At the CCA Summit during the 2021 Annual Meeting of the American Society of Clinical Oncology (ASCO), Mitesh J. Borad, MD, Associate Professor of Medicine, Mayo Clinic, Phoenix, AZ, reviewed some of the key topics presented at ASCO 2021 related to cholangiocarcinoma (CCA) and other biliary tract cancers. Before turning to the specific presentations, Dr Borad welcomed the May 28, 2021, FDA approval of infigratinib (Truseltiq) for patients with advanced or metastatic CCA and FGFR2 fusions or rearrangements. Infigratinib follows pemigatinib (Pemazyre) as the second targeted therapy now available for this patient population.
The FIGHT-202 study investigated the safety and efficacy of pemigatinib (Pemazyre), a selective, oral FGFR1-3 inhibitor, in patients with previously treated, locally advanced or metastatic cholangiocarcinoma (CCA) and FGFR2 alterations, predominantly fusions and rearrangements. Ghassan K. Abou-Alfa, MD, MBA, Professor of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, presented updated, mature safety and efficacy data from the FIGHT-202 clinical trial.1
At the study cutoff on April 7, 2021, the FIGHT-202 study included 147 patients (aged ≥18 years) with CCA who had received ≥1 previous treatments for CCA and were randomized into 3 cohorts. Cohort A included 108 patients with CCA and FGFR fusions or rearrangements; cohort B included 20 patients with CCA and FGFR mutations or amplifications; and cohort C included 17 patients with no known FGFR mutations or other alterations.
At a median follow-up of 30.4 months, the median treatment duration was almost 6 (ie, 5.9) months. The overall response rate was 37%, which is “a very robust response rate, similar to what has been previously presented,” Dr Borad said.
In all, 4 (3.7%) patients had a complete response to therapy; it “would be interesting to know who these patients are,” he added.
“Notably, there were no responses in cohort B or C,” Dr Borad said. At the cutoff time, all the responses were in cohort A, so mainly the activity is in patients whose disease is associated with FGFR fusions or rearrangements, he noted.
The duration of response was 8.1 months, a “fairly durable” response, Dr Borad said. The median overall survival (OS) was 17.5 months in cohort A compared with 6.7 months in cohort B and 4 months in cohort C.
An analysis of the median OS in responders versus nonresponders “was not a preplanned analysis,” said Dr Borad, but showed a 30.1-month duration for responders (N = 40) versus 13.7 months for nonresponders (N = 68). This is “something to investigate further,” he suggested.
The adverse event profile was very similar to what has been presented previously in this category of agents, he noted. The most common all-cause adverse events were hyperphosphatemia (58.5%), alopecia (49.7%), diarrhea (46.9%), fatigue (43.5%), nausea (41.5%), and dysgeusia (40.8%). “These were the common adverse events that have previously been noted,” Dr Borad said.
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Juan W. Valle, MD, Professor in Medical Oncology, University of Manchester, and Professor and Honorary Consultant in Medical Oncology, The Christie NHS Foundation Trust, Manchester, England, presented results of a preplanned analysis of patient-reported outcomes (PROs) from the FOENIX-CCA2 clinical trial in patients with intrahepatic cholangiocarcinoma (CCA) and FGFR2 fusions or rearrangements.
This preplanned analysis focused on quality-of-life PROs of patients with CCA who received futibatinib, a highly selective, irreversible oral FGFR1-4 inhibitor.1
In this pivotal phase 2 study, the confirmed objective response rate with futibatinib was 41.7%, and the median duration of response was 9.7 months in patients with intrahepatic CCA and FGFR2 fusions or rearrangements, Dr Valle reported.
The FOENIX-CCA2 study included 103 patients who had previously received ≥1 lines of therapy. All patients received 20 mg daily of futibatinib in 21-day cycles. The patients’ quality of life was assessed at baseline, at cycles 2 and 4, and then every 3 cycles, up to cycle 13.
