R. Kate Kelley, MD, details the ongoing investigation of RLY-4008 for patients with advanced cholangiocarcinoma harboring FGFR2 fusions or rearrangements, other ongoing investigations in cholangiocarcinoma, and the importance of molecular testing to drive treatment decisions in this population.
The selective FGFR2 inhibitor RLY-4008 has generated higher response rates compared with historical data for prior pan-FGFR inhibitors in patients with cholangiocarcinoma harboring FGFR2 fusions or alterations who have not been exposed to a prior FGFR inhibitor, according to R. Kate (Katie) Kelley, MD.
Data from the phase 1/2 ReFocus trial (NCT04526106) previously presented at the 2022 ESMO Congress showed that patients treated at the recommended phase 2 dose of 70 mg daily experienced an overall response rate (ORR) of 88.2% (95% CI, 63.6%-98.5%) and a confirmed ORR of 82.4% (95% CI, 56.6%-96.2%). Across all dose levels, the ORR was 63.2% (95% CI, 46.0%-78.2%) and the confirmed ORR was 57.9% (95% CI, 40.8%-73.7%).1
Since RLY-4008 has a different mechanism of action compared with prior pan-FGFR inhibitors, Kelley noted that it could have a different mechanism of resistance, which could delay resistance in this patient population.
“[An] important future direction for RLY-4008 in the cholangiocarcinoma space will be to examine its activity in the context of a variety of different resistance mutations. We have patients who have progressed on other FGFR2 inhibitors [that are] now approved for clinical use, including pemigatinib [Pemazyre] and futibatinib [Lytgobi], and it will be important for us to catalog the activity of all these agents against the most prevalent FGFR2 kinase domain resistance mutations so we know which agents may be useful for [certain] patients,” Kelley, a professor of clinical medicine in the Department of Medicine (Hematology/Oncology), at the University of California, San Francisco (UCSF), in San Francisco, CA, said in an interview with OncLive®.
Kelley, who is also an affiliated faculty member of the Cancer Immunotherapy Program at UCSF, detailed the ongoing investigation of RLY-4008 for patients with advanced cholangiocarcinoma harboring FGFR2 fusions or rearrangements, other ongoing investigations in the cholangiocarcinoma space, and the importance of molecular testing to drive treatment decisions for this patient population.
Kelley: One of the biggest unmet needs is finding more effective therapies in the second- and later-line [settings] for a broad swath of the population. We have [seen] improvements in first-line therapy with the addition of immune checkpoint inhibitors to standard chemotherapy with gemcitabine and cisplatin.
These data came from the [phase 3] TOPAZ-1 trial [NCT03875235] of combining durvalumab [Imfinzi] with gemcitabine plus cisplatin, and, more recently, validating data from the [phase 3] KEYNOTE-966 trial [NCT04003636] showed similar improvement in overall survival from the addition of pembrolizumab [Keytruda] to gemcitabine and cisplatin. These are significant improvements in the first line.
Unfortunately, in the second and later lines, we have not seen much progress outside of specific molecularly defined subgroups. For those subgroups, there has been enormous progress. However, for patients without specific targetable mutations, we are in great need of more active, durable therapies.
With the advent of and access to tumor mutation profiling across solid tumors in oncology, it has become clear that cholangiocarcinoma is genomically heterogeneous. In some cases, the genetics of cholangiocarcinoma may be related to anatomy. Intrahepatic cholangiocarcinoma in particular harbors a variety of targetable mutations, including FGFR2 fusions or rearrangements in about 10% of [patients].
IDH1 mutations [occur] in around 15% of [patients with] intrahepatic cholangiocarcinoma. There are other targetable mutations present in smaller subgroups of [patients with] intrahepatic and all types of cholangiocarcinoma, including NTRK fusions or rearrangements, BRAF mutations, and microsatellite instability, just to name a few.
