Phase 2 BilT-02 Trial: Rucaparib and Nivolumab as Maintenance Therapy Following Chemotherapy in Patients With Advanced BTC

To improve survival in patients with biliary tract cancer, researchers are studying combinations of immunotherapy and poly-ADP ribose polymerase inhibitors; the BilT-02 study is summarized.

Despite chemotherapy, patients with advanced biliary tract cancer (BTC) have a median overall survival (OS) of <12 months.¹ The TOPAZ-1 trial found that durvalumab and gemcitabine/cisplatin (GemCis) was more effective than GemCis alone in patients with advanced BTC, which led to the addition of durvalumab to the current standard of care (GemCis) in these patients.^2,3 Research into immunotherapies and poly-ADP ribose polymerase (PARP) inhibitors is being conducted to improve outcomes for patients with advanced BTC. Nivolumab, a PD-1 inhibitor, prevents PD-1 on T cells from interacting with PD ligands, such as PD-L1 and PD-L2, on tumor cells, thereby restoring a patient’s tumor-specific T-cell response.^3,4 In addition, research suggests that cells with IDH1 mutations have a reduced capacity to repair double-stranded DNA breaks, potentially making them extremely vulnerable to PARP inhibition.⁵ Vaibhav Sahai, MBBS, MS, presented the findings from the BilT-02 study at the 2023 ASCO meeting.³

In BilT-02, a phase 2, multicenter trial, patients with advanced BTC who had progressed after receiving first-line platinum-based chemotherapy were given the PARP inhibitor rucaparib and the PD-1 inhibitor nivolumab as maintenance therapy.

In BilT-02, a phase 2, multicenter trial, patients with advanced BTC who had progressed after receiving first-line platinum-based chemotherapy were given the PARP inhibitor rucaparib and the PD-1 inhibitor nivolumab as maintenance therapy. The purpose of this trial was to investigate the potential for improved outcomes in patients with advanced BTC receiving rucaparib and nivolumab as maintenance therapy after chemotherapy. The primary study objective was to determine the progression-free survival (PFS) rate at 4 months of maintenance treatment with rucaparib and nivolumab.³ The secondary objective was to assess the clinical efficacy of this maintenance regimen by median PFS1 and OS1 (from start of study treatment), PFS2 and OS2 (from start of first-line platinum chemotherapy), and best objective response rate.³ A total of 31 patients with advanced BTC who were not eligible for curative resection and had received first-line platinum-based chemotherapy for 4 to 6 months without progression were enrolled in BilT-02.³ Of these, 19 had intrahepatic cholangiocarcinoma (CCA), 4 had extrahepatic distal CCA, and 7 had extrahepatic hilar CCA.³ Patients received 240 mg of nivolumab intravenously on days 1 and 15 and 600 mg of rucaparib orally twice a day on days 1 to 28 until disease progression or intolerance.³ The primary end point was not met, and the observed PFS rate at 4 months was 54.8%.³ The estimated median for PFS1 was 4.6 months, OS1 was 15.9 months, PFS2 was 9.9 months, and OS2 was 21.4 months.³

The most common grade ≥3 treatment-related adverse events included fatigue (29%), anemia (22.6%), neutropenia (19.3%), and elevated aspartate aminotransferase (16.1%) and alanine transaminase (12.9%).³ Although the primary end point was not met, this combination therapy was well tolerated, and initial efficacy observations warrant further evaluation of rucaparib and nivolumab as maintenance therapy in patients with advanced BTC.³

References

1. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273-1281.
2. Oh D-Y, He AR, Qin S, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer (TOPAZ-1). NEJM Evid. 2022;1(8).
3. Sahai V, Griffith KA, Mohan A, et al. Phase 2 multicenter trial of rucaparib and nivolumab as maintenance therapy following first-line platinum-based chemotherapy in patients with advanced biliary tract cancer. Poster presented at: ASCO 2023 Annual Meeting, June 2-6, 2023; Chicago, IL.
4. Guo L, Zhang H, Chen B. Nivolumab as programmed death-1 (PD-1) inhibitor for targeted immunotherapy in tumor. J Cancer. 2017;8(3):410-416.
5. Sulkowski PL, Corso CD, Robinson ND, et al. 2-hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci Transl Med. 2017;9(375).