The focus of the PROs was on the impact of futibatinib on quality of life, using well-established tools, Dr Borad noted, including the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30), the EuroQol (EQ)-5D-3L, and the EQ and Visual Analog Scale (EQ-VAS).
Overall, the PRO survey had a “very high response rate,” Dr Borad said. Among the 103 enrolled patients, 92 (89.3%) had completed PRO data at baseline and during at least 1 follow-up assessment. At baseline, this mean EORTC-QLQ-C30 global health status score was 70.1, and the EQ-VAS score was 71.7. The mean EORTC-QLQ-C30 global health status score was maintained through cycle 13, representing 9 months of futibatinib treatment. The individual scores for these measures, including global health, physical health, cognitive and emotional well-being, were also stable between baseline and treatment cycle 13.
“These scores were maintained for up to a cycle 13 on all the scales. So clearly, the quality of life was maintained, based on these assessment tools. None of the scores changed more than 10 points, which is statistically significant,” Dr Borad said. “These results demonstrate that futibatinib has a very important impact on the patient’s quality of life,” he concluded.
In April 2021, the FDA granted futibatinib a breakthrough therapy designation for patients with advanced or metastatic CCA and FGFR2 fusions or rearrangements.
The final results from the phase 3 ClarIDHy clinical trial were presented at the meeting by Ghassan K. Abou-Alfa, MD, MBA, Professor of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, in a poster session.1 Earlier results have been presented at previous meetings. The ClarIDHy study was a global, randomized, double-blind phase 3 clinical trial that evaluated the efficacy and safety of ivosidenib (Tibsovo) versus placebo in patients with previously treated cholangiocarcinoma (CCA) and an IDH1 mutation. Dr Abou-Alfa focused on the study’s final results.
Ivosidenib is a first-in-class oral IDH1 inhibitor that was initially approved for newly diagnosed patients with acute myeloid leukemia and IDH1 mutation. In May 2021, the FDA granted ivosidenib a priority review for the treatment of advanced CCA and IDH1 mutation. Overall, 20% of patients with intrahepatic CCA harbor the IDH1 mutation, Dr Abou-Alfa noted.
As of May 31, 2020, a total of 187 patients with CCA and IDH1 mutation were randomized to ivosidenib (N = 126) or to placebo (N = 61). Most (91%) patients had intrahepatic CCA, and 93% had metastatic disease.
The primary end point was progression-free survival (PFS); the secondary end points were overall survival (OS), overall response rate, investigator-assessed PFS, safety, and quality of life. Crossover was allowed, “which is an important caveat,” said Dr Borad, with 70% of the patients crossing over from placebo to ivosidenib. “A statistical methodology called rank-preserving structural failure time [RPSFT] was used to account for the crossover,” he explained.
At the time of this analysis, 13 patients were still receiving ivosidenib therapy, according to Dr Abou-Alfa. The median OS was 10.3 months in the ivosidenib arm versus 7.5 months in the placebo arm, which was not a significant difference (hazard ratio [HR], 0.79; P = .93).
However, this lack of statistical significance “is largely likely due to crossover using the methodology I described,” Dr Borad said.
The RPSFT-adjusted median OS was 10.3 months in the ivosidenib arm versus 5.1 months in the placebo arm, a significant difference (HR, 0.49; P <.0001). The OS data were mature, amounting to 79 events in the experimental arm versus 82 events in the placebo arm.
Ivosidenib was well-tolerated, with an adverse-event profile similar to what has been described before, said Dr Borad. Treatment-related events included nausea (41%), diarrhea (35%), fatigue (31%), cough (25%), abdominal pain (24%), decreased appetite (24%), ascites (23%), vomiting (23%), anemia (18%), and constipation (15%), but all these events were low grade (grade 1-2). Grade 3 or 4 treatment-related adverse events were 7% in the ivosidenib arm versus 0% in the placebo arm. Overall, 7% of patients discontinued ivosidenib treatment because of adverse events compared with 9% of patients in the placebo arm.
