Durvalumab Combos Tested in Women's Cancers, and to be Tested in Basket Trial

Jung-min Lee, MD

Durvalumab, an investigational PD-L1 targeting drug, is the subject of a unique ongoing basket trial being conducted by the National Institutes of Health, according to a poster presented June 3, 2016 at the ASCO Annual Meeting in Chicago.¹

The poster reported data from a single arm phase I combination therapy study of the drug in 19 patients with cervical cancer, triple negative breast cancer (TNBC), ovarian cancer, or uterine leiomyosarcoma.

The trial combined durvalumab with olaparib (Lynparza), a PARP inhibitor that has been approved by the FDA and EMA as fourth-line therapy for advanced ovarian cancer patients with germlineBRCAmutations, or cediranib, a VEGF inhibitor that previously failed experimental efforts in colorectal cancer, kidney cancer, and non—small cell lung cancer (NSCLC). The antitumor activity of durvalumab was expected to complement either inhibitor in the treatment of women’s cancers.

Researchers found that the combination of durvalumab and olaparib was tolerable and active in ovarian cancer and TNBC patients. Intriguingly, researchers also found the combination effective in patients without germlineBRCAtumors, yielding a 67% disease control rate in such patients.

Study of the durvalumab plus cediranib combination will continue and will analyze a new intermittent dosage schedule.

“Normally we don’t expect single agent activity inBRCAwild-type patients, but researchers at ASCO 2014 presented data showing that olaparib had efficacy in non-hereditary cancers.²Six out of 12 wild type patients are still on the study with a durable response, and 1 of the 12 is on the study with a partial response,” said Jung-min Lee, MD, assistant clinical investigator at the NIH Center for Cancer Research in Bethesda, Maryland, and lead author of the study.

Two Thirds of Non-Germline BRCA Patients Experience Benefit

In the study, 19 cancer patients with good end-organ function received durvalumab with either olaparib or cediranib in parallel dose escalations. The median age of subjects was 66 (range 39-70), and they had received a median of 4 prior therapies. Those in the olaparib arm included 10 ovarian cancer patients and 2 TNBC patients. The cediranib cohort included 4 ovarian cancer patients, 2 cervical cancer patients, and 1 uterine leiomyosarcoma patient.

“What we know is that the combination is well-tolerated, with interesting activity in non-BRCAmutation patients. Durvalumab plus cediranib has more activity based on continuous dosing of cediranib, but maybe it’s not tolerable, so I’m testing a regiment of 5 days on, 2 days off,” said Lee. “We already have 6 patients on the new dose level cohort, and I think I will present data at the 2017 AACR meeting,” she added.

There were 8 incidents of grade 3/4 adverse events (AEs) experienced by 7 patients out of 12 (58%) in the olaprib arm, including 2 cases of hypertension, 1 case of pulmonary hypertension, and 2 cases of pulmonary embolism. In the cediranib arm, grade 3/4 AEs included 2 patients each (29%) with hypertension, diarrhea, or pulmonary embolism, and 1 patient each (14%) with pulmonary hypertension or lymphopenia.

Five patients in the cediranib arm required dosage reductions, including 1 in the first dosage level group, and 4 in the second dosage level group, while 2 patients in the first group required early discontinuation from cediranib treatment due to pulmonary embolism. No olaparib discontinuations were reported.

In the olaparib arm, 1 patient had a partial response (PR), and 5 patients had stable disease (SD) for at least 4 months. Two patients receiving durvalumab plus cediranib had PR and 2 patients had SD for at least 4 months.

Basket Trial in the Works

“We are looking at a different patient population that is not yet molecularly defined. Dr. Lee is identifying responders. But we have not developed this drug ourselves; based on Dr. Lee’s scientific interest, she sought it out,” explained Christina Annunziata, MD, PhD, clinical director of the women’s malignancy branch at the NCI, and co-author of the poster.

“This study is looking at all-comers, it’s not a gene-oriented therapy, but the NCI is a biomarker-oriented scientific organization, so in phase II, we’re collecting tissue samples before and after treatment. We’re looking at pathways of gene mutations, including some 50 to 60 genes. For example, in addition to germlineBRCA, we are looking at ATM, RAD 51, and RAD 51c,” Lee added.

“Phase II is like a basket trial, because the drug has potential benefit in all of these disease types. For example, in ovarian cancer, we intend to recruit 35 patients in each arm (durvalumab with olaparib or cedirinab),” Lee noted. The researchers plan to do the same for NSCLC patients, but plan to try durvalumab only with olaprib in subjects with TNBC, prostate, or small cell lung cancer, she said.

Lee J, Dos A, Zimmer S, et al. Phase I study of the PD-L1 inhibitor, durvalumab (MEDI4736; D) in combination with a PARP inhibitor, olaparib (O) or a VEGFR inhibitor, cediranib (C) in women's cancers (NCT02484404).J Clin Oncol.2016;34 (suppl; abstr 3015).

Liu J, Barry WT, Birrer MJ, et al. A randomized phase 2 trial comparing efficacy of the combination of the PARP inhibitor olaparib and the antiangiogenic cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer.J Clin Oncol.32:5s, 2014 (suppl; abstr LBA5500).