Advances With Erdafitinib Exemplify the Push For Precision Medicine in Urothelial Cancer

Petros Grivas, MD, PhD

In an interview with OncLive^®, Petros Grivas, MD, PhD, expanded on key updates in the management of urothelial cancer, as presented at the ​​Second Annual Miami Cancer Institute Precision Oncology Symposium.

Second-line advancements include the FDA approval of erdafitinib (Balversa) for patients with locally advanced or metastatic urothelial cancer harboring susceptible FGFR2/3 alterations and progressing on or following 1 or more prior lines of systemic therapy in January 2024. Data from cohort 1 of the confirmatory phase 3 THOR trial (NCT03390504) supported the full approval of the pan-FGFR inhibitor, which now serves as a pivotal second-line option for this population. Grivas noted, however, that the optimal sequencing of erdafitinib alongside other second-line therapeutics requires further investigation.

“The [symposium] itself represents an opportunity to learn across tumor types about how we can expand our knowledge and use precision oncology examples,” Grivas said in the interview. “Erdafitinib is a great example because it uses a particular molecular alteration that [lends itself to] a more personalized approach for patients who [harbor that alteration in their] tumors.”

Novel therapies targeting HER2 are also ushering in a new era of individualized precision medicine, Grivas added, underscoring the importance of biomarker-driven approaches in advancing therapeutic outcomes for metastatic urothelial carcinoma and other solid tumors.

He also spotlighted the impact of data from the phase 3 CheckMate 901(NCT03036098) and EV-302/KEYNOTE-A39 (NCT04223856) trials on the first-line treatment paradigm in a concurrent interview.

Grivas is a physician at Seattle Cancer Care Allliance; an associate professor in the Department of Medicine of the Division of Oncology and clinical director of the Genitourinary Cancers Program at the University of Washington School of Medicine; and an associate member in the Clinical Research Division at Fred Hutchinson Cancer Center, in Seattle, Washington.

OncLive: What have been some of the most significant advances and updates in the management of advanced urothelial carcinoma over the past few years?

Grivas: We’re very excited for the significant evolution and revolution in the field of advanced urothelial carcinoma. At the ​​Second Annual Miami Cancer Institute Precision Oncology Symposium, organized by the Miami Cancer Institute, we had the opportunity to discuss multiple significant updates. We have new data from practice-changing phase 3 trials that we discussed at the meeting. Those include data from the phase 3 EV-302/KEYNOTE-A39 trial [NCT04223856] as well as data from the phase 3 CheckMate 901 trial [NCT03036098]. Both trials are in the frontline setting of advanced urothelial carcinoma. [I also] contextualized [these findings] with the previously known data from the phase 3 JAVELIN Bladder 100 trial [NCT02603432]. Additionally, I discussed subsequent lines of therapy, such as data from the THOR trial looking at erdafitinib and other recent developments in the field. I was very excited to cover this rapid explosion of new datasets in this wonderful precision oncology conference.

What did findings from cohorts 1 and 2 of the THOR study indicate about the use of erdafitinib in patients with select FGFR2/3 alterations?

The THOR trial had 2 cohorts. One cohort was erdafitinib vs salvage rescue chemotherapy, which was a taxane in the United States or vinflunine in Europe. That trial mandated prior [exposure to] checkpoint inhibitors, and most patients had also received platinum-based chemotherapy before. You could argue that it was technically a third-line trial. That [cohort] experienced a significant overall survival and progression-free survival benefit plus a high response rate with the erdafitinib vs a taxane or vinflunine. That led to the full approval of erdafitinib by the FDA for patients who have tumors that harbor FGFR3-susceptible alterations; these are activating mutations or fusions in the FGFR3 gene. They are not amplifications, just mutations or fusion rearrangements that are activating the FGFR3 gene.

The approval [for erdafitinib] is following prior therapy, including immunotherapy, unless [the patient has] a contraindication to immunotherapy. However, the recommendation is to give immunotherapy first. That comes from cohort 2 of the THOR cohort, which compared pembrolizumab [Keytruda] with erdafitinib in this selected population of patients with FGFR3-activating mutations or fusions in the platinum-refractory setting. In this [cohort,] no significant difference in OS or PFS [was observed between the erdafitinib and pembrolizumab arms.] We saw a higher response rate of approximately 40% with erdafitinib and a lower response rate of approximately 22%, but more durable responses [were observed] with pembrolizumab.

How does erdafitinib fit into the second-line treatment landscape, and what questions still exist regarding its optimal role?

We have a previous trial [showing an] OS benefit with pembrolizumab compared with a taxane or vinflunine in the second-line setting after patients become platinum refractory. That probably explains [why] people may get immunotherapy before erdafitinib unless that is a contraindication discussed with the patient. Having said that, the response rate itself is almost doubled with erdafitinib vs pembrolizumab. Nowadays, if people use enfortumab vedotin-ejfv [Padcev] plus pembrolizumab in the first line, then erdafitinib becomes a relevant subsequent option for select patients expressing an FGFR3 mutation or fusion.

The question is whether you use erdafitinib or gemcitabine/cisplatin in the second line post pembrolizumab and enfortumab vedotin. We don’t have data comparing erdafitinib with gemcitabine/cisplatin [in this setting]. In cohort 1 of THOR, most patients received platinum-based chemotherapy before erdafitinib, so it becomes a discussion with patients. It’s good to have options. It is important to perform tumor testing for FGFR3 alterations to [determine whether] the patient has a susceptible alteration, mutation, or fusion [that would make them candidates] for erdafitinib. It’s good to have that test done early on, at the time of diagnosis of metastatic disease, to have the results available later.

What novel or emerging therapies in advanced urothelial carcinoma are shifting the treatment paradigm toward a more individualized approach?

We’re still looking for more therapeutic targets and biomarkers. We have new data with anti-HER2 therapies. We have a recent FDA approval for the anti-HER2 antibody-drug conjugate [ADC] fam-trastuzumab deruxtecan-nxki [Enhertu; T-DXd]. This drug has been used in breast cancer for a long time, and now we have a pan-tumor approval for tumors that have a high immunohistochemical [IHC] expression, or IHC 3+. Data with this agent are very relevant.

It’s important to test these tumors for HER2 by IHC. We’re talking to our pathology departments about that. That includes metastatic urothelial carcinoma across all these other solid tumors. That’s a second example of precision oncology [in urothelial cancer], and it is great to see that. We also have targeted therapies and ADCs such as enfortumab vedotin and sacituzumab govitecan-hziy [Trodelvy], which is an ADC against TROP-2 carrying the payload of a topoisomerase inhibitor. All of these [options] are great examples of precision oncology, and I [enjoyed] hearing more and learning from my colleagues at this wonderful meeting.

Reference

FDA approves erdafitinib for locally advanced or metastatic urothelial carcinoma. FDA. January 19, 2024. May 14, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-erdafitinib-locally-advanced-or-metastatic-urothelial-carcinoma