The genomic profile of patients with cholangiocarcinoma (CCA) harboring IDH1 or IDH2 has not been defined, according to a study presented during the Clinical Science Symposium of the ASCO 2021 meeting, although 20% of patients with intrahepatic CCA harbor those genomic mutations.
Shalini Makawita, MD, MSc, Fellow, Hematology/Oncology, M.D. Anderson Cancer Center, Houston, TX, presented the results of this comprehensive genomic and immune profiling study, focusing on patients with IDH1- or IDH2-driven intrahepatic CCA and their molecular and immune profile.1
Dr Makawita and colleagues performed comprehensive genomic profiling on 3067 patients with advanced-stage intrahepatic CCA, using a hybrid capture–based FDA-approved assay and next-generation sequencing to analyze the genomic and immune profiles of patients with CCA and IDH1 or IDH2 mutations. The investigators reviewed the patients’ tumor mutational burden (TMB), supplemented by an immunohistochemistry (IHC) assay to measure PD-L1 expression. In 100 samples from 96 patients, 14 immune markers were assessed, using IHC on tissue microarrays. These data were then analyzed in aggregated.
Among the 3067 patients, 426 (14%) had intrahepatic CCA with IDH1 mutation and 125 (4%) had IDH2 mutation, and these were mutually exclusive. Overall, IDH1 and IDH2 had fewer co-occurring genomic alterations than those with IDH wild-type.
“These results are very consistent with what has been reported in other larger data sets. IDH1 mutations tend to occur at the R-132 locus; IDH2 predominantly at the R-172 and R-140 loci,” Dr Borad said. In patients with IDH1 or IDH2 drivers, “We don’t usually see other [co-occurring] drivers, as was shown in this study, such as BRAF or FGFR2,” which are the other actionable drivers often seen in patients with CCA, he noted.
“Of course, there’ll be some exceptions to this rule,” Dr Borad said. For example, among the 2516 patients with IDH wild-type intrahepatic CCA in the study, microsatellite instability high TMB was more than 10 mut/Mb, and PD-L1 expression was also more common in patients with IDH1 mutation than in those with IDH1 wild-type.
But overall, “these immune or genomic features we look for are more common in the IDH wild-type compared with patients with IDH1 or IDH2 mutations,” Dr Borad said. Similarly, P16 alterations, MTAP alterations, and TP53 mutations were also more common in the wild-type IDH.
“This gives us a preview” of the differences between the immune and genomic profiles of patients with IDH-driven versus IDH wild-type cases, Dr Borad concluded.
A study reviewing the natural history of patients with advanced cholangiocarcinoma (CCA) and FGFR2 fusions or rearrangements versus patients with FGFR2 wild-type was presented by Rachna T. Shroff, MD, MS, Chief, Section of GI Medical Oncology, University of Arizona Cancer Center, Tucson.1
Despite a growing understanding of the importance of molecular profiling to guide treatment decisions, real-world data are lacking about the natural history of patients with CCA and FGFR2 alterations who are receiving treatment for advanced disease, according to Dr Shroff. And yet, FGFR2 fusions are common in CCA, occurring in 10% to 16% of patients.
“This is a very important study,” said Dr Borad. This was a US-based study, using the Clinico-Genomic Database from Flatiron Health and Foundation Medicine. This database collects data from 280 US clinics and more than 800 sites in the United States, “so this is definitely a real-world study,” Dr Borad said.
The study’s primary objective was overall survival (OS) in patients with FGFR2 fusions or rearrangements versus FGFR2 wild-type between the date of advanced CCA diagnosis and the time of death. A key focus was to determine the role of FGFR alterations on OS.
