Pembrolizumab plus olaparib after induction with pembrolizumab and chemotherapy for locally recurrent inoperable or metastatic TNBC
Results from the phase II KEYLINK-009 study demonstrated that the combination of pembrolizumab and olaparib resulted in similar efficacy outcomes compared with continued chemotherapy and pembrolizumab in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) who had clinical benefit from induction with first-line pembrolizumab plus platinum-based chemotherapy. Importantly, the combination of pembrolizumab and olaparib resulted in a more favourable safety profile.
In the phase III KEYNOTE-355 study, pembrolizumab plus chemotherapy (chemo) showed statistically significant improvements in progression-free survival (PFS) and overall survival (OS) vs. placebo plus chemo in patients with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) whose tumours expressed PD-L1 with a combined positive score (CPS) ≥10. However, tolerable and effective maintenance regimens after induction therapy are needed to sustain clinical benefit. The PARP inhibitor olaparib is an established maintenance therapy for multiple platinum-sensitive tumour types and prior data suggest that PARP inhibitors combined with PD-1/PD-L1 inhibitors could provide an improved therapeutic effect. Therefore, the KEYLINK-009 study evaluates the efficacy and safety of maintenance pembrolizumab plus olaparib vs. pembrolizumab plus chemo in patients with locally recurrent inoperable or metastatic TNBC who had clinical benefit from induction with first-line pembrolizumab plus platinum-based chemo.
Study design
Eligible patients with measurable, locally recurrent inoperable or metastatic TNBC that had not been previously treated with chemo in the metastatic setting received induction therapy for up to 6 cycles of pembrolizumab 200 mg + chemo (carboplatin AUC 2 + gemcitabine 1.000 mg/m2 on days 1 and 8) every 3 weeks (Q3W). Patients with complete response (CR), partial response (PR), or stable disease (SD) after 4-6 treatment cycles were randomised 1:1 to receive pembrolizumab 200 mg Q3W + olaparib 300 mg twice daily or pembrolizumab + chemo (continued induction regimen). Olaparib or chemo was continued until progression or unacceptable toxicity. Pembrolizumab was continued for up to 35 cycles (including induction treatment), progression, or unacceptable toxicity. Patients were stratified by induction response (CR or PR vs. SD, by RECIST v1.1), tumour PD-L1 status (CPS ≥1 vs. CPS < 1), and tumour genomic status (tBRCAm vs. tBRCAwt). Dual primary endpoints were PFS per RECIST v1.1 by BICR and OS from randomisation in all patients.
Results
In total, 460 patients received induction treatment with pembrolizumab and chemotherapy. Of them, 271 patients were randomly allocated to pembrolizumab plus olaparib (N= 135) or pembrolizumab plus chemo (N= 136). At the data cut-off on December 15th, 2022, the median follow-up was 17.2 months. Maintenance treatment with pembrolizumab and olaparib did not significantly improve PFS (HR[95%CI]: 0.98[0.72-1.33], p= 0.4556) or OS (HR[95%CI]: 0.95[0.64-1.40]) as compared to pembrolizumab and chemo. The 6- and 12-month PFS and 12- and 18-month OS rates were highly comparable between both treatment arms in the ITT population. However, median PFS was longer with pembrolizumab plus olaparib vs. pembrolizumab plus chemo in patients with tBRCAm (median PFS of 12.4 and 8.4 months, respectively, HR[95%CI]: 0.70[0.33-1.48]).
With regard to safety, any-grade treatment-related adverse events (TRAEs) occurred in 84.4% and 96.2% of patients on pembrolizumab plus olaparib and pembrolizumab plus chemo, respectively. Grade 3-5 TRAEs were less frequent in the pembrolizumab plus olaparib arm as compared to the pembrolizumab plus chemotherapy arm (32.6% vs. 68.4%), with no grade 5 event in the olaparib arm, as compared to two events in the chemotherapy arm. A total of 8.9% and 19.5% of patients, respectively, experienced a TRAE that led to treatment discontinuation. Additionally, any-grade and grade 3-4 immune-mediated AEs and infusion reactions occurred in 19.3% and 4.4% of patients on pembrolizumab plus olaparib vs. 23.3% and 4.5% of those on pembrolizumab plus chemotherapy. Overall, haematologic toxicities and infusion reactions were more frequent with chemotherapy than with olaparib.
Conclusion
After induction pembrolizumab plus chemotherapy for metastatic TNBC, pembrolizumab plus olaparib in an unselected population with responding or stable disease showed similar efficacy outcomes compared to continued pembrolizumab plus chemotherapy. However, in patients with tBRCAm, there was a positive trend for PFS and OS for those receiving pembrolizumab plus olaparib vs. pembrolizumab plus chemotherapy. The treatment-related AE profile observed in patients treated with pembrolizumab plus olaparib was consistent with the known safety profiles of both monotherapies and a lower incidence of TRAEs was reported in patients receiving pembrolizumab plus olaparib vs. pembrolizumab plus chemotherapy.
Reference
Rugo H, et al. Pembrolizumab + Olaparib vs Pembrolizumab + Chemotherapy After Induction With Pembrolizumab + Chemotherapy for Locally Recurrent Inoperable or Metastatic TNBC: Randomized Open-Label Phase 2 KEYLYNK-009 Study. Presented at SABCS 2023; Abstract GS01-05.
