Abstract
BackgroundStrategies to improve activity of immune checkpoint inhibitors are needed. We hypothesized enhanced DNA damage by olaparib, a PARP inhibitor, and reduced VEGF signaling by cediranib, a VEGFR1–3 inhibitor, would complement anti-tumor activity of durvalumab, a PD-L1 inhibitor, and the 3-drug combination would be tolerable.MethodsThis phase 1 study tested the 3-drug combination in a 3 + 3 dose escalation. Cediranib was taken intermittently (5 days on/2 days off) at 15 or 20 mg (dose levels 1 and 2, respectively) with durvalumab 1500 mg IV every 4 weeks, and olaparib tablets 300 mg twice daily. The primary end point was the recommended phase 2 dose (RP2D). Response rate, pharmacokinetic (PK), and correlative analyses were secondary endpoints.ResultsNine patients (7 ovarian/1 endometrial/1 triple negative breast cancers, median 3 prior therapies [2–6]) were treated. Grade 3/4 adverse events include hypertension (1/9), anemia (1/9) and lymphopenia (3/9). No patients experienced dose limiting toxicities. The RP2D is cediranib, 20 mg (5 days on/2 days off) with full doses of durvalumab and olaparib. Four patients had partial responses (44%) and 3 had stable disease lasting ≥6 months, yielding a 67% clinical benefit rate. No significant effects on olaparib or cediranib PK parameters from the presence of durvalumab, or the co-administration of cediranib or olaparib were identified. Tumoral PD-L1 expression correlated with clinical benefit but cytokines and peripheral immune subsets did not.ConclusionsThe RP2D is tolerable and has preliminary activity in recurrent women’s cancers. A phase 2 expansion study is now enrolling for recurrent ovarian cancer patients.Trial registrationClinicalTrials.gov identifier: NCT02484404. Registered June 29, 2015.
Highlights
Immunotherapy has emerged as a major therapeutic modality in oncology
The combination of olaparib and cediranib, a VEGFR1–3 inhibitor, has been demonstrated to be clinically superior to olaparib monotherapy in recurrent platinum-sensitive ovarian cancer [8]. We extended this concept with our hypothesis that reduced VEGF signaling by cediranib and increased DNA damages by olaparib would complement anti-tumor activity of the immune checkpoint inhibitor
Dose optimization and toxicities The dose level 2 was identified as the recommended phase 2 dose (RP2D), with durvalumab 1500 mg IV every 4 weeks in combination with olaparib 300 mg twice daily and cediranib 20 mg daily (5 days on/2 days off )
Summary
The majority of patients with women’s cancers do not derive benefit from immune checkpoint blockade monotherapy, creating the need to optimize combination treatment strategies [1]. Data suggest increased DNA damage by radiation or DNA repair inhibitors promotes local antigen release resulting in systemic anti-tumor immune responses [2]. Such neoantigen release and high tumor mutational burden (TMB) are shown to be associated with clinical response to immune checkpoint inhibition in solid tumors [3]. Increased DNA damages from PARPi exposure may yield greater TMB, potentially increasing neoantigens, and affect the immune milieu, complementing the clinical benefit of immune checkpoint blockade in subsets of recurrent women’s cancer. We hypothesized enhanced DNA damage by olaparib, a PARP inhibitor, and reduced VEGF signaling by cediranib, a VEGFR1–3 inhibitor, would complement anti-tumor activity of durvalumab, a PD-L1 inhibitor, and the 3-drug combination would be tolerable
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