Promising Data Follow on First Targeted Therapy Approval in Biliary Tract Cancer

Targeted Therapies in OncologyJuly 2 2020
Volume 9
Issue 10
Pages: 62-63

Like never before, presentations related to systemic therapies for biliary tract cancers are taking center stage at medical and oncology conferences, generating hope that treating physicians will have multiple options in the near future.

A recent FDA action for the FGFR1/2/3 inhibitor pemigatinib (Pemazyre) marked the first approval of a targeted agent for cholangiocarcinoma, and the oncology field is likely to see additional systemic therapy approvals for bile duct cancers. The incidence of biliary tract cancers, which are typically broken down into subgroups of intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer, are rising, which experts associate with obesity and other etiologic risk factors. These cancers are aggressive, and few treatment options, aside from a handful of chemotherapy regimens, including gemcitabine/cisplatin in the frontline setting and FOLFOX (folinic acid, fluorouracil, and oxaliplatin) in the second line, are available.1

Like never before, presentations related to systemic therapies for biliary tract cancers are taking center stage at medical and oncology conferences, generating hope that treating physicians will have multiple options in the near future.

Targeted Therapies for Intrahepatic Cholangiocarcinoma

In April of this year, the FDA granted accelerated approval to pemigatinib for the treatment of patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma that harbors an FGFR2 aberration as detected by an FDA-approved test.2 Occurring in up to 16% of patients, FGFR2 fusions and rearrangements are found almost exclusively in intrahepatic cholangiocarcinoma, and the presence of this aberration has motivated investigators to explore the use of FGFR inhibitors in this disease.

FGFR2 Fusions/Rearrangements

The trial that led to the approval, the single-arm phase 2 FIGHT-202 study (NCT02924376), comprised 3 cohorts: patients with FGFR2 fusions or rearrangements (n = 107), those with other FGF/FGFR alterations (n = 20), and those with no FGF/FGFR alterations (n = 18). At the median follow-up of 17.8 months, the cohort with FGFR2 fusions or rearrangements achieved an objective response rate (ORR) of 35.5%, made up of 3 complete responses (CRs; 2.8%) and 35 partial responses (PRs; 32.7%). The median time to first response was 2.7 months, and the median duration of response was 7.5 months. No patients in the other cohorts achieved responses.3

In line with previously reported data for the agent, hyperphosphatemia was the most common adverse effect (AE), occurring in 60% of patients overall. Grade 3 or greater AEs affected 64% of patients, including hyperphosphatemia in 12% and arthralgia, stomatitis, hyponatremia, abdominal pain, and fatigue in 5% each.3

Although the trial investigators urged against cross-trial comparisons, these data compare favorably against historical controls of patients with cholangiocarcinoma treated in the second-line setting and beyond.3

“The antitumor activity of pemigatinib in patients with FGFR2 fusions or rearrangements compares favorably with that reported for other second-line chemotherapy and targeted therapies,” the study investigators, who were led by Ghassan K. Abou-Alfa, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, wrote. “The observed proportion of patients with an objective response and the progression-free survival in this study suggests that pemigatinib has encouraging clinical activity in patients with FGFR2 fusions or rearrangements.”

Futibatinib (TAS-120), another highly selective drug, inhibits FGFRs 1 through 4. The agent was investigated in a phase 1 trial of patients with advanced solid tumors and showed an ORR of 25% in patients with advanced refractory cholangiocarcinomas that harbor FGFR2 fusions.4

Phase 2 FOENIX-CCA2 trial (NCT02052778) data reported as part of the American Society of Clinical Oncology 2020 Virtual Scientific Program further supported these findings, with an ORR of 37.3% observed in 67 patients treated with a continuous dose of 20 mg daily of futibatinib. The investigators noted 1 CR and 24 PRs; 30 patients (44.8%) had stable disease, leading to a disease control rate (DCR) of 82.1%. Reponses were durable, with an average duration of response of 8.3 months. At the analysis, 25 were still receiving therapy.

At a follow-up of 11.4 months, the median progression-free survival (PFS) was 7.2 months, with rates of PFS at 6 and 12 months of 61.0% and 39.4%, respectively.4

Serious treatment-related AEs occurred in 10.4% of patients. Investigators reported drug interruptions and dose reductions in 55.2% and 50.7% of patients, respectively. Similar to pemigatinib, a high rate of all-grade hyperphosphatemia was observed, at 88.1%.4

The study results led to the phase 3 FOENIX- CCA3 trial (NCT04093362) of futibatinib versus gemcitabine/cisplatin as frontline therapy for patients with advanced cholangiocarcinoma with FGFR2 gene rearrangements.