Turning back to intrahepatic cholangiocarcinoma, FGFR2 fusions or rearrangements have evolved as a meaningful target for therapy. FGFR2, as a gene, has oncogenic capacity. When it is uncontrolled—either because of dysregulation from a fusion or rearrangement linking it to a promoter under different regulation than its normal gene, or through an activating mutation within the kinase domain—the FGFR2 gene promotes cell proliferation, metastasis, angiogenesis, and all the other hallmarks of malignancy. It is a clear-cut driver in a lot of settings, including cholangiocarcinoma. For this reason, it is an appealing therapeutic target. We have seen with a variety of different types of inhibitors that it is an active target with meaningful response.
There are multiple FGFR inhibitors now available in the clinic for [patients with] cholangiocarcinoma harboring FGFR aberrations, as well as other tumor types. The earliest FGFR inhibitors have been pan-FGFR inhibitors, with activity across a variety of the FGFR isoforms—specifically FGFR1/2/3/4, with most activity usually [seen] at FGFR1/2/3.
Having this broader spectrum of activity could be advantageous when trying to target, for example, a [tumor with] an FGFR3 fusion or rearrangement, which is more common in bladder cancers or urothelial malignancies [vs] biliary [tract cancers]. However, there can be downsides [to pan-FGFR inhibition], including off-target toxicity, particularly with FGFR1 as a target. Older [FGFR] inhibitors, such as infigratinib [Truseltiq], pemigatinib, and erdafitinib [Balversa], are adenosine triphosphate [ATP] competitive, and these are pan-FGFR inhibitors with a certain mechanism of action that is across more than just the FGFR2 isoform.
RLY-4008 is a highly selective, purely FGFR2 inhibitor without much activity on FGFR1/3/4, [and it has] a different mechanism of action. It is a covalent inhibitor and binds to FGFR2 with a unique conformational dynamic [that is] not purely ATP competitive. One of the advantages of being FGFR2 selective is the lack of off-target toxicity due to FGFR1 inhibition. We have seen with RLY-4008 that there is a very low rate of hyperphosphatemia, for example.
One of the other hypothetical advantages of [RLY-4008’s] different mechanism of action is that perhaps there will be different mechanism of resistance, or its highly selective and potent activity at FGFR2 may delay the emergence of resistance. This is at the hypothesis stage and will require validation in clinical cohorts with longitudinal follow-up.
ReFocus is a phase 1/2 trial began as a first-in-human study, but has now enrolled over 200 patients. The ReFocus design includes multiple cohorts, including patients with and without exposure to prior FGFR inhibitors.
Some of the intriguing early data were presented by Lipika Goyal, MD, [of Massachusetts General Hospital] at the [2021 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics].2 Intriguingly, in a cohort of patients with all types of FGFR alterations combined, including fusions with and without prior [treatment with a] FGFR inhibitor, as well as patients with FGFR mutations and amplification, [66%] of patients [n = 25/38] had radiographic reduction [of at least 10%]. This is a very encouraging metric. Those responses appeared quite durable, with [58%] of patients [n = 26/48] still on treatment at that time.
When we look at more recent data with longer follow-up, we saw that these results were bearing out. Antoine Hollebecque, MD, [of Gustave Roussy Cancer Center] presented updated results from the ReFocus trial at the 2022 ESMO Congress. The cohort Dr Hollebecque focused on [included] patients who were had intrahepatic cholangiocarcinoma with FGFR2 fusions who were naive to prior treatment with FGFR inhibitors.
In those 38 patients who were naive to prior FGFR inhibitor, the objective response rate was [63.2%] and 92% of patients had some degree of tumor reduction. A majority of these were [confirmed] partial responses. Within that 38-patient cohort, 17 patients were treated at the recommended phase 2 dose of 70 mg per day. Among those patients, the ORR was [88.2%]. These responses were quite durable, with the majority of patients [n = 15/17] remaining on treatment at the time of reporting.
