Combination Therapy of Immune Checkpoint Therapy and PARP Inhibitors

PARP inhibitors could attenuate anticancer immunity via upregulating the level of PD-L1 in breast cancer cell lines and animal models. Inhibition of PD-L1 signaling resensitized PARP-treated cells to T-cell killing.48 The combination of PARP inhibition and PD-L1 blockade significantly delayed tumor outgrowth in vivo. The MEDIOLA trial (NCT02734004) evaluated whether the combination of olaparib and durvalumab could lead to clinical activity in BRCA1/2-mutated and HER-2-negative MBC. Eligible patients were not allowed to receive PARP inhibitors or immunotherapy, and had previous received no more than two lines of chemotherapy. Patients were administrated with 300mg bid olaparib daily for 4 weeks, followed by 1.5g intravenous durvalumab once every 4 weeks in addition to olaparib. The dual primary endpoints were disease control rate (DCR) at 12 weeks and safety. 34 patients were analyzed for safety, and 30 patients for efficacy analysis. The DCR at 12 weeks was 24/30 (80%). The DCR at 28 weeks was 15/30 (50%). 19 confirmed responses were observed. This combination was well-tolerated with safety consistent with the individual agent profiles.49 Conclusively, the combination of PARP inhibition and immune checkpoint therapy showed preliminary clinical activity in BRCA1/2-mutated HER-2-negative MBC.

The TOPACIO/Keynote-162 study (NCT02657889) evaluated the safety and efficacy of a combination therapy regimen with niraparib + pembrolizumab in patients with mTNBC. Patients were administrated with 200mg of oral niraparib once daily and 200mg of intravenous pembrolizumab on day 1 of each 21-day cycle. The primary endpoint was ORR. Recently, the preliminary results were reported. Forty-seven patients were evaluable for efficacy and treated with a median of 1 prior line of therapy in the metastatic setting. The ORR was 21%, including 5 CRs, 5 confirmed PRs, 13 SDs. Besides, of the 15 evaluable patients with BRCA mutations, 7 had objective responses (ORR was 47%; 90% CI, 24–70%), and median PFS was 8.3 months (95% CI, 2.1 months to not estimable). Among the 27 patients with tumor BRCA wild-type status, the ORR included 3 (11%; 90% CI, 3–26%), and median PFS was 2.1 months (95% CI, 1.4–2.5 months). The patients with germline BRCA1/2 mutations had higher ORR than patients with wild-type tumors. Patients with PD-L1-positive disease had better responses than those with PD-L1-negative cancers. Preliminary efficacy is encouraging with durable responses in patients with mTNBC.50,51 However, the previous trials have obvious limitations with the lack of a comparator arm. Therefore, we could not draw strong conclusions on the role of combination therapy in mTNBC management. The findings presented here need to be validated in a larger clinical trial.

Combination Therapy of Immune Checkpoint Therapy and Cyclin-Dependent Kinases 4/6 (CDK4/6) Inhibitors

Pharmacological inhibitors of CDK4/6 have shown significant activity in patients with ER-positive, HER2-negative metastatic breast cancer.52–54 Inhibition of CDK4/6 works primarily by suppressing retinoblastoma phosphorylation and inducing G1 cell cycle arrest in cancer cells. CDK4/6 inhibitors have been also proven to enhance anti-tumor immune response. It can stimulate the production of type III interferons, thereby increasing tumor antigen presentation. Besides, CDK4/6 inhibition could significantly inhibit the proliferation of immunosuppressive regulatory T cells.55 These findings indicate that there may be a clinically effective synergy between CDK4/6 inhibitors and immunotherapy. This has been validated in murine syngeneic tumor models. As a selective CDK4/6 inhibitor, monotherapy of Abemaciclib resulted in delayed tumor growth, which was associated with an increased T cell inflammatory signature in tumors.56 A phase I study (JPBJ, NCT02079636) investigated abemaciclib plus pembrolizumab in patients with HR+, HER2- MBC. The primary endpoint was to study the safety profile of combination therapy. Twenty-eight patients were enrolled. Four patients (14%) showed an objective response at 24 weeks. This response was higher than the response (11%) observed in patients treated with abemaciclib monotherapy at corresponding early time points in the MONARCH 1 study. Besides, the combination group demonstrated a generally manageable profile.57

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Dual Checkpoint Blockade Therapy

In melanoma, concurrent therapy with anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab) had a manageable safety profile. The deep and durable clinical tumor responses were observed in patients treated with the combination therapy comparing favorably to monotherapy with ipilimumab or nivolumab alone.58,59 This suggests that combination therapy could “rescue” participants who were less likely to respond to a single anti-PD1/PD-L1 agent. These data have inspired clinical trials of dual checkpoint blockade therapy in metastatic breast cancer, but only a small pilot study has reported outcomes to date. This single-arm pilot study was designed to determine the ORR of anti-PD-L1 (durvalumab) and anti-CTLA-4 (tremelimumab) in metastatic ER-positive BC and TNBC.60 18 patients were accrued (11 ER-positive breast cancer; 7 TNBC). 3 responses were achieved and only observed in patients with TNBC. Conclusively, in this small pilot study, combination durvalumab and tremelimumab have low response rates in unselected MBC; however, higher rates of clinical benefit were observed in TNBC. Further research is warranted in TNBC to confirm the findings.

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