IDH1 as a Viable Target in Intrahepatic Disease

According to data published in The Lancet Oncology, around 13% of intrahepatic cholangioarcinomas will harbor a mutation in IDH1. Phase 1 study data previously demonstrated rationale for the use of IDH1 inhibition in patients with cholangiocarcinoma from a clinical trial cohort of patients with advanced solid tumors.5

The small molecule inhibitor ivosidenib (Tibsovo) demonstrated statistically significant improvement in PFS compared with placebo when administered to patients with previously treated IDH1-mutant cholangiocarcinoma in the randomized phase 3 ClarIDHy trial (NCT02989857). The IDH1 inhibitor already has an FDA indication for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who are 75 years or older or in patients with AML that is relapsed or refractory and harbors a susceptible IDH1 mutation.6

The reduction in the risk of disease progression or death with ivosidenib was 63% compared with placebo, with median PFS in months of 2.7 versus 1.4 (HR, 0.37; 95% CI, 0.25-0.54; P <.0001). There was also substantial improvement in the proportion of patients remaining progression free at 6 months (32% vs 0%) and 12 months (22% vs 0%) with ivosidenib following the start of therapy. These benefits were observed regardless of the number of prior therapies and were consistent across subgroups, according to the study investigators, who were led by Abou-Alfa.

Median overall survival (OS) was 10.8 months with ivosidenib and 9.7 months for placebo (HR, 0.69; 95% CI, 0.44-1.10; P = .060). Rates of survival at 6 months (67% vs 59%) and 12 months (48% vs 38%) also favored ivosidenib. At data cutoff, 57% of patients treated with placebo had crossed over to the experimental arm, and the investigators observed a favorable OS result for ivosidenib versus placebo in the overall population. In an analysis that accounted for crossover, the adjusted median OS was 6.0 months for patients in the placebo group (HR, 0.46; 95% CI, 0.28-0.75; P = .0008).

Serious AEs occurred at rates of 30% and 22% in the ivosidenib and placebo groups, respectively, and were deemed treatment related in 2% of patients on ivosidenib. None of the serious AEs in the placebo group were identified as treatment related.

“Although the findings reported here are specific to patients with IDH1-mutant, advanced cholangiocarcinoma, representing a relatively small subset of the disease population, the incidence of intrahepatic cholangiocarcinoma is increasing internationally and represents an area of growing unmet need,” Abou-Alfa et al wrote in the paper.

Immunotherapy Agents in Biliary Tract Cancer

Recent data also demonstrated the validity of immunotherapies in the treatment of advanced biliary tract cancers, and these systemic therapies are gaining a foothold in the space.

PD-1 and PD-L1 inhibitors such as nivolumab (Opdivo) and durvalumab (Imfinzi), respectively, have shown promise as either single agents or in combination with standard-of-care chemotherapy in both the treatment-naïve and relapsed settings.

Single-Agent Nivolumab

In a phase 2 study (NCT02829918) of patients (n = 54) with histologically confirmed, advanced relapsed biliary tract cancer, nivolumab monotherapy induced an investigator-assessed ORR of 22% that included all PRs and a DCR of 59%. Four responders demonstrated durable objective responses lasting at least 1 year. Median PFS and OS were 3.7 months (95% CI, 2.3-5.7) and 14.2 (95% CI, 6.0-NR), respectively.7

All patients with responses were determined to have mismatch repair–proficient tumors. Because mismatch repair deficiency is associated with responses to PD-1/L1 inhibitors, the f indings led the investigators to conclude that further investigation on biomarkers of therapy for this agent is warranted. In addition, PD-L1 expression was strongly associated with longer PFS (HR, 0.23; 95% CI, 0.10-0.51; P < .001). They concluded that further studies of nivolumab as monotherapy in this patient population are warranted to support the findings and evaluate for tumor biomarkers that may indicate benefit with this treatment strategy.

