Abstract
On September 2, 2022, the Food and Drug Administration (FDA) approved durvalumab in combination with cisplatin and gemcitabine, for the treatment of patients with unresectable or metastatic biliary tract cancers (BTC). On October 31, 2023, the FDA approved pembrolizumab in combination with cisplatin and gemcitabine for the same indication. Approvals were based on two randomized, multiregional, placebo-controlled trials, which randomly allocated patients to receive durvalumab (TOPAZ-1) or pembrolizumab (KEYNOTE-966) in combination with chemotherapy or placebo in combination with chemotherapy. Overall survival (OS) was the primary endpoint in both studies. In both studies, a statistically significant and clinically meaningful improvement in OS was demonstrated. In the TOPAZ-1 trial the median OS of patients receiving durvalumab was 12.8 months (95% confidence interval [CI] 11.1, 14.0) and 11.5 months (95% CI 10.1, 12.5) in patients receiving placebo (HR 0.80 [95% CI 0.66, 0.97]). In the KEYNOTE-966 trial, the median OS of patients receiving pembrolizumab was 12.7 months (95% CI 11.5, 13.6) and 10.9 months (95% CI 9.9, 11.6) in patients receiving placebo (HR 0.83 [95% CI 0.72, 0.95]). The addition of checkpoint inhibitors to standard of care chemotherapy for this indication did not reveal any new adverse event signals and the safety profile was generally consistent with the known clinical experience with durvalumab, pembrolizumab, and the backbone chemotherapy regimen. The approvals of durvalumab and pembrolizumab in combination with standard of care cisplatin and gemcitabine for the treatment of unresectable or metastatic BTC add two new therapeutic option for these patients.
Introduction
Biliary tract cancers (BTC) are adenocarcinomas, grouped based on the anatomical site of origin of the tumor including intra (iCCA) and extrahepatic cholangiocarcinoma (eCCA), gallbladder cancer (GBC), and ampulla of Vater cancer (AVC).
BTCs are rare, accounting for approximately 3% of all gastrointestinal neoplasms (1). There is substantive geographic variation in the incidence for each subtype, in part related to differences in underlying risk factors. In a review of BTC statistics in the United States from 2001 to 2015 (2), the overall incidence was 5.04 per 100,000 persons/year and increased by 1.76% yearly (95% confidence interval [CI] 1.59, 1.92) during the 14- year study period. Incidence for each subtype (per 100,000 persons/year) was 1.57 for GBC, 1.25 for eCCA, 1.17 for iCCA, and 0.76 for AVC. Incidence was lower in women compared to men for all BTC subtypes (4.85 versus 5.31), except for GBC (1.92 versus 1.14).
Outcomes are poor and there is a need for new effective treatments for patients with BTC. Typically, BTC is diagnosed in the advanced stages when patients already have metastatic disease. The overall 5-year survival for BTC is 15.2%, but only 3% in the metastatic setting (2).
Cisplatin in combination with gemcitabine has been the standard of care treatment of newly diagnosed unresectable or metastatic BTC for more than a decade. The ABC-02 trial (3) reported cisplatin plus gemcitabine demonstrated a survival benefit (hazard ratio [HR] 0.64, p<0.001) with a median overall survival of 11.7 months (95% CI 9.5, 14.3) for the combination versus 8.1 months (95% CI 7.1, 8.7) for gemcitabine alone.
In this paper, we describe FDA’s review of marketing applications submitted for the approval of durvalumab (IMFINZI, AstraZeneca Pharmaceuticals) on September 2, 2022, and for pembrolizumab (KEYTRUDA, Merck, Sharp & Dohme) on October 31, 2023, for the treatment of adult patients with locally advanced or metastatic BTC.
The authors summarize the FDA’s review of data and regulatory considerations supporting these 2 approvals.
Trial Design
The approvals of durvalumab (an anti-program cell death ligand 1 [PD-L1] monoclonal antibody) and pembrolizumab (an anti-PD-1 monoclonal antibody) were based on the results of the TOPAZ-1 (NCT03875235) and KEYNOTE-966 (NCT04003636) trials, respectively. The Investigators’ analyses and interpretation of these trials were previously published (4,5).
TOPAZ-1 and KEYNOTE-966 were multiregional, randomized, double-blind trials designed to compare overall survival (OS) in patients with previously untreated, unresectable or metastatic BTC, not including AVC. Patients who received prior systemic neoadjuvant or adjuvant therapy completed at least 6 months before the diagnosis of unresectable or metastatic disease were eligible. Other key eligibility criteria included disease measurable per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible.
