Ongoing Trials Underscore Need for Further Precision Medicine Approaches in Bladder Cancer


Guru P. Sonpavde, MD, discusses key data presented from the phase 3 THOR and SWOG S1011 studies at the 2023 ASCO Annual Meeting, and details ongoing trials that could help advance precision medicine approaches for patients with bladder cancer.

Guru P. Sonpavde, MD

Guru P. Sonpavde, MD

The continued emergence and investigations of novel targets and agents within the bladder cancer realm demonstrate that individualized treatment approaches will become a more integral part of this treatment paradigm, according to Guru P. Sonpavde, MD.

“There is still a lot to learn in terms of the biology of bladder cancer. Precision medicine will become more and more important when you have more and more agents to treat these patients. It will become more important to select the right patient for the right treatment,” Sonpavde, emphasized.

In an interview with OncLive®, Sonpavde, the medical director of the Genitourinary (GU) Oncology, the assistant director of the Clinical Research Unit, and the Christopher K. Glanz Chair of Bladder Cancer Research at AdventHealth Cancer Institute in Orlando, Florida, discussed key trial data presented at the 2023 ASCO Annual Meeting, including findings from the phase 3 THOR (NCT03390504) and SWOG S1011 (NCT01224665) studies, and detailed ongoing trials that could help advance precision medicine approaches for patients with bladder cancer.

OncLive: What are the potential clinical implications of findings from THOR?1

Sonpavde: The key study [results] that I personally was looking forward to and eagerly anticipated was the THOR trial. THOR was a phase 3 trial, which compared erdafitinib [Balversa], an FGFR inhibitor, vs historically used salvage agents in patients [with disease progression after] prior systemic therapy. Erdafitinib is already [FDA] approved on an accelerated basis in patients with [locally advanced or metastatic] urothelial carcinoma [who have progressed] post–platinum chemotherapy and have FGFR3 or FGFR2 activating mutations or fusions.2

This phase 3 trial was a confirmatory trial, comparing erdafitinib vs the historically used chemotherapy drugs such as docetaxel, paclitaxel, or vinflunine. Notably, the trial also allowed pembrolizumab [Keytruda] as one of the agents in the standard-of-care arm.

This trial was eagerly expected because the drug is already out there and being used in the clinic. It [was] nice to see a validation of an improvement in [overall] survival [HR, 0.64; 95% CI, 0.47-0.88; P = .005] in this phase 3 trial to back up the improved response rate that led to its FDA [accelerated] approval.

What results were derived from the SWOG S1011 trial in patients with muscle-invasive bladder cancer (MIBC)?3

The second trial that I was keen on highlighting was the SWOG S1011 trial. This was a phase 3 surgical study that compared the extent of lymph node dissection in patients with MIBC going for radical cystectomy. The comparison was between a standard pelvic lymph node dissection vs an extended lymph node dissection beyond the pelvis up to the bifurcation of the aorta.

The trial essentially showed that it is not necessary to do an extended lymph node dissection. There was not an improvement in outcomes with extended lymph node dissection. There was an increase in toxicities and post-operative complications from extended lymph node dissection, [and there was] also slight increase in post-operative mortality. Therefore, this study could be practice changing based on these results, suggesting that standard pelvic lymph node dissection of the internal and external iliac nodes and the obturator nodes is adequate. You don't have to go all the way up to an extended dissection, which goes up to the bifurcation of the aorta.

The phase 2 NORSE trial (NCT03473743) investigated erdafitinib with or without cetrelimab in patients with advanced urothelial carcinoma harboring FGFR alterations. What were the key findings from this study?4

The third trial I was interested in was the randomized phase 2 [NORSE] trial. This trial evaluated patients with advanced urothelial carcinoma in the first-line setting who were cisplatin ineligible and had an activating FGFR3 or FGFR2 mutation or fusion. The study randomly assigned patients to erdafitinib, the pan-FGFR inhibitor, or erdafitinib plus cetrelimab, which is a PD-1 inhibitor. There were 43 [evaluable] patients in [the monotherapy] arm [and 44 in the combination arm] for a total of 87 patients evenly divided between the 2 arms.

