Phase 2 Study of Copanlisib plus Gemcitabine and Cisplatin in Advanced CCA

2020 Year in Review: Cholangiocarcinoma — December 19, 2020

Preliminary results of a phase 2 study suggest that the addition of the PI3K inhibitor copanlisib to chemotherapy in the first-line setting was not associated with survival benefit in patients with advanced CCA.

While chemotherapy with gemcitabine and cisplatin remains the current standard of care as first-line therapy for patients with advanced CCA, survival outcomes are suboptimal with a median OS of <1 year, underscoring the need for novel approaches to improve treatment outcomes.1 Based on the rationale that PI3K/AKT activation may increase resistance to chemotherapy, it is hypothesized that inhibiting the PI3K/AKT axis may improve outcomes.2

Copanlisib (Aliqopa) is a potent and reversible pan-class 1 PI3K inhibitor, with pilot studies showing promising activity in patients with biliary cancers.3 Therefore, a phase 2 study (NCT02631590) is evaluating the safety and efficacy of copanlisib in combination with gemcitabine and cisplatin in advanced CCA, the results of which were presented at the American Society of Clinical Oncology (ASCO) 2020 Gastrointestinal Cancers Symposium.

The study enrolled patients with histologically confirmed or advanced unresectable BTC or gallbladder cancer including CCA between July 2016 and April 2019, who were chemotherapy-naïve, although adjuvant chemotherapy with or without radiation was permitted. Eligible patients received cisplatin 25 mg/m2, gemcitabine 1000 mg/m2, and copanlisib 60 mg on day 1 and day 8, administered on an every-21-days schedule. The primary end point was progression-free survival (PFS) at 6 months. Secondary end points were response rate, median overall survival (OS) and PFS, and safety and tolerability.

A total of 24 patients with advanced CCA and gallbladder cancer were enrolled, with a median age of 64 years (range, 35-80 years). The majority (62.5%) of enrolled patients were female and had intrahepatic CCA as the primary tumor location (N = 17; 70.8%); 16.7% of patients had extrahepatic CCA, and 12.5% gallbladder carcinoma. Of the 19 evaluable patients for tumor response assessment, 6 patients achieved partial response (31.5%) and stable disease was achieved by 11 patients (57.9%). The primary end point of the study was not met, with 6-month PFS of 57.9%, which was lower than the ≥72% prespecified criteria of success. Median PFS was 6.2 months (95% confidence interval [CI], 1.3-11.1) and median OS was 13.9 months (95% CI, 6.8-17.9). The 12-month PFS was 45.6%, 6-month OS was 73.9%, and 12-month OS was 53.2%. In terms of safety, grade ≥3 adverse events included decreased neutrophil count (54.1%), decreased lymphocyte count (37.5%), decreased platelet count (33%), hypertension (29.2%), anemia (29.2%), increased lipase (25%), and decreased white blood cell count (16.7%).

Based on these results, the addition of copanlisib to the gemcitabine and cisplatin platform did not provide any survival benefit as first-line treatment in patients with advanced CCA.

Source: Tan E, et al. J Clin Oncol. 2020;38(4_suppl). Abstract 556.

References

  1. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362:1273-1281.
  2. Leelawat K, Narong S, Udomchaiprasertkul W, et al. Inhibition of PI3K increases oxaliplatin sensitivity in cholangiocarcinoma cells. Cancer Cell Int. 2009;9:3.
  3. Lui N, Rowley BR, Bull CO, et al. BAY 80-6946 is a highly selective intravenous PI3K inhibitor with potent p110α and p110δ activities in tumor cell lines and xenograft models. Mol Cancer Ther. 2013;12:2319-2330.

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