ADCs and Immunotherapy Are Redefining Urothelial Cancer Treatment

Manojkumar Bupathi, MD, MS

The combination of enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) for patients with previously untreated urothelial carcinoma has established targeted therapy as the frontline standard of care for patients in this population, shifting treatment practices away from the use of chemotherapy, according to Manojkumar Bupathi, MD, MS.

In the phase 3 EV-302 trial (NCT04223856), patients treated with enfortumab vedotin plus pembrolizumab (n = 442) achieved a median progression-free survival of 12.5 months (95% CI, 10.4-16.6) vs 6.3 months (95% CI, 6.2-6.5) for those who received chemotherapy (n = 44), translating to a 55% reduction in the risk of progression or death (HR, 0.45; 95% CI, 0.38-0.54; P < .00001). The median overall survival (OS) was 31.5 months (95% CI, 25.4-not reached) with the investigational combination vs 16.1 months (95% CI, 13.9-18.3) with chemotherapy, translating to a 53% reduction in the risk of death (HR, 0.47; 95% CI, 0.38-0.58; P < .00001).¹ The findings from this trial supported the December 2023 FDA approval of enfortumab vedotin plus pembrolizumab in patients with locally advanced or metastatic urothelial cancer.²

“Going forward, I don’t think most patients will receive chemotherapy anymore, and [instead] will receive enfortumab vedotin plus pembrolizumab, regardless of platinum eligibility,” Bupathi said in an interview following an OncLive® Institutional Perspectives in Cancer (IPC) webinar on genitourinary (GU) cancers, which he chaired.

In the interview, Bupathi, a medical oncologist at Rocky Mountain Cancer Centers in Littleton, Colorado, highlighted key points that were presented at the meeting, including the implications of the EV-302 trial findings; data updates from the phase 1/2 ICRA trial (NCT03871036); and future directions for urothelial cancer, renal cell carcinoma (RCC), and prostate cancer management.

In ICRA, patients with metastatic urothelial carcinoma who had progressed on platinum-based chemotherapy and a PD-1/PD-L1 inhibitor were randomly assigned to receive tremelimumab (Imjudo) monotherapy or paclitaxel plus tremelimumab with or without durvalumab (Imfinzi). Patients in the tremelimumab (n = 12), paclitaxel/tremelimumab (n = 19), and paclitaxel plus tremelimumab and durvalumab (n = 12) arms achieved respective objective response rates (ORRs) of 8% (88% CI, 0.5%-33%), 26% (88% CI, 14%-37%), and 8% (88% CI, 0.5%-33%).³

OncLive: What have been some of the most important evolutions in urothelial cancer management over the past few months?

Bupathi: [Regarding the] updates in urothelial cancer, [at the IPC] we predominantly discussed data that were presented at the 2023 ESMO Congress. [Those updates were] the most exciting changes that have been presented at recent conferences. [Research with] the combination of enfortumab vedotin plus pembrolizumab [in patients with treatment-naive locally advanced urothelial cancer] was presented as a presidential symposium, and it showed substantial results, specifically the highest ORR observed to date [for patients in this population]. The ORR was 67.7%, with 29.1% of patients having a complete response. [This combination] drastically changed the frontline therapy for patients with advanced urothelial cancer.

What were some of the key findings from the ICRA trial?

One of the trials I presented [at the IPC] was the ICRA trial, which [investigated] the efficacy of paclitaxel plus tremelimumab with or without durvalumab in patients with urothelial carcinoma after progression on platinum-based chemotherapy and PD-L1 inhibitors. The rationale was trying to see whether any anti-CTLA4 taxanes in this combination had efficacy. The research question was: Can we use high-dose CTLA4 inhibition in combination with taxanes to induce responses in patients with advanced urothelial carcinoma who have previously not responded to other therapies?

The combination of paclitaxel and tremelimumab [induced tumor reduction] in 50% of patients, and 67% of patients [experienced tumor reduction with] paclitaxel and tremelimumab plus durvalumab. The OS seems to be slightly better with the triplet combination. The combination met [the trial’s] primary end point, with 26% of patients responding with paclitaxel in combination with tremelimumab. This combination appeared to be more active than CTLA4 inhibitor monotherapy. There were no additional or new safety signals in this trial.

What is your main message for colleagues regarding treatment advances across the spectrum of GU malignancies?

In bladder cancer, chemotherapy is not used anymore. The first-line therapy for patients with advanced urothelial carcinoma is enfortumab vedotin plus pembrolizumab, regardless of whether they are platinum eligible.

For patients with RCC, you can use any immune-oncology [IO]/TKI combination or IO/IO combination for first-line therapy, but using one therapy, understanding the nuances of that therapy, and managing the adverse effects is important. For the second line and beyond, the field has been moving, and it will change. There’s no role for continuing immunotherapy once patients have progressed on first-line therapy. We’ll see more data that will come about that. One [treatment strategy] that could help [patients with RCC who have progressed on frontline therapy] is switching the type of TKI you’re using, [which we know from] the phase 2 LITESPARK-003 [NCT03634540] data.

In prostate cancer, genetic testing, whether upfront or later, is important for understanding whether we can use PARP inhibitors, specifically. [In the upfront setting, we should consider] using triplet combinations for patients who have more advanced disease.

Many exciting new trials are happening in GU cancer. We’re doing a lot of therapies that are using antibody-drug conjugates, bispecific molecules, CAR T cells, etc. A lot of new therapies are evolving from a drug-development standpoint.

References

1. Powles TB, Valderrama BP, Gupta S, et al. EV-302/KEYNOTE-A39: open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). Ann Oncol. 2023;34(suppl 2):1340. doi:10.1016/j.annonc.2023.10.106
2. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed December 20, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer
3. Einerhand SMH, van Dorp J, de Feijter J, et al. ICRA: efficacy of paclitaxel with tremelimumab +/- durvalumab in metastatic urothelial carcinoma after progression on platinum chemotherapy and anti-PD-(L)1. Ann Oncol. 2023;34(suppl 2):1342-1343. doi:10.1016/j.annonc.2023.10.109