Is there a role for combined anti–PD‐1/CTLA‐4 checkpoint blockade in the management of advanced biliary tract cancers?

Sahai et al. recently reported on a randomized phase 2 trial (BilT‐ 01) investigating chemoimmunotherapy (including the anti–PD‐1 antibody nivolumab) versus combined anti–PD‐1/CTLA‐4 checkpoint blockade (using nivolumab and ipilimumab) in patients with advanced biliary tract cancers. Although the trial did not meet its primary end point in either arm, the 24‐month survival in the chemoimmunotherapy arm was superior to that for historical controls treated with chemotherapy alone and was comparable to data that were recently reported from the phase 3 TOPAZ‐1 trial, which investigated the anti–PD‐L1 antibody durvalumab in combination with chemotherapy. Both trials (TOPAZ‐1 and BilT‐01) have demonstrated that approximately a quarter of patients treated with cisplatin/gemcitabine chemotherapy in combination with an anti– PD‐1/PD‐L1 antibody are alive at 2 years; this represents a substantial improvement over chemotherapy treatment alone. As pointed out by the authors, a currently ongoing phase 3 trial (KEYNOTE 966) is investigating the addition of the anti–PD‐1 antibody pembrolizumab to chemotherapy, and it may add further evidence supporting this treatment modality as a new standard of care for treatment‐naive patients with advanced biliary tract cancers. The efficacy of the combination immunotherapy using ipilimumab and nivolumab in BilT‐01 was disappointing, with the treatment cohort showing a low response rate and short progression‐free and overall survival; the authors did not discuss these findings in the context of already published data demonstrating significant activity of the same treatment regimen in pretreated patients with biliary tract cancer. CA209‐538 was a clinical trial using ipilimumab/nivolumab combination immunotherapy in patients with advanced rare malignancies; it was conducted at five academic centers in Australia. Thirty‐nine patients with advanced biliary tract cancers were enrolled, and an overall response rate of 23% was observed, with a subset of patients enjoying a durable response exceeding more than 4 years. The clinical benefit in this trial was limited to patients with intrahepatic cholangiocarcinoma and gallbladder carcinoma, and none of the enrolled patients had microsatellite‐unstable tumors, which are known to be exquisitely sensitive to checkpoint inhibitor therapy. The differences in clinical outcomes between CA209‐ 538 and BilT‐01 are not well explained and may be related to an inclusion bias due to the small but comparable numbers of patients treated in each trial (39 patients), the patient demographics, the anatomical subtypes, the lines of treatment (treatment‐naive vs. pretreated), or the nivolumab/ipilimumab dosing regimen. CA209‐538 used an induction regimen of four combination doses (every 3 weeks) followed by nivolumab maintenance treatment, whereas a continuous treatment regimen was administered in BilT‐01 with ongoing administration of ipilimumab every 6 weeks. Two other recent reports support the activity of ipilimumab/ nivolumab combination immunotherapy in patients with advanced biliary tract cancer who have progressed on chemotherapy and/or anti–PD‐1 monotherapy and subsequently have obtained durable responses to combination immunotherapy. In view of these findings, ipilimumab/nivolumab combination therapy may have a role in the treatment of advanced biliary tract cancers in later lines of therapy. Biomarker research will be crucial for better defining the patient population that derives a treatment benefit; the tumor mutation burden of the 39 patients with biliary tract cancer who were enrolled in CA209‐538 was overall low and did not differ between responders and nonresponders, whereas PD‐ L1 expression on tumor cells was enriched for response (O Klein MD, A Behren PhD May 2021). In addition, genomic aberrations in the homologous recombination DNA repair pathway may predict for a treatment response. Further studies are required to determine the benefit of ipilimumab/nivolumab combination treatment in biliary tract cancers. CA209‐6D6/MoST‐CIRCUIT is an ongoing, Australia‐wide trial in selected rare cancers that will enroll a cohort of 60 patients with advanced intrahepatic cholangiocarcinoma and gallbladder carcinoma and add to the existing data sets to better define the clinical activity of the ipilimumab/nivolumab regimen in patients with advanced biliary tract cancers.