In TOPAZ-1, patients were randomized in a 1:1 ratio to durvalumab 1500 mg administered by intravenous (IV) infusion every 3 weeks (Q3W), or placebo in combination with gemcitabine and cisplatin. Randomization was stratified according to disease status (initially unresectable vs. recurrent) and primary tumor location (iCCA vs. eCCA vs. GBC). In KEYNOTE-966, patients were randomized 1:1 to receive pembrolizumab 200 mg IV Q3W or placebo. Randomization was stratified according to geographical region (Asia vs. non-Asia), disease stage (locally advanced vs. metastatic), and site of origin (iCCA vs. eCCA vs. GBC). In both trials, patients received gemcitabine 1000 mg/m2 IV and cisplatin 25 mg/m2 IV on Day 1 and Day 8 of each 3-week cycle. In TOPAZ-1, chemotherapy was discontinued after 8 cycles. In KEYNOTE-966, cisplatin was limited to 8 cycles but gemcitabine could have been continued as per investigator’s discretion. In both trials, the immune checkpoint inhibitor or placebo were continued until intolerable toxicity or disease progression; in KEYNOTE-966, pembrolizumab could be continued up to 35 cycles. In TOPAZ-1, disease recurrence/progression was assessed every 6 weeks for the first 24 weeks and every 8 weeks thereafter; in KEYNOTE-966, these assessments were conducted every 6 weeks for the first 54 weeks and every 12 weeks thereafter.
The primary endpoint of both trials was overall survival, defined as the time from randomization to death due to any cause. Progression-free survival (PFS), defined as time from the date of randomization until the date of disease progression or death was a main secondary endpoint. PFS was assessed by the site investigators in TOPAZ-1 and by blinded independent central review (BICR) in KEYNOTE-966. PFS and objective response rate (ORR) as assessed by BICR were a main secondary endpoints included in the multiple testing strategy in KEYNOTE-966. TOPAZ-1 had 90% power at a two-sided alpha level of 4.2% at the planned final analysis to detect a HR of 0.745. One interim analysis (IA) for OS at 397 events was planned. KEYNOTE-966 had 93% power to detect a significant effect at a one-sided overall alpha level of 2.5%. Two interim analyses for OS were planned: the first when approximately 585 events were observed and approximately 26 months had passed since start of randomization, and the second when approximately 695 events were observed and approximately 32 months had passed since start of randomization.
The primary efficacy analysis population in both trials was conducted in the intent-to-treat (ITT) population. The stratified log-rank test was used to compare both OS and PFS between study arms, and the stratified Cox proportional hazards model was used to estimate the hazard ratio. The Kaplan-Meier (KM) product-limit method was applied to summarize OS and PFS. Multiplicity was controlled in both trials.
Results
TOPAZ-1 Efficacy Results:
In TOPAZ-1, a total of 685 patients were randomized to receive durvalumab with chemotherapy (n=341) or placebo with chemotherapy (n=344). All but 5 randomized patients (3 patients in the durvalumab arm and 2 patients in placebo arm) were treated per protocol. The ITT population demographic and baseline disease characteristics are presented in Table 1 and were mostly balanced across study arms. TOPAZ-1 enrolled 14 Black patients (2%) and 46 Hispanic or Latino patients (7%) across both arms.
Table 1.
