Safety and Clinical Activity of the Programmed Death-Ligand 1 Inhibitor Durvalumab in Combination With Poly (ADP-Ribose) Polymerase Inhibitor Olaparib or Vascular Endothelial Growth Factor Receptor 1-3 Inhibitor Cediranib in Women's Cancers: A Dose-Escalation, Phase I Study

Abstract

Purpose Data suggest that DNA damage by poly (ADP-ribose) polymerase inhibition and/or reduced vascular endothelial growth factor signaling by vascular endothelial growth factor receptor inhibition may complement antitumor activity of immune checkpoint blockade. We hypothesize the programmed death-ligand 1 (PD-L1) inhibitor, durvalumab, olaparib, or cediranib combinations are tolerable and active in recurrent women's cancers. Patients and Methods This phase I study tested durvalumab doublets in parallel 3 + 3 dose escalations. Durvalumab was administered at 10 mg/kg every 2 weeks or 1,500 mg every 4 weeks with either olaparib tablets twice daily or cediranib on two schedules. The primary end point was the recommended phase II dose (RP2D). Response rate and pharmacokinetic analysis were secondary end points. Results Between June 2015 and May 2016, 26 women were enrolled. The RP2D was durvalumab 1,500 mg every 4 weeks with olaparib 300 mg twice a day, or cediranib 20 mg, 5 days on/2 days off. No dose-limiting toxicity was recorded with durvalumab plus olaparib. The cediranib intermittent schedule (n = 6) was examined because of recurrent grade 2 and non-dose-limiting toxicity grade 3 and 4 adverse events (AEs) on the daily schedule (n = 8). Treatment-emergent AEs included hypertension (two of eight), diarrhea (two of eight), pulmonary embolism (two of eight), pulmonary hypertension (one of eight), and lymphopenia (one of eight). Durvalumab plus intermittent cediranib grade 3 and 4 AEs were hypertension (one of six) and fatigue (one of six). Exposure to durvalumab increased cediranib area under the curve and maximum plasma concentration on the daily, but not intermittent, schedules. Two partial responses (≥15 months and ≥ 11 months) and eight stable diseases ≥ 4 months (median, 8 months [4 to 14.5 months]) were seen in patients who received durvalumab plus olaparib, yielding an 83% disease control rate. Six partial responses (≥ 5 to ≥ 8 months) and three stable diseases ≥ 4 months (4 to ≥ 8 months) were seen in 12 evaluable patients who received durvalumab plus cediranib, for a 50% response rate and a 75% disease control rate. Response to therapy was independent of PD-L1 expression. Conclusion To our knowledge, this is the first reported anti-PD-L1 plus olaparib or cediranib combination therapy. The RP2Ds of durvalumab plus olaparib and durvalumab plus intermittent cediranib are tolerable and active. Phase II studies with biomarker evaluation are ongoing.

Figures

Fig 1.

(A) Duration in the study, and (B, C) best response. Color code defines dose level of treatment with arbitrary patient number assignment. Blue, gold, and gray horizontal bars represent dose levels (DL) 1 to 3, respectively. Patients are denoted as follows: patients with ovarian cancer (gold squares), and two with triple-negative breast cancer in durvalumab plus olaparib (D + O) arm and two cervical and three endometrial cancers in durvalumab plus cediranib (D + C) arm are unmarked. The blue dot indicates patients with partial response. The red arrows indicate those who received drug at data lock. The gray diamond indicates patients who received poly (ADP-ribose) polymerase inhibitor (PARPi) before study enrollment. Homologous recombination deficiency (HRD) status is marked as a triangle (red, RAD51C methylation; blue, BRCA1 methylation; pink, BRCA2 somatic mutation; gold, BRCA1 somatic mutation). One patient receiving D + O had clinical progression before the first restaging scans. One of 12 evaluable patients receiving D + C had clinical progression before the first restaging scans. R, platinum-resistant recurrent ovarian cancer; S, platinum-sensitive recurrent ovarian cancer.

Fig 1.

