FDA Grants Priority Review to Durvalumab/Chemo Combo for Locally Advanced or Metastatic Biliary Tract Cancer

The FDA has accepted a supplemental biologics license application (sBLA) and granted priority review to durvalumab (Imfinzi) in combination with standard gemcitabine and cisplatin for the treatment of patients with locally advanced or metastatic biliary tract cancer.¹

The application was supported by findings from the phase 3 TOPAZ-1 trial (NCT03875235), in which durvalumab plus chemotherapy (n = 341) was found to improve overall survival (OS) compared with chemotherapy alone (n = 344), at 12.8 months (95% CI, 11.1-14.0) and 11.5 months (95% CI, 10.1-12.5), respectively (hazard ratio [HR], 0.80; 95% CI, 0.66-0.97; P = .021); this translated to a 20% reduction in the risk of death with the addition of durvalumab.²

Moreover, the durvalumab regimen reduced the risk of disease progression or death by 25% vs chemotherapy alone. The median progression-free survival (PFS) in the investigative arm was 7.2 months (95% CI, 6.7-7.4) vs 5.7 months (95% CI, 5.6-6.7) in the control arm (HR, 0.75; 95% CI, 0.63-0.89; P = .001).

The regulatory agency is slated to decide on the sBLA during the third quarter of 2022.

“People with advanced biliary tract cancer have faced poor outcomes and limited treatment options for too long, and today’s news for the TOPAZ-1 trial underscores the urgency to deliver new, effective therapies in this setting,” Susan Galbraith, executive vice president of Oncology R&D at AstraZeneca, stated in a press release. “We are working closely with the FDA to bring the first immunotherapy-based option to patients with this devastating cancer and potentially set a new standard of care with [durvalumab] plus chemotherapy.”

The double-blind, multicenter, global, phase 3 trial enrolled patients with locally advanced or metastatic biliary tract cancer who had an ECOG performance status of 0 or 1. Patients who were previously untreated were permitted if their disease was unresectable or metastatic at initial diagnosis. Those with recurrent disease more than 6 months following curative surgery or adjuvant therapy were also included.

A total of 685 participants were randomized 1:1 to receive durvalumab at 1500 mg every 3 weeks plus gemcitabine and cisplatin for up to 8 cycles followed by durvalumab at 1500 mg every 4 weeks until disease progression (n = 341), or placebo every 3 weeks plus gemcitabine/cisplatin for up to 8 cycles followed by placebo every 4 weeks until disease progression (n = 344).

Stratification factors comprised disease status (initially unresectable vs recurrent) and primary tumor location (intrahepatic cholangiocarcinoma vs extrahepatic cholangiocarcinoma vs gallbladder cancer).

The primary end point was OS, and a key secondary end point was PFS. Other secondary end points included objective response rate (ORR), duration of response (DOR), efficacy by PD-L1 status, and safety.

The median age of participants was 64 years (range, 20-85), and approximately half of patients were female. Slightly more than half of patients in the investigative and control arms, respectively, were Asian (54.3% and 58.4%) and from Asia (52.2% and 57.0%). Moreover, 50.7% of those in the durvalumab arm and 47.4% of those in the placebo arm had an ECOG performance status of 0 at screening.

In the investigative arm, 55.7% of patients had intrahepatic cholangiocarcinoma at diagnosis, 19.4% had extrahepatic cholangiocarcinoma, and 24.9% had gallbladder cancer; these rates were 56.1%, 18.9%, and 25.0%, respectively, in the control arm. Moreover, at the time of randomization, 80.4% of those in the durvalumab arm had initially unresectable disease status and 19.6% had recurrent disease; in the control arm, these rates were 81.1% and 18.6%, respectively. The majority of patients in both arms had metastatic disease.

Of the 341 patients randomized to the durvalumab/chemotherapy arm and the 344 randomized to the chemotherapy-alone arm, 338 and 342 patients, respectively, received treatment on the trial; 18.6% and 5.8% of patients, respectively, were still receiving treatment at a data cutoff of August 11, 2021.