TOPAZ-1 and KEYNOTE-966: Demographic and Disease Characteristics
| TOPAZ-1 | KEYNOTE-966 | |||
|---|---|---|---|---|
| Durvalumab+GC N = 341 |
Placebo+GC N=344 |
Pembrolizumab+GC N= 533 |
Placebo+GC N= 536 |
|
| Median age (range) | 64 (20–84) | 64 (31–85) | 64 (23–85) | 63 (28–84) |
| Age ≥ 65 y.o. -n (%) | 160 (47) | 160 (47) | 264 (50) | 238 (44) |
| Sex – n (%) | ||||
| Women | 172 (50) | 168 (49) | 253 (48) | 264 (49) |
| Men | 169 (50) | 176 (51) | 280 (53) | 272 (51) |
| Race – n (%) | ||||
| Asian | 185 (54) | 201 (58) | 245 (46) | 250 (47) |
| White | 131 (38) | 124 (36) | 256 (48) | 268 (50) |
| Black/African American | 8 (2) | 6 (2) | 11 (2) | 3 (1) |
| Ethnicity – n (%) | ||||
| Hispanic or Latino | 27 (8) | 19 (6) | 59 (11) | 52 (10) |
| Geographic region – n (%) | ||||
| Asia | 178 (52) | 196 (57) | 242 (45) | 244 (45) |
| Non-Asia | 163 (48) | 148 (43) | 291 (55) | 292 (55) |
| ECOG PS – n (%) | ||||
| 0 | 173 (51) | 163 (47) | 258 (48) | 228 (43) |
| 1 | 168 (49) | 181 (53) | 274 (51) | 308 (58) |
| Primary tumor location – n (%) | ||||
| iCCA | 194 (57) | 197 (57) | 320 (60) | 313 (58) |
| eCCA | 62 (18) | 63 (18) | 98 (18) | 105 (20) |
| GBC | 85 (25) | 84 (24) | 115 (22) | 118 (22) |
| Disease status – n (%) | ||||
| Metastatic | 303 (89) | 286 (83) | 473 (89) | 470 (88) |
| Locally advanced | 38 (11) | 57 (17) | 60 (11) | 66 (12) |
| Viral etiology – n (%) | ||||
| No viral hepatitis | 187 (55) | 174 (51) | 355 (67) | 361 (67) |
| PD-L1 expression – n (%) | ||||
| High (≥ 1)a | 197 (58) | 205 (60) | 363 (68) | 365 (68) |
| MSI - n (%) | ||||
| High | 3 (1) | 2 (1) | 6 (1) | 4 (1) |
| Non-MSI-H | 160 (47) | 168 (49) | 433 (81) | 422 (79) |
| Missing/indeterminate | 178 (52) | 174 (51) | 94 (18) | 110 (21) |
GC: gemcitabine and cisplatin; ECOG PS: Eastern Cooperative Group Performance Status; iCCA: intrahepatic cholangiocarcinoma; eCCA: extrahepatic cholangiocarcinoma; GBC: gallbladder cancer; PD-L1: Programmed Death-Ligand 1; MIS-H: Mismatch Repair Instability-High
TOPAZ-1 used tumor and/or immune cell positivity (TIP) as per the Ventana PD-L1 IHC assay; KEYNOTE-966 used combined positivity score (CPS) as per the IHC 22C3 pharmDx assay
At a prespecified interim analysis of OS (data cutoff August 11, 2021), 424 deaths had occurred. TOPAZ-1 demonstrated a statistically significant improvement in OS, with an estimated HR of 0.80 (95% CI: 0.66, 0.97; two-sided p-value= 0.021); the estimated median OS was 12.8 months (95% CI: 11.1, 14.0) and 11.5 months (95% CI: 10.1, 12.5) in the durvalumab and placebo arms, respectively (Figure 1). Subgroup analyses show that the overall treatment effect was generally consistent across most exploratory subgroups. TOPAZ-1 also demonstrated a statistically significant improvement in investigator-assessed PFS, with an estimated HR of 0.75 (95% CI: 0.63, 0.89; two-sided p-value=0.001); the estimated median PFS was 7.2 months (95% CI: 6.7, 7.4) and 5.7 months (95% CI : 5.6, 6.7) in the durvalumab and placebo arms, respectively (Figure 2). The results of the efficacy analyses are summarized in Table 2.
Figure 1.
TOPAZ-1 OS Kaplan Meier curves
Figure 2.
KEYNOTE-966 – OS Kapan Meier curves
Table 2.