The primary end point was overall response rate [ORR], and the ORR looked better with the combination, which is interesting and exciting. The ORR was 44.2% for erdafitinib alone, which was similar to was seen with erdafitinib in the salvage, post-platinum setting. The ORR was 54.5% for erdafitinib plus cetrelimab. There was also an improvement in complete response rate seen for the combination. The toxicities were as expected.

This combination appears promising and might warrant further evaluation in terms of the larger trials, such as phase 3 trials, in the future.

What ongoing or future studies could influence the bladder cancer treatment paradigm?

The future is very exciting. One of the things to look at down the road is that we soon may [see data] from the [phase 3] CheckMate901 trial [NCT03036098], which compared ipilimumab [Yervoy] and nivolumab [Opdivo] vs gemcitabine and carboplatin in cisplatin-ineligible patients in the first-line, advanced-disease setting. This trial also had a sub study comparing gemcitabine/cisplatin vs gemcitabine/cisplatin with nivolumab in cisplatin-eligible patients. We look forward to seeing those results soon.

There are novel targets on the horizon that are looking exciting. HER2 is an exciting target. The novel antibody-drug conjugate [ADC] disotumab vedotin [RC48-ADC] had promising activity in HER2-expressing patients, [meaning those who were] HER2-positive by immunohistochemistry. That drug has been combined with PD-1 inhibition in HER2-positive patients. A phase 3 trial [NCT05911295] has been launched to compare the combination of disotumab vedotin and [pembrolizumab] vs gemcitabine [plus] platinum chemotherapy. That is also an exciting direction to go with this novel target.

There are some other interesting studies out there that are worth mentioning. We have a [phase 1] study [NCT04724018] that we launched at Dana-Farber Cancer Institute [in Boston, Massachusetts], combining 2 ADCs—enfortumab vedotin-ejfv [Padcev] and sacituzumab govitecan-hziy [Trodelvy]—in patients with advanced urothelial carcinoma. We are very excited about the combination given the different membrane targets and the different payloads in these agents. That could be something to be on the lookout for because [the combination] could have a high response rate given the non-overlapping targets.

Why is developing an improved precision medicine approach important for patients with bladder cancer?

Precision medicine is important, and so is evaluating novel, tolerable combinations. We know that the enfortumab vedotin and pembrolizumab combination is out there now in the United States as first-line therapy for cisplatin-ineligible disease. We await [results] of the phase 3 [EV-302 trial [NCT04223856] comparing enfortumab vedotin/pembrolizumab vs gemcitabine plus platinum chemotherapy in all comers.

All these trials are likely to shake up the landscape. We also await the results of adjuvant and neoadjuvant trials. We have adjuvant nivolumab approved, and we are eagerly awaiting the phase 3 AMBASSADOR trial [NCT03244384], which looked at adjuvant pembrolizumab in high-risk, muscle-invasive urothelial carcinoma.

Editor’s note: This interview was conducted prior to the 2023 ASCO Annual Meeting.


  1. Loriot Y, Matsubara N, Park SH, et al. Phase 3 THOR study: results of erdafitinib (erda) versus chemotherapy (chemo) in patients (pts) with advanced or metastatic urothelial cancer (mUC) with select fibroblast growth factor receptor alterations (FGFRalt). J Clin Oncol. 2023;41(suppl 17):LBA4619. doi:10.1200/JCO.2023.41.17_suppl.LBA4619
  2. FDA grants accelerated approval to erdafitinib for metastatic urothelial carcinoma. News release. FDA.
  3. Lerner SP, Tangen C, Svatek RS, et al. SWOG S1011: A phase III surgical trial to evaluate the benefit of a standard versus an extended lymphadenectomy performed at time of radical cystectomy for muscle invasive urothelial cancer. J Clin Oncol. 2023;41(suppl):4508. doi:10.1200/JCO.2023.41.16_suppl.4508
  4. Siefker-Radtke AO, Powles T, Moreno V, et al. Erdafitinib (ERDA) vs ERDA plus cetrelimab (ERDA+CET) for patients (pts) with metastatic urothelial carcinoma (mUC) and fibroblast growth factor receptor alterations (FGFRa): Final results from the phase 2 Norse study. J Clin Oncol. 2023;41(suppl 16):4504. doi:10.1200/JCO.2023.41.16_suppl.4504.

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