Phase 2 study of pembrolizumab (pembro) monotherapy for previously treated metastatic triple-negative breast cancer (mTNBC): KEYNOTE-086 cohort A.

Abstract

1008 Background: In KEYNOTE-012, pembro showed durable activity and manageable safety in patients (pts) with PD-L1+ mTNBC. Cohort A of KEYNOTE-086 (NCT02447003) examined the efficacy/safety of pembro in previously treated mTNBC, regardless of PD-L1 expression. Methods: Pts with centrally confirmed mTNBC, ≥1 prior chemotherapy for metastatic disease, and ECOG PS 0-1 had pembro 200 mg Q3W for up to 24 mo; imaging q 9 wk for the first 12 mo, then q 12 wk. Clinically stable pts with PD could remain on pembro until PD confirmed on next assessment. Primary endpoints: ORR (RECIST v1.1, central review) in all pts and pts with PD-L1+ tumors, and safety. Secondary endpoints: DOR, disease control rate (DCR; CR + PR + SD ≥24 wk), PFS, and OS. Planned enrollment was 160 pts; analysis based on data as of Nov 10, 2016. Results: 60% of screened PD-L1-evaluable pts had PD-L1+ tumors (combined positive score ≥1%). Of 170 pts enrolled (100% women; median age 54 y), 44% had ≥3 prior lines of therapy, 51% had elevated LDH, 74% had visceral mets and 62% had PD-L1+ tumors. After a median follow-up of 10.9 mo, 9 (5%) pts remained on pembro. Treatment-related AEs (TRAEs) of any grade and grade 3-4 occurred in 60% and 12% of pts, respectively; 4% discontinued due to TRAEs. There were no deaths due to AE. Overall ORR was 5% regardless of PD-L1 expression (Table). Best overall response was 0.6% CR, 4% PR, 21% SD; not evaluable (3%). DCR was 8% (95% CI 4-13). Median DOR was 6.3 mo (range 1.2+ to 10.3+); 5 (63%) responders w/o PD at data cutoff. Median PFS and OS were 2.0 mo (95% CI 1.9-2.0) and 8.9 mo (95% CI 7.2-11.2), with 6-mo rates of 12% and 69%, respectively. ORR was numerically lower in pts with poor prognostic factors (e.g., high LDH, liver/visceral mets; Table). Conclusions: In KEYNOTE-086 Cohort A, pembro monotherapy showed manageable safety and durable responses in a subset of pts with heavily pretreated mTNBC. Randomized studies of monotherapy and combination therapy are ongoing. Clinical trial information: NCT02447003. [Table: see text]

Targeting immune checkpoints in breast cancer: an update of early results

“…37 Results have been reported for cohorts A and B, but not yet for cohort C. For the 170 previously treated patients enrolled in cohort A, RR was 4.7% regardless of PD-L1 positivity, with 1 CR and 7 PRs. 36 In subgroup analyses, objective response rate (ORR) was improved in patients with a low tumour burden, normal LDH at baseline and non-visceral disease and appeared independent of PD-L1 expression. Preliminary results for the first 52 untreated patients preselected based on PD-L1 expression enrolled in cohort B revealed an ORR of 23.1%, whereas stable disease (SD) (≥24 weeks) and PD were observed in 17% and 58% of the patients, Solinas respectively.…”

“…ICB agents targeting inhibitory molecules expressed on the surface of immune cells, such as cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1) or its ligand, the programmed death-ligand 1 (PD-L1) expressed by both tumour and immune cells, have been evaluated in several early-phase trials in BC. [31][32][33][34][35][36][37][38][39][40][41] In the metastatic setting, these drugs showed promising results as single agents, with higher response rates (RRs) observed in the TNBC subtype, 32 PD-L1-positive tumours 32 33 and also in combination with chemotherapy (CT). 35 38 More recent studies have revealed that the PD-1/PD-L1 blockade combined with CT in the neoadjuvant setting increases pathological complete response (pCR) rates with manageable safety profiles in TNBC and HER2-negative BC.…”

“…Patients were split into three cohorts depending on their clinical treatment setting and PD-L1 status (table 1). A combined positive score (CPS) evaluating PD-L1 expression on tumour and immune cells was used to determine PD-L1 status and was positive in 62% of the tumours in cohort A 36 and in 58% of the screened tumours in cohort B. 37 Results have been reported for cohorts A and B, but not yet for cohort C. For the 170 previously treated patients enrolled in cohort A, RR was 4.7% regardless of PD-L1 positivity, with 1 CR and 7 PRs.…”

Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer

“…Among 27 evaluable patients with a median of 2 prior therapies for metastatic disease, the objective response rate was 18.5% [58]. The subsequent KEYNOTE-086 Phase II trial evaluated pembrolizumab in metastatic TNBC patients that were previously treated with any level of PD-L1 expression (Cohort A) and as 1st line treatment in patients with PD-L1+ status (Cohort B) [59]. Among 170 patients enrolled in cohort A, 105 (61.8%) had PD-L1+ status and 43.5% had received 3 or more prior lines of therapy.…”

Checkpoint Inhibitors in Breast Cancer - Current Status and Future Directions

“…In this trial, tumors were considered PD-L1-positive when PD-L1 was expressed in 5% of the infiltrating immune cells. The clinical activity of pembrolizumab in this subset has been confirmed by the analysis of an extended cohort of BC patients (n = 170) with an ORR of 23% in the first-line setting [14]. However, it is noteworthy that the efficacy of PD-(L)1 inhibitors in BC as a single agent appears to be modest.…”