TOPAZ-1 and KEYNOTE-966: Major Efficacy Outcomes
| TOPAZ-1 | KEYNOTE-966 | |||
|---|---|---|---|---|
| Durvalumab+GC N = 341 |
Placebo+GC N=344 |
Pembrolizumab+GC N= 533 |
Placebo+GC N= 536 |
|
| Overall survival (OS) | ||||
| Number of deaths (%) | 198 (58) | 226 (66) | 414 (78) | 443 (83) |
| Median OS (months) (95% CI)a |
12.8 (11.1, 14.0) | 11.5 (10.1, 12.5) | 12.7 (11.5, 13.6) | 10.9 (9.9, 11.6) |
| Hazard ratio (95% CI)b | 0.80 (0.66, 0.97) | 0.83 (0.72, 0.95) | ||
| p-value | 0.021c | 0.0034e | ||
| Progression-free survival (PFS) | ||||
| Number of events (%) | 276 (81) | 297 (86) | 361 (68) | 391 (73) |
| Median PFS (months) (95% CI) |
7.2 (6.7, 7.4) | 5.7 (5.6, 6.7) | 6.5 (5.7, 6.9) | 5.6 (5.1, 6.6) |
| Hazard ratio (95% CI) | 0.75 (0.63, 0.89) | 0.86 (0.75, 1.00) | ||
| p-value | 0.001d | NS | ||
| Overall response rate (ORR) | ||||
| ORR % (95% CI) | 27 (22, 32) | 19 (15, 23) | 29 (25, 33) | 29 (25, 33) |
| Median DOR (months) (95% CI) |
6.4 (5.9, 8.1) | 6.2 (4.4, 7.3) | 8.3 (6.9, 10.2) | 6.8 (5.7, 7.1) |
| p-value | Not Applicable | NS | ||
NS: non-significant
Kaplan-Meier estimated median with 95% CI derived using Brookmeyer-Crowley method
Based on Cox stratified proportional hazards model
2-sided p-value based on a stratified log-rank test compared with alpha boundary of 0.030
2-sided p-value based on a stratified log-rank test compared with alpha boundary of 0.048
1-sided p-value based on a stratified log-rank test compared with alpha boundary of 0.0194
KEYNOTE-966 Efficacy Results:
In KEYNOTE-966, a total of 1069 patients were randomized to receive pembrolizumab with chemotherapy (n=533) or placebo with chemotherapy (n=536). All but 6 randomized patients (4 patients in the pembrolizumab arm and 2 patients in the placebo arm) were treated per protocol. Baseline demographics and disease characteristics for patients in the ITT population are presented in Table 1 and were mostly balanced across study arms. KEYNOTE-966 enrolled 14 Black patients (1.3%) and 111 Hispanic or Latino patients (10%) across both arms.
At the final analysis of OS (data cutoff December 15, 2022), 857 deaths had occurred. KEYNOTE-966 demonstrated a statistically significant improvement in OS, with an estimated HR of 0.83 (95% CI: 0.72, 0.95; one-sided p-value= 0.0034); the estimated median OS was 12.7 months (95% CI: 11.5, 13.6) and 10.9 months (95% CI: 9.9, 11.6) in the pembrolizumab and placebo arms, respectively (Figure 1). The primary analysis of PFS as assessed by BICR (data cutoff December 15, 2021) did not meet statistical significance, with an estimated HR of 0.86 (95% CI: 0.75, 1.00); the estimated median PFS was 6.5 months (95% CI: 5.7, 6.9) and 5.6 months (95% CI: 5.1, 6.6) in the pembrolizumab and placebo arms, respectively (Figure 2). The primary analysis of ORR as assessed by BICR (data cutoff December 15, 2021) also did not meet statistical significance, with an estimated ORR of 29% (95% CI: 25%, 33%) in both arms. The results of the efficacy analyses are summarized in Table 2. While the overall treatment effect appeared generally consistent across most exploratory subgroups (age, sex, ECOG PS, PD-L1 CPS status, etc.), the treatment effect appeared smaller in magnitude in patients with eCCA (n=203) and GBC (n=233). For example, the OS HR was 0.99 (95% CI: 0.73, 1.35) for patients with eCCA and 0.96 (95% CI: 0.73, 1.26) for patients with GBC. However, given the exploratory, post-hoc nature of these subgroup analyses, results should be interpreted with caution; no formal testing was planned for any subgroups, thus the sample size in each subgroup was not planned to have adequate power to detect a treatment effect.
TOPAZ-1 Safety Results:
The safety analysis of TOPAZ-1 was based on 680 patients who received at least one dose of durvalumab (n= 338) or placebo (n= 342) in combination with cisplatin and gemcitabine. Patients in the durvalumab arm completed a median number of 10 cycles (range 1–29), while patients in the placebo arm completed a median of 8 cycles (range 1–26. Eight cycles of gemcitabine were completed by 60% of patients in the durvalumab arm compared to 52% patients in the placebo arm. Eight cycles of cisplatin was completed by 59% patients in the durvalumab arm compared to 50% patients placebo arm. Durvalumab or placebo were discontinued for treatment emergent adverse events (TEAEs) in 6% and 5% of patients respectively.
