Grivas Expands on Key Data From the 2023 ESMO Congress in Urothelial Cancer

Petros Grivas, MD, PhD, spotlighted key advancements and research in urothelial cancer reported at the 2023 ESMO Congress in an interview with OncLive®, detailing findings from the phase 3 CheckMate 901 (NCT03036098), EV-302/KEYNOTE-A39 (NCT04223856), and THOR (NCT03390504) trials, as discussed in his presentation at a recent OncLive® State of the Science Summit™ (SOSS) on genitourinary cancers.

“In 2023, [we saw] remarkable achievements and progress in the field of advanced urothelial carcinoma, with the major highlights coming from the 2023 ESMO Congress,” Grivas, who is the clinical director of the Genitourinary Cancers Program and a professor in the Division of Medical Oncology at the University of Washington School of Medicine in Seattle, stated during the interview.

As chair of the event, Grivas, who is also a physician and professor in the Clinical Research Division at Fred Hutch, provided further insights from his colleagues’ presentations in another interview.

OncLive: What was the most important research in urothelial cancer to come out of the 2023 ESMO Congress?

Grivas: At this SOSS event, I presented updates from the recent data in urothelial carcinoma and provided background on how we have been treating this disease over the last few decades. Platinum-based chemotherapy, ideally cisplatin-based chemotherapy, has been the cornerstone in the frontline setting of advanced urothelial carcinoma for many years. Recently, we saw data from 2 very important trials: the CheckMate 901 and EV-302/KEYNOTE-A39 trials. Those trials are challenging the standard of care [SOC].

What were the key findings from the CheckMate 901 trial?

In June 2020, we saw the results from the [phase 3] JAVELIN Bladder 100 trial [NCT02603432], [which was] a randomized study comparing avelumab [Bavencio] plus best supportive care with best supportive care alone in patients who had [achieved] stable disease on platinum-based chemotherapy. That established maintenance with avelumab as the SOC in several countries for patients who did not experience disease progression on platinum-based chemotherapy.

At this year’s ESMO Congress, we saw the CheckMate 901 trial comparing nivolumab [Opdivo] and gemcitabine/cisplatin vs gemcitabine/cisplatin alone. That trial was designed before the results of the JAVELIN Bladder 100 trial came out, and only [approximately] 20% of patients in the chemotherapy control group received maintenance avelumab. These patients continued on the experimental arm with concurrent nivolumab with chemotherapy [for] up to 2 years afterwards, as we had a continuation maintenance approach.

CheckMate 901 showed a significant overall survival [OS] benefit with a HR of 0.78 favoring nivolumab plus gemcitabine and cisplatin over gemcitabine/cisplatin. The response rate was slightly higher with the triplet vs the doublet, and [21.7%] of patients had complete responses [CRs] with [the triplet vs 11.8% with the doublet]. Patients given the triplet had a medium duration of response of 37.1 months, so there is a subset of patients with durable responses. Toxicity, as expected, was higher with the triplet, but it was manageable toxicity as we know from chemo-immunotherapy combinations.

How has data reported from the EV-302 trial influenced the current treatment paradigm in urothelial cancer?

The CheckMate 901 trial was positive, [but] the results [may have been] overshadowed by impressive data from the EV-302 trial. That trial compared pembrolizumab [Keytruda] plus enfortumab vedotin-efjv [Padcev] vs platinum-based chemotherapy in the frontline setting of advanced urothelial carcinoma. It was also presented at ESMO and we’re waiting for the publication. The trial was also designed before the JAVELIN Bladder 100 trial was reported, so approximately one-third of patients in the chemotherapy control arm received maintenance avelumab. Overall, more than half of patients in the chemotherapy control arm received some form of immunotherapy afterwards. That trial showed impressive benefit in progression-free survival with a HR of 0.45, and OS with a HR of 0.47, favoring the combination vs platinum-based chemotherapy. However, the toxicity must be discussed. More than half of patients had grade 3 or higher treatment-related adverse effects with pembrolizumab and enfortumab vedotin; this was 70% with chemotherapy. Overall, both of those trials are practice changing.

I want to point out that pembrolizumab and enfortumab vedotin [produced] a 29.1% CR rate, and some of those responses were durable. Moreover, the median OS was doubled from 16.1 months to 31.5 months. Only very few patients in the chemotherapy control arm had access to enfortumab vedotin. If there was more access, the magnitude of difference would probably have been lower. However, the results are still impressive and practice changing.

Pembrolizumab plus enfortumab vedotin is a new SOC for patients who can tolerate this combination, which is most patients in practice, and in countries where this combination can be reimbursed. That’s a whole other discussion about reimbursement and equal access to care in global oncology.

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

At the SOSS, we discussed data from cohorts 1 and 2 of the phase 3 THOR study presented at this year’s ESMO Congress. This [trial evaluated] erdafitinib in patients selected based on genomic sequencing. Their tumors [were required to have] FGFR2/3 susceptible alterations. Erdafitinib was better than chemotherapy in cohort 1. Cohort 2 compared erdafitinib with pembrolizumab in patients with platinum-refractory disease in the second-line setting and no significant OS and PFS difference [were observed] between erdafitinib and pembrolizumab.

However, there was almost a doubling of overall response rate [with] erdafitinib in selected patients harboring FGFR2/3 activating mutations or fusions. If you need a high response rate [for patients with] visceral metastases, symptomatic disease, or high volume, you may potentially think about using erdafitinib over pembrolizumab. Of course, there are many other agents being tested, and clinicians must select the right treatment for the right patient at the right time.

Looking ahead, what are some promising agents in development in genitourinary cancers?

Ongoing clinical trials in the field include [the phase 3] TROPiCS-04 trial [NCT04527991] of sacituzumab govitecan-hziy [Trodelvy] vs taxane chemotherapy. The trial has finished accrual and results are pending. Sacituzumab govitecan has an accelerated approval right now in the US for patients after platinum-based chemotherapy or immunotherapy. We discussed a little bit about the data from this antibody-drug conjugate as well. Overall, there’s so much progress being made in the field, and we’re very excited for the future.