Of the 571 patients with CCA who were identified for the study, 496 patients (95% with intrahepatic CCA, and 68% with stage IV disease at diagnosis) had FGFR2 wild-type and 75 patients (95% with intrahepatic CCA; 55% with stage IV at diagnosis) had FGFR2 fusion or rearrangement.
The median OS was 12.1 months for patients with FGFR2-positive disease compared with 7.1 months for patients with FGFR2 wild-type CCA (log rank, P = .184). “Although this was not statistically significant, we can see that there’s a numerical difference,” said Dr Borad.
Similarly, in the subgroup of 437 patients with intrahepatic CCA, the OS was 12.1 in those with FGFR2 alterations versus 7.8 months in patients with FGFR2 wild-type (log rank, P = .375). “Perhaps larger studies would be needed to identify differences in the intrahepatic subtype, which is where all these events occur,” Dr Borad suggested.
In these OS analyses, a not significant trend was seen toward longer OS in patients with FGFR2 genomic alterations. “So it might not be a significant factor in and of itself,” he noted, “but as larger studies are done, we’ll definitely be keeping an eye on the natural history.”
Overall, 68% of the patients with FGFR2 alterations had stage IV disease compared with 55% of patients with FGFR2 wild-type, “So perhaps some of the differences we saw were not because of the alteration, but because of the stage,” Dr Borad concluded.
According to Dr Shroff, a sub-analysis is ongoing to evaluate the OS from the time of initiation of second-line therapy in patients with FGFR2 fusions or rearrangements.
The current use of gemcitabine-based chemotherapy in patients with advanced intrahepatic cholangiocarcinoma (CCA) continues to result in poor prognosis. This single-arm phase 2 clinical trial presented by Zhou Jian, MD, PhD, Liver Cancer Institute, Zhongshan Hospital, Shanghai, China, evaluated gemcitabine oxaliplatin chemotherapy plus the investigational PD-1 inhibitor toripalimab and the oral kinase inhibitor lenvatinib (Lenvima) for first-line treatment of advanced intrahepatic CCA.1
The study’s primary end point was objective response rate (ORR). The secondary end points were progression-free survival (PFS), overall survival (OS), and safety. Several translational evaluations were conducted with whole-exome sequencing of tumor tissue, as well as PD-L1 expression using immunohistochemistry. This is a “small but very provocative study,” Dr Borad observed.
A total of 30 patients with advanced intrahepatic CCA were enrolled in the study. At the end of the last follow-up on February 1, 2021, the ORR was 80%, which is “among the higher response rates we’ve seen in first-line studies,” Dr Borad said.
The disease control rate was 93%, including 1 complete response, and 3 (10%) patients were downstaged and then underwent resection. By the last follow-up, these 3 patients still were free of cancer. The median PFS was 10 months, and the median duration of response was 9.8 months.
“So very, very promising numbers in this small, but provocative, study,” Dr Borad noted. The median OS was not reached, and the 1-year OS was 73.3%. The high ORR seen in this study was primarily (and significantly) associated with PD-L1 expression (P = .048) and DNA damage repair–related mutations (P = .022) evaluations.
Adverse events “were what you would appreciate with these kinds of drugs,” said Dr Borad, including myelosuppression, rash, hypertension, vomiting, and hemorrhaging. Overall, this combination of chemotherapy plus a PD-1 inhibitor and a kinase inhibitor provided “remarkable efficacy and reasonable tolerability” in patients with advanced intrahepatic CCA, according to Dr Jian and colleagues.
The presence of TP53 mutation is known to be linked to poor prognosis in various cancers, but its impact on overall survival (OS) among patients with advanced or metastatic biliary tract cancers has not been elucidated. Sunyoung S. Lee, MD, PhD, Assistant Professor, GI Medical Oncology, M.D. Anderson Cancer Center, Houston, TX, presented the results of a retrospective analysis of clinical outcomes in patients with advanced or metastatic biliary tract cancers and TP53 mutation.1
The data came from databases collected through institutional next-generation sequencing essays, Foundation One, and Guardant360. Among a total of 149 patients with biliary tract cancers and TP53 mutation, 90 patients had advanced or metastatic disease and were not candidates for surgery, radiation, or liver-directed therapy.