Immunotherapy Plus Targeted MEK Therapy

Atezolizumab (Tecentriq) with the MEK inhibitor cobimetinib (Cotellic) has the potential to prolong PFS versus atezolizumab monotherapy in biliary tract cancer following prior therapies, according to results of a phase 2 trial presented at the 2020 American Association for Cancer Research Virtual Annual Meeting I.1

MEK inhibition has shown immunomodulatory effects in preclinical models of biliary tract cancer but not enough to pursue monotherapy indications, so 1 of the 2 arms in the randomized trial added daily cobimetinib to the administration of the PD-L1 inhibitor atezolizumab in patients with pretreated disease. The trial met its primary end point of statistically significant improvement in PFS with the combination versus atezolizumab monotherapy, at 111 days versus 57 days, respectively (P = .0268).1

Disease control rates for the combination (n = 38) and single-agent (n = 39) arms were 45.2% and 32.4%, respectively. Each arm had 1 PR and no CRs. One patient with a microsatellite instability–high tumor was included in each arm, but neither patient had an objective response. Mark Yarchoan, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland, who presented the f indings, said the ORR of 2.9% observed with single-agent atezolizumab is low compared with the response rates seen in other immunotherapy trials and supports the notion that PD-L1 inhibitor therapy alone has limited activity in biliary tract cancer, historically considered an immunolgically cold tumor.1

AEs were manageable and consistent with the known toxicities of both study drugs. Treatment-related grade 3 events occurred in 38.5% of patients receiving the single agent and 44.7% of those in the combination group. The manageable safety profile coupled with the potential for PFS benefit led the trial investigators to call for further investigation into the combination.1

Combining PD-L1/CTLA-4 Inhibition

The efficacy and tolerability of durvalumab (Imfinzi) plus tremelimumab added to standard-of-care cisplatin/gemcitabine was evaluated in a phase 2 trial (NCT03046862) with 3 treatment arms: a biomarker cohort of patients treated with chemotherapy alone (n = 30), patients treated with cisplatin/ gemcitabine plus durvalumab (n = 45), and those receiving cisplatin/gemcitabine plus durvalumab and tremelimumab (n = 46).8

ORRs for the durvalumab and the durvalumab plus tremelimumab arms were 73.4% and 73.3%, respectively; this compared favorably with the control arm, which had a response rate of 50.0%. In addition, promising OS was observed with both immunotherapy arms, with medians of 18.1 months for durvalumab and 20.7 months for durvalumab and tremelimumab.8

Although the investigators warned against drawing conclusions from these data, the promising efficacy seen here warrants further exploration. The durvalumab plus cisplatin/ gemcitabine is being explored in the phase 3 TOPAZ-1 trial (NCT03875235).8


1. Yarchoan M, Cope L, Anders RA, et al. A multicenter randomized phase 2 trial of atezolizumab as monotherapy or in combination with cobimetinib in biliary tract cancers (BTCs): a NCI Experimental Therapeutics Clinical Trials Network (ETCTN) study. Presented at: 2020 American Association for Cancer Research Virtual Annual Meeting I; April 27-28, 2020. Abstract CT043.

2. FDA grants accelerated approval to pemigatinib for cholangiocarcinoma with an FGFR2 rearrangement or fusion. FDA. April 17, 2020. Updated April 20, 2020. Accessed June 23, 2020.

3. Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020;21(5):671-684. doi:10.1016/S1470-2045(20)30109-1

4. Goyal L, Meric-Bernstam F, Hollebacque A, et al. FOENIX-CCA2: a phase II, open-label, multicenter study of futibatinib in patients (pts) with intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 gene fusions or other rearrangements. J Clin Oncol. 38(suppl 15):108. doi:10.1200/ JCO.2020.38.15_suppl.108

5. Lowery MA, Burris HA 3rd, Janku F, et al. Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma: a phase 1 study. Lancet Gastroenterol Hepatol. 2019;4(9):711-720. doi:10.1016/ S2468-1253(19)30189-X

6. Tibsovo. Prescribing information. Agios Pharamceuticals, Inc; 2018. Accessed June 23, 2020.

7. Kim RD, Chung V, Alese OB, et al. A phase 2 multi-institutional study of nivolumab for patients with advanced refractory biliary tract cancer. JAMA Oncol. 2020;6(6):1-8. doi:10.1001/jamaoncol.2020.0930

8. Oh DY, Lee KH, Lee DW, et al. Phase II study assessing tolerability, efficacy, and biomarkers for durvalumab (D) ± tremelimumab (T) and gemcitabine/cisplatin (GemCis) in chemo-naïve advanced biliary tract cancer (aBTC). J Clin Oncol. 38(suppl 15):4520. doi:10.1200/JCO.2020.38.15_ suppl.4520

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