(A) Duration in the study, and (B, C) best response. Color code defines dose level of treatment with arbitrary patient number assignment. Blue, gold, and gray horizontal bars represent dose levels (DL) 1 to 3, respectively. Patients are denoted as follows: patients with ovarian cancer (gold squares), and two with triple-negative breast cancer in durvalumab plus olaparib (D + O) arm and two cervical and three endometrial cancers in durvalumab plus cediranib (D + C) arm are unmarked. The blue dot indicates patients with partial response. The red arrows indicate those who received drug at data lock. The gray diamond indicates patients who received poly (ADP-ribose) polymerase inhibitor (PARPi) before study enrollment. Homologous recombination deficiency (HRD) status is marked as a triangle (red, RAD51C methylation; blue, BRCA1 methylation; pink, BRCA2 somatic mutation; gold, BRCA1 somatic mutation). One patient receiving D + O had clinical progression before the first restaging scans. One of 12 evaluable patients receiving D + C had clinical progression before the first restaging scans. R, platinum-resistant recurrent ovarian cancer; S, platinum-sensitive recurrent ovarian cancer.

Fig 2.

Pharmacokinetic (PK) effects of durvalumab on olaparib or cediranib. (A) PK effects of durvalumab with olaparib. There was a significant (P = .004) matched-pairs difference (Wilcoxon matched-pairs signed rank test) in dose-normalized area under the curve (AUC/D; nine of 10 patients had increasing exposure), consistent with prior multiple-dose olaparib tablet monotherapy (ratio of approximately 1.5 and reflecting time-dependent cytochrome P450 3A4 [CYP3A4] inhibition), although the mean values (unpaired analysis from Mann-Whitney test, P = .089) were not statistically different, suggesting that durvalumab does not affect the PK of olaparib. (B) Exposure to durvalumab increases cediranib AUC and (C) maximum plasma concentration (Cmax) with the daily cediranib schedule, because of (D) decreased cediranib clearance. Two of eight patients had no samples after durvalumab for PK analysis. Seven of eight patients before durvalumab and five of six patients after durvalumab had calculable elimination rates for AUC calculation. There did seem to be greater AUCτ/D in two patients who developed pulmonary hypertension (one; gold open square) and colitis (one; gold open circle). (E, F) Exposure to durvalumab does not increase cediranib AUC and Cmax with intermittent cediranib schedule. The cediranib schedule of 5 days on, 2 days off provided sufficient washout time to avoid measurable cediranib PK changes in the presence of durvalumab. AUCinf, area under the plasma concentration versus time curve from time zero to infinity; CL/F, apparent oral total systemic clearance (first dose); CLss/F, apparent oral total systemic clearance at steady state.

Fig 3.

Carcinoma cell PD-L1 labeling is seen in responders and nonresponders. Patient 012 had a partial response ≥ 15 months. Her high-grade serous ovarian cancer (arrow) contained (A) 3+ tumor-infiltrating lymphocytes (TILs; stars; hematoxylin and eosin, × 200), with (B) both TIL (stars) and carcinoma cell (arrow) PD-L1 labeling (PD-L1, × 200). Patient 002 had progressive disease while in the trial. (C) Her primary high-grade serous ovarian cancer (arrow) contains minimal TILs (hematoxylin and eosin, × 200), but (D) exhibits carcinoma cell (arrow) PD-L1 positivity (PD-L1, × 200).

Fig A1.

CA125 response. Serial serum CA125 measurements were performed in 18 patients with ovarian cancer (10 who received durvalumab plus olaparib [D + O] and eight who received durvalumab plus cediranib [D + C]). Color code defines dose level of treatment with arbitrary patient number assignment: blue, gold, and gray horizontal bars represent dose levels (DL) 1 to 3, respectively.

Fig A2.

Pharmacokinetic parameters. Exposure to durvalumab does not affect olaparib (A) maximum plasma concentration (Cmax) and (B) clearance. There were no significant differences in any dose-normalized or dose-independent pharmacokinetic parameters for olaparib alone before durvalumab (first dose) versus olaparib after durvalumab (steady state). (C) Exposure to durvalumab does not decrease cediranib clearance with intermittent cediranib schedule. The cediranib intermittent schedule (5 days on/2 days off) demonstrated sufficient washout of cediranib in the presence of durvalumab. CL/F, apparent oral total systemic clearance (first dose); CLss/F, apparent oral total systemic clearance at steady state.

Fig A3.

Interferon (IFN)-γ and interleukin (IL)-6. There were no significant differences in IFN-γ and IL-6 between pretreatment and (A, E) post durvalumab plus olaparib (D + O) or (B, F) durvalumab plus cediranib (D + C), irrespective of the schedule of cediranib (once-daily cediranib [C, G] and intermittent cediranib [D, H]). (G) There was no significant increase of IL-6 in two patients who developed pulmonary hypertension (one; gold open square) and colitis (one; gold open circle).