Frontline Pembrolizumab Plus Chemo Approaches EU Approval for Biliary Tract Cancer

Marjorie Green, MD

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of pembrolizumab (Keytruda) combined with gemcitabine and cisplatin in the frontline treatment of adult patients with locally advanced unresectable or metastatic biliary tract cancer.¹

The positive opinion is based on findings from the phase 3 KEYNOTE-966 trial (NCT04003636) in which the chemoimmunotherapy combination (n = 533) significantly improved overall survival (OS) compared with chemotherapy alone (n = 536), at a median of 12.7 months (95% CI, 11.5-13.6) and 10.9 months (95% CI, 9.9-11.6), respectively (HR, 0.83; 95% CI, 0.72-0.95; 1-sided P = .0034).²

“Patients diagnosed with locally advanced unresectable or metastatic biliary tract cancer face a challenging disease with poor survival outcomes, underscoring the need for new treatment options that may help extend their lives,” Marjorie Green, MD, senior vice president and head of late-stage oncology and global clinical development at Merck Research Laboratories,” stated in a press release. “The CHMP’s positive opinion brings us one step closer to providing a new immunotherapy regimen, which has shown an OS benefit compared to chemotherapy alone, to these patients in the European Union.”

A total of 1069 patients with locally advanced unresectable or metastatic biliary tract cancer who had not received prior systemic treatment for advanced disease were enrolled to the trial. They were randomized 1:1 to receive 200 mg of pembrolizumab or placebo on day 1 plus 1000 mg/m2 of gemcitabine and 25 mg/m2 of cisplatin on day 1 and day 8 every 3 weeks. They received treatment until they experienced progressive disease PD) or unacceptable toxicity.

Patients were able to continue to receive the pembrolizumab combination after PD by RECIST v1.1 criteria if they were clinically stable and were determined to be deriving clinical benefit per investigator assessment.

The trial’s primary end point was OS, and other key end points comprised progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) per blinded independent central review (BICR) and RECIST v1.1 criteria, which was modified to follow up to 10 target lesions and up to 5 target lesions per organ.

Findings from a prespecified PFS and ORR final analysis showed that the median PFS achieved with pembrolizumab plus chemotherapy was 6.5 months (95% CI, 5.7-6.9) vs 5.6 months (95% CI, 5.1-6.6) with chemotherapy alone, an improvement that was not determined to be of statistical significance (HR, 0.86; 95% CI, 0.75-1.00). The chemoimmunotherapy combination induced an ORR of 29% (95% CI, 25%-33%) compared with 29% (95% CI, 25%-33%) with chemotherapy alone. The complete response rates in the pembrolizumab and placebo arms were 2.1% and 1.3%, respectively; the partial response rates were 27% and 27%, respectively.

Regarding safety, 55% of patients experienced adverse effects (AEs) that led to dose interruptions of pembrolizumab. These toxicities comprised neutrophil count (18%), reduced platelet count (10%), anemia (6%), decreased white blood count (4%), pyrexia (3.8%), fatigue (3.0%), cholangitis (2.8%), increased alanine aminotransferase (ALT; 2.6%), increased aspartate aminotransferase (AST; 2.5%), and biliary obstruction (2.3%).

Moreover, a 5% or higher incidence in AEs was observed between those in the chemoimmunotherapy and chemotherapy-alone arms with regard to pyrexia (26% vs 20%), rash (21% vs 13%), pruritus (15% vs 10%) and hypothyroidism (9% vs 2.6%). No clinically meaningful differences in incidences of grade 3 or 4 AEs were reported between arms. A difference of at least 5% incidence in laboratory abnormalities was observed in the pembrolizumab and placebo arms with regard to decreased lymphocytes (69% vs 61%). No clinically meaningful differences in incidences of grade 3 or 4 laboratory abnormalities were observed between the arms.

In November 2023, the FDA approved pembrolizumab plus gemcitabine and cisplatin for use in patients with locally advanced unresectable or metastatic biliary tract cancer based on KEYNOTE-966 data.³

The European Commission will now review the recommendation and determine whether marketing authorization in the European Union will be granted.¹ The decision is expected in the fourth quarter of 2023.

References

Merck receives positive EU CHMP opinion for Keytruda (pembrolizumab) plus gemcitabine and cisplatin as first-line treatment for locally advanced unresectable or metastatic biliary tract cancer. News release. Merck. November 10, 2023. Accessed November 10, 2023. https://www.merck.com/news/merck-receives-positive-eu-chmp-opinion-for-keytruda-pembrolizumabplus-gemcitabine-and-cisplatin-as-first-line-treatment-for-locally-advanced-unresectable-or-metastatic-biliary-tract-cancer/

Kelley RK, Yoo C, Finn RS, et al. Pembrolizumab (pembro) in combination with gemcitabine and cisplatin (gem/cis) for advanced biliary tract cancer (BTC): phase 3 KEYNOTE-966 study. Cancer Res. 2023;83(suppl 8):CT008. doi:10.1158/1538-7445.AM2023-CT008

FDA approves Merck's Keytruda (pembrolizumab) plus gemcitabine and cisplatin as treatment for patients with locally advanced unresectable or metastatic biliary tract cancer. News release. November 1, 2023. Accessed November 10, 2023. https://www.merck.com/news/fda-approves-mercks-keytruda-pembrolizumab-plus-gemcitabine-and-cisplatin-as-treatment-for-patients-with-locally-advanced-unresectable-or-metastatic-biliary-tract-cancer/