The most common TEAEs in both arms of TOPAZ-1 were similar (Table 3). Grade 3–4 TEAEs in ≥ 5% patients in either arm (including laboratory abnormalities) were neutropenia (48% and 49% in the durvalumab and placebo arms respectively), anemia (31% and 28%), leukopenia (28% in both arms), lymphopenia (23% and 15%), thrombocytopenia (18% and 19%), hyponatremia (18% and 13%), GGT increased (12% and 13%), bilirubin increased (10% and 14%), AST increase (8% in each arm), ALT increased (7% and 6%), cholangitis (7% and 3%), creatinine increased (5% and 2%), and hypomagnesemia (5% and 2%).
Table 3.
TOPAZ-1 and KEYNOTE-966: Most common adverse events (incidence ≥ 20%)
| TOPAZ-1 | KEYNOTE-966 | |||
|---|---|---|---|---|
| Durvalumab+GC N = 338 |
Placebo+GC N=342 |
Pembrolizumab+GC N= 529 |
Placebo+GC N= 534 |
|
| Adverse reactions – all grades | % | % | % | % |
| Fatiguea | 42 | 43 | 53 | 54 |
| Nausea | 40 | 34 | 44 | 46 |
| Constipation | 32 | 29 | 35 | 36 |
| Decreased appetite | 26 | 23 | 27 | 29 |
| Abdominal painb | 24 | 23 | 24 | 32 |
| Vomiting | 18 | 18 | 23 | 24 |
| Rashc | 23 | 14 | 24 | 16 |
| Fever | 20 | 16 | 26 | 19 |
| Diarrhea/colitisd | 17 | 15 | 20 | 19 |
| Select laboratory abnormalities * | ||||
| Hemoglobin decreased | 90 | 89 | 91 | 89 |
| ANC decreased | 75 | 75 | 77 | 77 |
| Platelets decreased | 71 | 67 | 68 | 69 |
| AST increased | 41 | 38 | 57 | 58 |
| ALT increased | 51 | 49 | 55 | 63 |
| Bilirubin increased | 25 | 32 | 33 | 36 |
ANC: absolute neutrophil count; AST: aspartate aminotransferase; ALT: alanine aminotransferase
As per laboratory dataset analysis
Includes fatigue, malaise, cancer fatigue and asthenia.
Includes abdominal pain, abdominal pain lower, abdominal pain upper, flank pain gastrointestinal pain, hepatic pain, flank pain, esophageal pain.
Includes rash, rash macular, rash maculopapular, rash morbilliform, rash papular, rash pruritic, rash pustular, rash erythematous, rash pruritic, dermatitis acneiform, dermatitis bullous, dermatitis exfoliative, drug eruption, eczema, erythema, and dermatitis.
includes diarrhea, colitis, enterocolitis, immune mediated colitis, immune-mediated enterocolitis
Fatal TEAEs were reported in 4% of patients in both the durvalumab and placebo arms in the TOPAZ-1 trial
KEYNOTE-966 Safety Results:
The safety analysis of KEYNOTE-966 was based on 1063 patients who received at least one dose of pembrolizumab (n= 529) or placebo (n= 534) in combination with cisplatin and gemcitabine. Patients in the pembrolizumab arm completed a median number 9 cylces (range 1–51), while patients in the placebo arm completed a median of 8 cycles (range 1–42). At least 8 cycles of gemcitabine were completed by 55% patients in the pembrolizumab arm compared to 52% patients in the placebo arm. Eight cycles of cisplatin was completed by 49% patients in the pembrolizumab arm compared to 48% patients placebo arm. In the pembrolizumab and placebo arms, gemcitabine was continued beyond Cycle 12 in 32% and 27% of patients respectively and beyond Cycle 24 in 8% and 7% of patients respectively. Pembrolizumab or placebo were discontinued for TEAEs in 15% and 12% of patients respectively.
The most common TEAEs in both arms of KEYNOTE-966 were similar (Table 3). Grade 3–4 TEAEs in ≥ 5% patients in either arm (including laboratory abnormalities) were neutropenia (55% and 50% in the pembrolizumab and placebo arms respectively), anemia (32% in both arms), leukopenia (32% and 27%), lymphopenia (32% and 24%), thrombocytopenia (24% and 25%), hypokalemia (7% and 9%), fatigue (7% in both arms), hyperkalemia (4% and 6%), hyponatremia (4% and 5%), AST increased (6% vs. 9%), ALT increased (5% and 7%), creatinine increased (5% and 7%), cholangitis (5% and 4%), and hypomagnesemia (3% in both arms).