The investigators looked at the full range of TP53 mutations and found that the most common TP53 mutations in this study population were R175H (N = 5) and R248Q (N = 4) mutations. In addition, among the co-occurring genetic mutations, the most common mutations included KRAS (N = 15), ARID1A (N = 15), FGFR2 (N = 14), and IDH1 (N = 13).
Overall, the presence of co-mutations TP53 plus either FGFR2 or IDH1 improved the median progression-free survival (PFS) and median OS compared with patients who had TP53 mutation without FGFR2 or IDH1.
For example, the median PFS with first-line chemotherapy in patients with TP53 plus IDH1 co-mutations was 9.5 months versus 3.7 months in patients without IDH1 (P <.05); the median PFS in patients with TP53 plus FGFR2 was 6.9 months compared with only 3.7 months in patients with TP53 but without FGFR2 (P <.05).
Similarly, the median OS was 34.5 months in patients with TP53 and co-mutation FGFR2, 22 months in those with TP53 and IDH1 co-mutation, and only 13.1 months in patients without either of these co-mutations.
Overall, in patients with advanced or metastatic biliary tract cancers, the presence of TP53 mutation alone reduced the OS or PFS compared with patients without this mutation. However, the presence of FGFR2 or IDH1 co-mutation improves survival, including PFS and OS, in patients who receive first-line chemotherapy, according to this study.
Based on the results of this study, TP53 “can have prognostic value, particularly on a co-mutation perspective, which will need to be validated with multi-institutional, larger studies,” Dr Borad suggested.
Molecular alterations have increasingly been used to look at biliary tract cancer subtypes. Kabir Mody, MD, Vice Chair, Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Jacksonville, FL, presented the results of a study of multimodal profiling of biliary tract cancers to investigate the relationship between the many mutational alterations and the differences in immune-related signatures, by disease subtypes.1
Therefore, the investigators “integrated next-generation sequencing and immunological data in this multi-institutional study—a very impressive effort,” Dr Borad said.
The study included data for 455 patients with intrahepatic and extrahepatic bile duct cancer, as well as gallbladder from the Tempus database. Across all disease subtypes, the most common genomic alterations included P53, ARID1A, KMT2C, BAP1, KRAS, TERT, and IDH1. By contrast, FGFR2 fusion or alteration had a low rate.
“The fusion rate was on the lower side; it could have been because of the anatomical bias of 2.6% only,” Dr Borad said. Overall, actionable alterations—including FGFR2 and NTRK1-3 fusion, IDH1 and BRAF V600E mutations, mutational tumor burden (TMB) >10, HER2 expression, and microsatellite instability—were observed in 21.1% of all the patients, and in 28.6% of those with intrahepatic disease.
Mutually exclusive genomic alterations were seen between P53 and BAP1, KRAS and BAP1, P53 and IDH1, KRAS and IDH1, and SMAD4 and BAP1. But “as I said, there’s exceptions for every rule,” Dr Borad reminded meeting participants.
Of note, he said, gallbladder cancer was found to be more inflamed based on immune RNA signatures and had more involvement of classical immune pathways in this study than intrahepatic biliary tract cancer. Furthermore, PD-L1 expression was higher in gallbladder cancer than in the other subtypes.
Higher rates of TMB were seen in ARID1A, BRCA1, and P53, as well as higher rates of association of PD-L1 with BAP1 and NRAS. These results can help guide the development of targeted therapies and encourage use of immune profiling in biliary tract cancers, Dr Mody noted.
“Again, these may be early observations, and larger studies may be needed, but...a very interesting study,” Dr Borad concluded.