Moreover, 81.4% of those in the investigative arm and 94.2% of those in the control arm discontinued treatment. In the durvalumab/chemotherapy arm, the most common reason for discontinuation was radiological disease progression (56.2%), followed by subjective disease progression (12.7%), toxicity (5.9%), patient decision (3.8%), another unspecified reason (2.1%), severe non-compliance (0.3%), and condition improvement or patient recovery (0.3%).

Additionally, 42.5% of those in the durvalumab arm vs 49.4% of those in the chemotherapy-alone arm went on to receive subsequent anticancer treatment. In the investigative arm, these therapies included cytotoxic chemotherapy (40.2%), an unspecified therapy (4.4%), targeted therapy (3.5%), taxane chemotherapy (1.5%), immunotherapy (0.9%), or an antiangiogenic therapy (0.3%).

Additional data presented during the 2022 Gastrointestinal Cancers Symposium indicated that the HR for OS for time up to 6 months with durvalumab/chemotherapy vs chemotherapy alone was 0.91 (95% CI, 0.66-1.26). The HR for OS for time after 6 months was 0.74 (95% CI, 0.58-0.94).

Moreover, the 6-month PFS rates in the investigative and control arms were 58.3% and 47.2%, respectively; at 9 months, these rates were 34.8% and 24.6%, respectively, and at 12 months, these rates were 16.0% and 6.6%, respectively.

The combination of durvalumab and chemotherapy induced an ORR of 26.7% vs 18.7% with chemotherapy alone (odds ratio, 1.60; 95% CI, 1.11-2.31; P = .011). Of those who responded in the investigative arm, 2.1% achieved a complete response and 24.6% experienced a partial response. The DCRs in the durvalumab and placebo arms were 85.3% and 82.6%, respectively.

Moreover, the median DOR was slightly longer with the addition of durvalumab vs chemotherapy alone, at 6.4 months (95% CI, 4.6-17.2) and 6.2 months (95% CI, 3.8-9.0), respectively. The median time to response in the investigative arm was 1.6 months (range, 1.3-3.0) vs 2.7 months (range, 1.4-4.1).

Regarding safety, the addition of durvalumab to chemotherapy did not result in additional toxicity. No new safety signals were identified from the known toxicity profiles of each individual agent.

Specifically, 92.9% of those in the durvalumab arm experienced an any-grade treatment-related adverse effect (TRAE) vs 90.1% of those in the chemotherapy-alone arm; 62.7% and 64.9% of patients, respectively, experienced TRAEs that were grade 3 or 4 in severity.

The most common grade 3 or 4 TRAEs reported in the investigative and control arms, respectively, included neutrophil count decrease (20.7% vs 25.4%), neutropenia (19.2% vs 20.2%), anemia (18.9% vs 18.7%), platelet count decrease (8.0% vs 7.6%), white blood cell count decrease (4.1% vs 5.8%), thrombocytopenia (3.6% vs 5.3%), fatigue (2.7% vs 2.3%), leukopenia (2.1% vs 0.6%), and asthenia (1.2% vs 2.0%).

Serious TRAEs occurred in 15.7% of those in the durvalumab/chemotherapy arm vs 17.3% of those in the chemotherapy-alone arm. Immune-mediated toxicities occurred in 12.7% and 4.7% of patients, respectively.

TRAEs resulted in discontinuation in 8.9% of those in the investigative arm and 11.4% of those in the control arm. Two patients who received the durvalumab/chemotherapy combination died from a TRAE vs 1 patient who received chemotherapy alone.

Previously, in December 2020, the FDA granted an orphan drug designation to durvalumab for use as a potential therapeutic option in biliary tract cancer.

References

1. Imfinzi plus chemotherapy granted priority review in the US for patients with locally advanced or metastatic biliary tract cancer based on TOPAZ-1 phase III trial. News release. AstraZeneca. May 4, 2022. Accessed May 4, 2022. https://bit.ly/3MOUKLA
2. Oh D-Y, He AR, Qin S, et al. A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (gemcis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1. J Clin Oncol. 2022;40(suppl 4):378. doi:10.1200/JCO.2022.40.4_suppl.378