Activity of durvalumab in advanced endometrial cancer (AEC) according to mismatch repair (MMR) status: The phase II PHAEDRA trial (ANZGOG1601).

Abstract

5501 Background: Deficient DNA mismatch repair (dMMR) occurs in approximately 15% of AEC and is associated with a high tumour mutation burden. Expression of PD-1 and PD-L1 has been reported in up to 90% of ECs, including those with proficient DNA mismatch repair (pMMR). We report here preliminary results of PHAEDRA, a single-arm phase 2 trial designed to determine the activity of single-agent durvalumab, an antibody to PD-L1, in 2 cohorts of women with AEC. Methods: Participants (pts) had pMMR AEC progressing after 1-3 lines of chemotherapy, or dMMR AEC progressing after 0-3 lines of chemotherapy, and were treated with durvalumab 1500mg IV Q4W. The primary endpoint was objective tumour response (OTR = complete response [CR] or partial response [PR] by iRECIST). Secondary endpoints included disease control at 16 weeks (DC16w = CR, PR, or stable disease at 16 weeks [SD16w]), immune-related adverse events (irAEs), PD-L1, germline mutations and MLH1 methylation. Other secondary endpoints include: OTR and DC by RECIST1.1, other AE, PFS, OS & quality of life will be reported later. Results: 71 pts with AEC were recruited from Feb 2017 to Sep 2018: 35 dMMR and 36 pMMR. Median follow-up were 8.3 vs 14.8 months in dMMR vs pMMR pts. Median age: 67 (range 36-81); ECOG PS: 0-1 in 68, and 2 in 3. Pathology: endometrioid in 94% and 58%; serous in 0% and 31%; grade: high in 42% and 83% (dMMR and pMMR respectively). Durvalumab was the 1st, 2nd and subsequent line of non-hormonal therapy in 15, 14, and 6 pts with dMMR and 0, 21, and 15 pts with pMMR. Among dMMR pts, the OTR rate was 40% (14/35, 95% CI 26-56), with 4 CR and 10 PR; 7 others had SD 16w for a DC16w rate of 60% (21/35, 95% CI 44-74). OTR rate was 40% as 1st line, 43% as 2nd line, and 33% as subsequent line treatment. Among pMMR pts, the OTR rate was 1/36 (3%, 95% CI 1-14) with 1 PR; 6 others had SD16w for a DC16w rate of 19% (7/36; 95% CI 10-35). IrAEs occurred in 14 pts: hyperthyroidism in 6, hypothyroidism in 6, pneumonitis in 1 and hepatitis in 1. Conclusions: Durvalumab monotherapy showed promising activity and safety in AEC with dMMR regardless of prior lines of chemotherapy, but there was limited evidence of activity in AEC with pMMR. Clinical trial information: ACTRN12617000106336.