Gemcitabine plus cisplatin is the standard of care for first-line treatment of patients with advanced biliary cancer, but resistance mechanisms have been associated with gemcitabine therapy. NUC-1031 is a novel form of gemcitabine that is designed to overcome these resistance mechanisms.
The NuTide:121 study is a phase 3 clinical trial that compares the combination of NUC-1031 and cisplatin versus gemcitabine and cisplatin for first-line treatment of patients with advanced biliary cancer.1 Jennifer J. Knox, MD, Clinician Investigator, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada, presented this poster at the meeting.
This phase 3, open-label ongoing study includes 828 patients with advanced biliary cancer (including cholangiocarcinoma, gallbladder, or ampullary cancer) who are randomized in a 1:1 ratio in 130 sites in North America, Asia Pacific, and Europe. The 828 patients are receiving either NUC-1031 at a dosing of 725 mg/m2 or gemcitabine at the standard dose of 1000 mg/m2. All patients are also receiving 25 mg/m2 of cisplatin.
“This is an ongoing study and is probably one of the largest studies that’s a phase 3 clinical trial in this patient population,” Dr Borad said, other than some of the studies done with immunotherapy. This is “a very large effort to keep our eyes on,” he emphasized.
The primary end points are overall survival and overall response rate. The secondary end points include progression-free survival, safety, and patient-reported quality-of-life outcomes. The study has passed the safety analysis. In all, 3 interim analyses are planned, said Dr Borad, “we’ll keep an eye on this.”
The last 2 topics Dr Borad discussed were poster presentations of 2 emerging FGFR inhibitors. The first study is investigating gunagratinib (ICP 192), a highly selective irreversible FGFR inhibitor, in patients with advanced solid tumors and FGFR alterations. The poster was presented by Ye Guo, MD, Department of Oncology, Tongji University Shanghai East Hospital, Shanghai, China.1
This is a phase 1 study, “so an early experience with gunagratinib, which, like futibatinib,” is a selective irreversible FGFR inhibitor, Dr Borad noted.
As of February 2021, 30 patients have received gunagratinib, at a dosing of 2 mg to 16 mg daily, and it looks like 12 mg is where they settled at, he added.
Of the 30 patients, 12 had FGFR2 fusions and translocations. The overall response rate with gunagratinib was 33% in this group, and the disease control was 92%, including 1 complete response. These are early data but very consistent with other FGFR inhibitors, according to Dr Borad.
He noted that the safety profile is similar to other agents in this class, with common adverse events, including hyperphosphatemia, liver enzyme elevation, and diarrhea, as well as hypercalcemia and hypertriglyceridemia.
The second early study is another clinical trial in progress, “but definitely one we want to keep an eye on,” Dr Borad said.
This is a first-in-human study of a highly selective FGFR inhibitor, RLY-4008, in patients with intrahepatic cholangiocarcinoma (CCA) or other solid tumors.1 The study was presented by Alison M. Schram, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center, New York, NY.
According to Dr Schram, RLY-4008 is a novel, oral FGFR2 inhibitor that is designed to address the resistance seen with nonselective, pan-FGFR inhibitors. This study is a global, multicenter first-in-human dose-escalation study that includes several cohorts of patients who receive daily and twice-daily RLY-4008 therapy. The plan is to enroll 50 patients in this study.
“The study uses a novel dose-escalation design, which is the optimal interval design,” Dr Borad said. “This allows for accelerated titration and accrual to multiple cohorts.”
Several expansion cohorts are planned, which will include treatment-naïve patients with fusion-positive CCA or with other solid tumors, as well as patients with FGFR2 mutation or amplification.
The study is investigating the spectrum of FGFR2 alterations, and as an early study, the primary end points are the maximum tolerated dose, the recommended phase 2B, and safety. Key secondary end points are FGFR2 genotype in blood and tissue tumor, and efficacy measures. Enrollment started in September 2020. “Definitely a study to keep an eye on,” Dr Borad concluded.
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