Checkpoint Inhibitors, FGFR Inhibitors Lead to Continued Advancements in Biliary Tract Cancer

James Harding, MD

Next-generation FGFR inhibitors such as KIN-3248 and immunotherapy-based quadruplet regimens including atezolizumab (Tecentriq), bevacizumab (Avastin), cisplatin, and gemcitabine are seeking to build off advances made with first-generation FGFR inhibitors and immunotherapy-based triplets for patients with advanced biliary tract cancer. These ongoing investigations aim to expand treatment options and enhance the efficacy of standard therapeutics, according to James Harding, MD.

“Advanced biliary tract cancer is a field that's been rapidly evolving over the past 5 to 10 years…hopefully to the betterment of patients,” said Harding, who is a gastrointestinal oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center in New York City, New York.

In findings presented at the 2023 Gastrointestinal Cancers Symposium, the combination of atezolizumab, bevacizumab, cisplatin, and gemcitabine led to a median progression-free survival (PFS) of 8.3 months (95% CI, 6.8-10.0) vs 7.9 months (95% CI, 6.2-8.4) with atezolizumab and gemcitabine/cisplatin as frontline therapy in patients with advanced biliary tract cancer (HR, 0.76; 95 CI, 0.51-1.14). Moreover, the median overall survival (OS) was not reached (95% CI, 11.0-not evaluable) with the quadruplet vs 11.4 months (95% CI, 10.6-NE) with the triplet.¹

Also presented at the meeting was the design of a first-in-human phase 1 study (NCT05242822) of KIN-3248 in patients with advanced and metastatic solid tumors harboring FGFR2/3 gene alterations.2 The next-generation, selective, irreversible, small molecule pan-FGFR inhibitor may overcome secondary FGFR2-mediated resistance, which is commonly seen with current FGFR inhibitors.

In an interview with OncLive^® following an Institutional Perspectives in Cancer (IPC) webinar, Harding highlighted current and emerging areas of research in biliary tract cancer, including key contributions from TOPAZ-1 (NCT03875235) and the phase 3 SWOG 1815 trial (NCT03768414), the development of immunotherapy and chemotherapy combinations, and continued efforts to utilize personalized medicine in clinical practice. 

OncLive^®: What key trials have contributed to the evolution of frontline chemoimmunotherapy approaches in biliary tract cancer?

Harding: Historically, the only treatment for biliary tract cancers that can't be removed with surgery or treated with local therapies has been systemic therapy with gemcitabine and cisplatin.

Recently, the large, global, phase 3 TOPAZ-1 study assessed the value of adding durvalumab (Imfinzi) to gemcitabine and cisplatin. This study, which was reported in 2022, demonstrated an improvement in OS for the combination of gemcitabine, cisplatin and durvalumab vs gemcitabine [and cisplatin] alone. Secondary end points like overall response rate [ORR] and PFS were also statistically significant and favored the triplet combination. Since then, there have been a number of updates from TOPAZ-1.

Additional follow-up confirmed a continued separation of the OS curves. Importantly, [it also showed] that 24% of the population remained alive at 24 months compared [with] only 10% [of patients] who received gemcitabine and cisplatin. In addition, subset analysis showed that this therapy benefits all patients that were tested. Emerging genetic analysis suggests that there is not a specific genetic subset that would benefit more [from the triplet], although [we] acknowledge [that this was] an ad hoc analysis and small sample size. [Based on] these data, gemcitabine, cisplatin and durvalumab represents another standard of care in the frontline setting.

Other works have looked at combination chemotherapies. Notably, [there was] a recent presentation of the SWOG [1815] intergroup study that evaluated the combination of gemcitabine, cisplatin, and nab-paclitaxel [Abraxane] versus gemcitabine and cisplatin alone. Unfortunately, this study was negative. [Although] it didn't result in statistical improvement [of] primary or secondary end points, it illustrated that a rare disease subset could be treated in the context of a clinical study in the United States and Canada.

As immunotherapy has become a central part of treatment in advanced biliary tract cancer, how should immune-related adverse effects (irAEs) be managed?

irAEs require close scrutiny and [attention] when treating a patient with an immune checkpoint inhibitor. Thankfully, with single-agent anti–PD-1 or anti–PD-L1 therapy, the rate of irAEs is relatively low. Most [irAEs] can be reversed with complete symptom resolution by instituting immunosuppression. Others are not reversible but are treatable when they occur. It's critical that patients are aware of these potential AEs and notify clinicians of any change in their clinical status. Hopefully, new therapies will be designed that reduce the risk of irAEs even further.

What future directions do you envision for the development of combination regimens in biliary tract cancer?

There are going to be continued efforts to evaluate immunotherapy combinations within biliary tract cancers. These include novel combinations [that] we saw at the 2023 Gastrointestinal Cancers Symposium [2023 ASCO GI]. [Data from] the [phase 2 IMbrave 151 trial] of atezolizumab and bevacizumab plus gemcitabine/cisplatin vs atezolizumab and gemcitabine/cisplatin was provocative and will require follow-up investigation.

How does new research on molecular targets build on efforts to integrate precision medicine into the treatment of biliary tract cancer?

There's still a team effort to evaluate precision medicines in biliary tract cancers. We [recently] saw continued data on the use of FGFR inhibitors in a cohort of patients with FGFR2 fusion[–positive] cholangiocarcinoma. [These patients were] treated with erdafitinib [Balversa], [which] showed a high ORR. [This result] adds to data [on the use of] pemigatinib [Pemazyre] and futibatinib [Lytgobi], [which demonstrates] that [FGFR inhibitors] are an important therapeutic strategy [for biliary tract cancers].

What other updates in precision medicine stood out to you from the 2023 Gastrointestinal Cancers Symposium?

We presented a poster of an in-progress trial of KIN-3248, which is a next-generation inhibitor [that] attempts to break previously known resistance mechanisms. There have been ample data for other compounds that have shown promise for this approach. Additionally, we're seeing anti-tumor activity from HER2-targeted therapies, and we also saw some emerging data for MDM2 inhibition in this disease.

Editor’s Note: Dr. Harding reports serving as a consultant or on a paid advisory board for Adaptimmune, AstraZeneca, Bristol Myers Squibb, Exelixis, Elevar, Eisai, Genoscience (uncompensated), Hepion, Imvax, Merck (DSMB) Medivir, QED, Tyra, Zymeworks (uncompensated); he reports receiving institutional research support from Bristol Myers Squibb, Boehringer Ingelheim, CytomX, Debiopharm, Eli Lilly, Genoscience, Incyte, Loxo @ Lilly, Novartis, Polaris, Pfizer, Zymeworks, Yiviva.

References

1. El-Khoueiry AB, Ren Z, Chon H, et al. IMbrave151: A phase 2, randomized, double-blind, placebo-controlled study of atezolizumab with or without bevacizumab in combination with cisplatin plus gemcitabine in patients with untreated, advanced biliary tract cancer. J Clin Oncol. 2023;41(suppl 3):491. doi:10.1200/JCO.2023.41.3_suppl.491
2. Harding JJ, Perez CA, Kato S, et al. First in human (FIH) phase 1/1b study evaluating KIN-3248, a next-generation, irreversible pan-FGFR inhibitor (FGFRi), in patients (pts) with advanced cholangiocarcinoma (CCA) and other solid tumors harboring FGFR2 and/or FGFR3 gene alterations. J Clin Oncol. 2023;41(suppl 4):TPS637. doi:10.1200/JCO.2023.41.3_suppl.TPS637