Several medical advances made in the treatment of cholangiocarcinoma (CCA) were presented at the 2024 CCA Summit, including updates in chemotherapy, targeted therapies, targeted protein degradation, antibody–drug conjugates, and liver-directed therapies.
Madhulika Eluri, MD, delivered a presentation on the latest advancements in chemotherapy for the treatment of CCA. She communicated that only 20% to 30% of patients with CCA are resectable; therefore, a majority will require systemic therapy.1 Currently approved chemotherapy regimens for the treatment of advanced CCA were based on 3 phase 3 trials, including ABC-02, which investigated gemcitabine and cisplatin (Gem-Cis) versus Gem; TOPAZ-1, which investigated Gem-Cis plus durvalumab versus Gem-Cis alone; and KEYNOTE-966, which investigated Gem-Cis plus pembrolizumab versus Gem-Cis alone. Despite immunotherapy combinations, the overall survival (OS) in each of these trials was found to be slightly over 1 year.1
Another chemotherapy regimen that has been investigated in patients with advanced CCA is the triplet therapy FOLFIRINOX, which was compared with Gem-Cis in the randomized phase 2/3 PRODIGE 38 AMEBICA study. The study included 191 chemotherapy-naïve patients with advanced biliary tract cancer (BTC). The 6-month progression-free survival (PFS), however, was not significant between the 2 therapies.1 The randomized phase 3 SWOG1815 study investigated Gem-Cis with or without nab-paclitaxel in 441 chemotherapy-naïve patients with advanced BTC. Results of this study showed there was no difference in OS between the 2 treatments. Another study, IMbrave 151, investigated Gem-Cis with or without atezolizumab and bevacizumab in 162 chemotherapy-naïve patients with advanced BTC. The PFS, however, was similar between the 2 treatment arms.1 The randomized phase 3 MITSUBA study, which compared Gem-Cis with or without S-1 in 246 chemotherapy-naïve patients with advanced BTC, showed promising results, with an OS hazard ratio of 0.79. However, Gem-Cis plus S-1 was associated with a higher percentage of diarrhea, stomatitis, and rash.1
In a survey conducted by the Cholangiocarcinoma Foundation, patients reported that the second most important factor when considering different therapies is their quality of life.1 When looking at adverse events from these clinical trials with chemotherapy regimens, up to 80% of patients have had grade 3 or 4 adverse events. Dr Eluri concluded by noting that it is important to incorporate supportive care and quality-of-life measures into clinical trials.1
Targeted therapies are a promising treatment option for patients with CCA. Adel Kardosh, MD, PhD, presented on the latest updates in this area. Dr Kardosh explained that FGFR2 gene fusions and rearrangements are present in approximately 15% of patients with intrahepatic CCA.2 There are 2 approved therapies, pemigatinib and futibatinib, targeting FGFR2 for patients who have progressed on or after 1 line of systemic therapy.2 These treatments are associated with an overall response rate (ORR) of 36% and 42%, respectively, as well as a median OS of approximately 21 months for both. Currently, second- and third-generation FGFR inhibitors are being developed, and include gunagratinib, lirafugratinib, and tinengotinib. They are irreversible binding agents with a higher affinity for FGFR and a different binding site, compared with pemigatinib and futibatinib. They not only affect rearrangements and fusions, but also alterations, including mutations, translocations, activation, and amplification.2
Another therapeutic target is isocitrate dehydrogenase (IDH). Mutations in IDH1 and IDH2 are found in approximately 15% to 20% of patients with BTC. Ivosidenib is currently the only approved treatment for pretreated IDH1-mutated CCA based on the ClarIDHy trial, which had a median OS of 10.3 months compared with 7.5 months with placebo. A phase 1 dose-escalation trial investigated LY3410738, an oral IDH1/2 inhibitor, as monotherapy or in combination with Gem-Cis as a first-line therapy for advanced IDH-mutant CCA. Results of this study showed a 46% ORR in the combination arm.2
Other novel targets include neurotrophic tropomyosin receptor kinase inhibitors, rearranged during transfection inhibitors, and multikinase inhibitors. This is a promising era for targetable therapies, with ongoing development of treatments aimed at both established and novel targets.2
