety were evaluated in relapsed/refractory CLL subjects following administration of idelalisib 150 mg twice daily (BID) in combination with ofatumumab (Study GS-US-312-0119).

Methods:

Idelalisib and GS-563117 plasma exposures (C_max, AUC_tau and C_tau) were generated using population pharmacokinetic models based on data from several phase 1/2/3 clinical studies. Efficacy and safety data from the Phase 3, randomized, open-label study (GS-US-312-0119) were included in the PK/PD analyses.

Efficacy endpoints including best overall response rate (BOR), duration of response (DOR), progression -free survival (PFS), sum of products of the greatest perpendicular diameters (SPD) of index lesions, and lymph node response rate (LNR) were evaluated against idelalisib plasma exposure (AUC_tau and C_tau). Safety endpoints evaluated included ≥ Grade 3 neutropenia, skin rash, infection, pneumonia, pneumonitis, diarrhea, colitis, and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation versus idelalisib and GS-563117 plasma exposure (AUC_tau and C_max). Kaplan-Meier survival analysis, Cox proportional hazard model/Logistic regression analyses were conducted for key efficacy and safety endpoints.

Results:

Median idelalisib exposures were similar between responders (complete response [CR] or partial response [PR]) versus nonresponders (stable disease [SD] or progressive disease [PD]) and across the 4 response categories (p≥0.67; Table 1). As idelalisib exposure increased over quartiles, there was no clear trend of prolonged DOR (p≥0.49), PFS (p≥0.15) or change in SPD. No relationship between LNR (responder versus non-responder) and idelalisib exposures was observed.

No association was observed between idelalisib or GS-563117 plasma exposure vs incidence of neutropenia, diarrhea (p≥0.50), skin rash, infection (p≥0.18), pneumonia (p≥0.38), pneumonitis (p≥0.20), colitis (p≥0.43), and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation.

Conclusions:

No exposure-response relationships were observed for efficacy or safety endpoints at idelalisib 150 mg BID. These results are consistent with previous findings of exposure to idelalisib in subjects with CLL (in combination with rituximab) and iNHL and support idelalisib 150 mg BID in combination with ofatumumab for the treatment of CLL.

Table 1: Summary of idelalisib C_tau in Study GS-US-312-0119 based on BOR category/status

	BOR Category		BOR Status
	Responder	Non-responder	CR	PR	SD	PD
N	131	40	1	130	30	1
Median (ng/mL)	353	377	298	353	338	583
Q1, Q3 (ng/mL)	229, 518	268, 504	298, 298	229, 518	233, 433	583, 583
Min, Max (ng/mL)	76.2, 1529	62, 1184	298, 298	76.2, 1529	62, 1184	583, 583

CR: complete responder, PR: partial responder, SD: stable disease, PD: progressive disease.

CR and PR were responder; SD and PD were non-responder.