Fatal TEAEs were reported in 6% and 9% in the pembrolizumab and placebo arms respectively in KEYNOTE-966.
Regulatory considerations
The approvals of durvalumab and pembrolizumab in combination with cisplatin and gemcitabine are the first approvals of immune checkpoint inhibitors in patients with BTC, previously available only for patients with MSI-H/dMMR BTC based on the tissue agnostic approval of pembrolizumab on May 23, 2017 (6). TOPAZ-1 and KEYNOTE-966 demonstrated an improvement in overall survival compared to chemotherapy alone for durvalumab and pembrolizumab, respectively, each in combination with cisplatin and gemcitabine.
Overall survival was the primary endpoint in both TOPAZ-1 and KEYNOTE-966, and when feasible in the context of a randomized controlled study is considered the most reliable cancer endpoint (7). While the magnitude of the treatment effect may appear similar across trials, caution should be used in interpretation of findings across trials and comparative assessments of TOPAZ-1 and KEYNOTE-966 should generally be avoided. Potential unknown confounders and heterogeneity across the study designs in these trials, such as differences in follow-up time, statistical analysis plans, , among others, preclude conclusive comparative assessments of these trials and consequently, of these drugs. For example, TOPAZ-1 limited chemotherapy to 8-cycles, whereas KEYNOTE-966 the use of maintenance gemcitabine after 8-cycles was left to investigator discretion. There were differences in the observed ORR in the placebo arms of both trials (19% vs. 29%), which may further illustrate the potential impact of heterogeneity across the two trials or two drugs. Direct comparisons between drugs require adequately designed and conducted randomized trials that directly test their non-inferiority or superiority.
A limitation of both TOPAZ-1 and KEYNOTE-966 is the low proportion of patients with GBC and eCCA, which limits the ability to specifically characterize the treatment effect in these BTC subtypes. Additionally, participants enrolled from the U.S., represented a mere 7% of the overall total number of participants in both studies (TOPAZ-1 n=65; KEYNOTE-966 n=61). The small number of participants enrolled in the U.S. impacts the representativeness of the trial population with respect to race and ethnicity. For example, of a total of 1754 patients enrolled in TOPAZ-1 and KEYNOTE-966, but Black or African American and Hispanic or Latino patients comprised only 1.6% and 9% of the study population, respectively. In multiregional clinical trials, enrollment across regions should ideally be balanced with an explicit consideration for the demographic characteristics of the study population. FDA has issued multiple recommendations to improve clinical trial diversity (8), and in April 2022 has further outlined the use of Diversity Plans to improve the enrollment of underrepresented racial and ethnic populations in clinical trials (9). In the US, BTCs comprise of only 3% of all gastrointestinal malignancies (1); as there is notable variation in prevalence of BTC across geographical regions and both durvalumab and pembrolizumab have been extensively used prior to this approval, FDA applied regulatory flexibility when evaluating the applicability of the study findings to the US patient population.
The addition of checkpoint inhibitors to standard of care chemotherapy for this indication did not reveal any new adverse event signals and the safety profile was generally consistent with the known clinical experience with durvalumab, pembrolizumab, and the backbone chemotherapy regimen. A common cause of morbidity and mortality in patients with biliary tract cancers is cholangitis and infections of the biliary tract. In TOPAZ-1, cholangitis and/or biliary tract infections occurred in 12% and 10% patients in the durvalumab and placebo arms, respectively. In KEYNOTE-966, 12% and 11% patients in the pembrolizumab and placebo arms experienced cholangitis and/or biliary tract infections. The risks of durvalumab or pembrolizumab in combination with cisplatin and gemcitabine were deemed largely manageable with patient surveillance, treatment delays, and supportive care, and felt to be acceptable given the demonstrated OS benefit in the context of incurable metastatic or unresectable disease.
Conclusion
The approval of the addition of either durvalumab or pembrolizumab to 1st line chemotherapy introduces immune checkpoint inhibition to the treatment of unresectable or metastatic BTC. Efficacy and safety results from the TOPAZ-1 and KEYNOTE-966 trials demonstrate a favorable benefit-risk profile and provided substantial evidence of efficacy and acceptable safety necessary to support the approval of these important therapeutic options.
Footnotes
Disclosure of Potential Conflicts of Interest: The authors report no financial interests or relationships with the commercial sponsors of any products discussed in this report.
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