Filip Janku, MD, PhD, then discussed targeted protein degradation, which has emerged as a novel approach to combat cancer and other diseases. This method can eliminate disease-causing proteins through CRISPR gene editing, RNA interference/antisense oligonucleotides, and molecular glue degraders (MGDs).3 MGDs offer a unique modality by enabling the interaction between the target protein and a ubiquitin ligase complex, leading to the protein’s degradation. Unlike proteolysis-targeting chimeras (PROTACs), MGDs are small molecules that do not require a binding pocket, have high selectivity, and tunable degradation. In contrast, PROTACs are heterobifunctional, require a binding pocket, and possess a high molecular weight.3 Examples of MGDs include immunomodulatory drugs such as lenalidomide and pomalidomide, while notable PROTACs include agents targeting various proteins such as ER, AR, BCL6, KRAS G12D, MDM2, STAT3, BTK, and BRAF.3
Sarina A. Piha-Paul, MD, explained that personalized cancer therapy is increasingly shifting toward a tumor-agnostic approach, selecting treatments based on specific biomarkers rather than the type of tumor.4 The idea of targeted drug delivery to tumors was first introduced by Paul Ehrlich, MD, who developed the concept of the “magic bullet.”4 This concept suggests that drugs can reach their intended cell targets without harming surrounding healthy tissue. Antibody–drug conjugates (ADCs) are a new class of drugs designed to harness the targeting ability of monoclonal antibodies (mABs) by linking them to cell-killing agents. The ideal ADC has a highly selective mAB, a potent cytotoxic drug, and a linker. Unfortunately, there are currently no FDA-approved ADCs for CCA.4
A new ADC of interest is puxitatug samrotecan (P-Sam), a B7-H4 targeting topoisomerase I inhibitor. P-Sam was evaluated in BLUESTAR, a first-in-human, phase 1/2a, open-label, multicenter study. Enrolled patients had advanced metastatic endometrial, ovarian, breast cancer or CCA, and were B7-H4 positive.4 Patients with CCA and treated with P-Sam had a 10% disease-control rate at 12 weeks. Another ADC, trastuzumab deruxtecan, was evaluated in the DESTINY-PanTumor02 phase 2 study, which enrolled patients with HER2-expressing solid tumors. Forty- one patients with CCA were enrolled and, for centrally confirmed HER2 immunohistochemistry 3+ CCA (n=16), the ORR was 56.3%.4
Dr Piha-Paul explained that a challenge of an ADC is that, although it is a targeted chemotherapy, it is still a therapy with potential toxicities. Acceptable toxicities depend on the context and the prognosis of the cancer.4 Future perspectives include optimizing patient selection, developing new ADC constructs, and investigating biomarkers for ADC combinations.4
Finally, Joseph M. Herman, MD, MSHCM, presented a unique liver-directed therapy for CCA, a technique known as histotripsy.5 Histotripsy utilizes a novel mechanism of action that mechanically destroys and liquefies tissue, inducing instantaneous cell death with exceptional precision and control. Ultrasound is emitted through the patient’s body noninvasively and activates a high pressure that generates water vapor to create microbubbles. When these microbubbles expand and contract, they mechanically destroy tissue. Histotripsy offers several advantages; most patients are able to return home either the same day or the next day after their procedure.5 Multiple tumors can be treated in a single session, and histotripsy may be less likely to denature antigens in the treated area. Imaging conducted after histotripsy demonstrates the destruction of the tumor while preserving the surrounding ducts and blood vessels. Long-term follow-up of patients treated with histotripsy indicated that hepatocyte repair occurs about a month after the treatment. As of October 2023, approximately 1000 tumors have been treated with histotripsy. This therapy presents a promising option for patients with cancer, including CCA, as it addresses some of the limitations associated with existing treatment modalities.5
With the development of both conventional and cutting-edge therapies, there is hope for improving outcomes for patients with CCA, although further research is warranted to optimize treatment efficacy and minimize toxicities.
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