The ReFocus trial data, particularly from the FGFR inhibitor–naïve cohort, reinforced that the selectivity of RLY-4008 and its potency for inhibiting FGFR2 translated into higher response rates then we've seen so far with pan-FGFR inhibitors, including the ATP-competitive inhibitors now in the clinic.
The provocative efficacy in the FGFR2 inhibitor–naïve subgroup of patients has prompted expansion of the ReFocus trial to grow this cohort and achieve much more robust data in hopes of establishing RLY-4008 as a first FGFR inhibitor option in patients with FGFR2 rearranged cholangiocarcinoma.
The trial has also expanded to include a first-line cohort [of patients who received] no prior chemotherapy. The question in our minds is, would a FGFR2 inhibitor, such as RLY-4008 with such potent activity, be superior to chemotherapy in this context? That is a very difficult trial to design and conduct, given the very small sample sizes and the fact that many patients [with cholangiocarcinoma] do not have their mutation results available at the start of first-line chemotherapy.
That said, the results from this small [chemotherapy-naïve] cohort planned in ReFocus will be informative as to how to proceed in that direction down the road.
There is a subset of patients with biliary tract cancer and patients with other tumor types who have de novo primary FGFR2 kinase domain mutations or FGFR2 activating mutations who may also be well served by RLY-4008 as a therapeutic agent. We look forward to the results from the ReFocus trial cohort looking at other FGFR2 activating mutations.
One promising development wasthe [FDA] approval of futibatinib [for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 fusions or other rearrangements], based on the results of the phase 2 FOENIX*-CCA2 trial [TAS-120-101; NCT02052778].3
The futibatinib data are quite intriguing because futibatinib also has a different mechanism of activity than the ATP-competitive inhibitors. [It is a] covalent pan-FGFR inhibitor, and it had an intriguing ORR [at 42%].
Down the road, we're looking forward to agents that can combat resistance and specifically inhibit the kinase domain resistance mutations that we know can occur after prolonged exposure [to an FGFR inhibitor]. This is analogous to the story of targeted therapy in lung cancer, where we have seen the next generations of drugs evolve to combat specific resistance mutations, as well as to stave off their development from the beginning. We hope that [therapy] the FGFR2-rearranged population within cholangiocarcinoma eventually evolve to a similar treatment paradigm.
The field is very dynamic right now in biliary tract cancers, and we foresee even more dynamic changes on the horizon, as we learn more about the relevant molecular subgroups within biliary tract cancers. This goes for not just molecular subgroups, but also immunologic subgroups.
A key direction beyond FGFR2 is identifying active therapies for other molecular subgroups. We now have a tumor agnostic approval for [dabrafenib (Tafinlar) in combination with trametinib (Mekinist)] for patients with BRAF V600E mutations, of which there are a small proportion in cholangiocarcinoma and biliary tract cancers.
Moreover, we are excited to see the evolution of HER2-targeted therapies for the subsets of [patients with] cholangiocarcinoma and gallbladder cancers with HER2 overexpression or amplification, which is another meaningful subgroup, accounting for up to 15% of gallbladder cancers.
Beyond molecular subgroups defined by tumor mutations or protein expression, we're also hoping to make further advances in the role of immune checkpoint inhibitors and immunotherapy in general in biliary tract cancers. Currently, the addition of checkpoint inhibitors to chemotherapy has been a huge advance in the first-line setting, but only a subset of patients benefit. We need to continue our efforts to better understand how to mobilize the immune system to achieve an immune response in the complex space of the liver and the biliary tract.
A key takeaway is the critical importance of performing tumor molecular profiling using a comprehensive panel that includes coating domains and is validated for fusion or rearrangement detection for FGFR2. Molecular profiling should also include testing for other potential candidates, such as for HER2 overexpression or amplification, microsatellite instability, and tumor mutation burden based on tumor agnostic FDA approvals.
To get these results as early as possible during therapy is essential to make good treatment decisions, including choice of second-line therapies. For patients who may not be demonstrating good response in the first line, they may have other options earlier in their course of treatment than we're currently used to [seeing].