IO and Targeted Therapies Advance the Metastatic Urothelial Cancer Treatment Landscape

Daniel P. Petrylak, MD

Many efficacious therapies have been approved in the first- and second-line setting for patients with metastatic urothelial carcinoma, and other promising therapies and combinations are currently in development, according to Daniel P. Petrylak, MD.¹

“Mutational burden is related to response with checkpoint inhibitors,” said Petrylak, professor of medicine and urology and coleader of the Cancer Signaling Networks at Yale Cancer Center, in New Haven, Connecticut, during a presentation during the 15th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies.“Cancer cells that are genetically unstable, can look foreign to the immune system and make apparent proteins which the T cells can recognize, and can be attacked and viewed as being foreign. Cancer cells can evade the immune attack by expressing PD-L1.”

In an overview of the treatment landscape Petrylak noted available options for patients with metastatic urothelial carcinoma include 2 immune checkpoint inhibitors approved for the frontline treatment of patients who are ineligible for cisplatin: atezolizumab (Tecentriq) and pembrolizumab (Keytruda). Three others are approved for patients who have previously received platinum-based chemotherapy: nivolumab (Opdivo), avelumab (Bavencio), and pembrolizumab.

“Atezolizumab and durvalumab [Imfinzi] have been removed from the list [of second-line treatment options] voluntarily,” Petrylak said, citing the 2021 withdrawn indications by Roche and AstraZeneca, respectively. The indication for atezolizumab was withdrawn after failing to show a marked improvement over standard-of-care chemotherapy missing the primary end point of the IMvigor211 trial (NCT02302807). “Durvalumab also did not do well in randomized trials compared with chemotherapy,” Petrylak said, citing data from the phase 3 DANUBE trial (NCT02516241).³

In discussing treatment determinations, Petrylak noted that for patients with low PD-L1 expression had decreased survival benefits compared with patients treated with chemotherapy in the monotherapy arms of the phase 3 KEYNOTE-361 (NCT02853305) and phase 3 IMVIGOR-130 (NCT02807636) trials. Patients with low PD-L1 expression should be treated with carboplatin-based chemotherapy and those with high PD-L1 expressions should receive either pembrolizumab or atezolizumab, Petrylak contended.

Following treatment with frontline chemotherapy—either cisplatin or carboplatin in combination with gemcitabine—Petrylak noted that a switch maintenance approach with avelumab is the preferred treatment choice. Data from the phase 3 JAVELIN Bladder 100 study (NCT02603432) showed that avelumab plus best supportive care (BSC) administered in the maintenance setting elicited a favorable response vs BSC alone.⁴

“I call this, ‘line 1.5,’ which is maintenance therapy after initial chemotherapy,” Petrylak said. Investigators randomly assigned 350 to each arm; 189 patients in the avelumab arm had PD-L1–positive disease compared with 169 patients in the BSC arm.

Among patients who received avelumab in the PD-L1-positive population, the median OS was not estimable (NE; 95% CI, 20.3-NE) compared with 17.1 months (95% CI, 13.5-23.7) in patients who received BSC alone (HR, 0.56; 95% CI, 0.40-0.79; P < .001). Unlike in the first-line setting, In the overall population, patients treated in the avelumab arm had a median progression-free survival (PFS) of 3.7 months (95% CI, 3.5-5.5) compared with 2.0 months (95% CI, 1.9-2.7) in the BSC alone arm (HR, 0.62; 95% CI, 0.52-0.75; P < .001). The 12-month PFS rates were 30% and 13%, respectively.⁴

“We have a more pronounced difference [in survival] in the PD-L1-positive population,” Petrylak noted. “Why are we seeing this difference with maintenance therapy vs [treatment with] upfront checkpoint inhibitors, where we haven’t seen combination therapy show an improvement in survival? It may be related to the changes in the tumor environment or the extracellular matrix that may be induced by chemotherapy.”

Despite the success with avelumab in this setting, results from a randomized phase 2 trial (NCT02500121) showed that pembrolizumab did not provide the same survival benefit as maintenance therapy. Although patients with metastatic urothelial carcinoma treated with pembrolizumab had a higher median PFS than those who received placebo (5.4 months vs 3.0 months, respectively), the OS benefit did not significantly improve (22 months vs 18.7 months, respectively).⁵

Targeted Treatments Show Efficacy

FGFR mutations have become a target of interest in metastatic urothelial carcinoma, as overexpression has been implicated in bladder cancer, Petrylak said. He noted that FGFR3 expression is detected in up to 20% of patients with metastatic urothelial carcinoma. In 2019, the FDA granted accelerated approval to the FGFR inhibitor erdafitinib (Balversa) for the treatment of patients with metastatic bladder cancer harboring an FGFR2 or FGFR3 alteration that has progressed during or after chemotherapy.⁶

In the phase 2 BLC2001 study (NCT02365597), patients with metastatic urothelial carcinoma who progressed after chemotherapy or were cisplatin-ineligible treated with erdafitinib (n= 99) achieved an overall response rate (ORR) of 40.4% (95% CI, 30.7%-50.1%). Those who had received prior immunotherapy (n = 22) had an ORR of 59%. Patients treated with erdafitinib also saw survival benefits: the median PFS was 5.5 months (95% CI, 4.2-6.0) and the median OS was 13.8 months (95% CI, 9.8-NE).⁷

“[These results] are pretty impressive,” Petrylak said. “The drug has toxicities, and they must be managed. [However], there were no grade 4 or 5 treatment-related adverse events.”

Other investigational FGFR inhibitors are being evaluated in metastatic urothelial carcinoma, including infigratinib (Truseltiq) in a phase 1 trial (NCT01004224) and rogaratinib in the phase 2/3 FORT trial (NCT03410693).

In available data from the phase 1 trial of infigratinib, the agent showed promising activity as a monotherapy. Patients who received infigratinib as a frontline therapy (n = 13) had an ORR of 30.8% (95% CI, 9.1%-61.4%) and patients who received it in the second line (n = 54) had an ORR of 42.6% (95% CI, 29.2%-56.8%). Median PFS was 3.65 months (95% CI, 0.95-7.43) among the treatment-naïve population and 3.75 months (95% CI, 3.09-5.42) for those treated in the second line.⁸

Moving away from immunotherapy in later lines of therapy, Petrylak turned his attention to the antibody-drug conjugates (ADCs). Enfortumab vedotin-ejfv (Padcev) is an ADC engineered to target nectin-4, which is expressed in approximately 90% of urothelial cancer cells. Investigators assessed enfortumab vedotin in metastatic urothelial carcinoma as a monotherapy in the phase 2 EV-201 trial (NCT03219333) and in combination with pembrolizumab in the phase 1/2 EV-103 trial (NCT03288545).

In EV-201, patients who received enfortumab vedotin had an ORR of 44% (n =110; 95% CI, 35.1%-53.2%), including 12% achieving complete responses (CRs). The median PFS was 5.8 months (95% CI 4.9-7.5), and the median OS was 11.7 months (95% CI, 9.1-not reached [NR]). Petrylak noted that responses were observed across all subgroups, including patients with primary tumor sites in the upper tract (ORR, 61%), with liver metastasis (ORR, 48%), and those who did not respond to prior PD-1/PD-L1 inhibitors (ORR, 48%).⁹

In EV-103, patients treated with enfortumab vedotin plus pembrolizumab (n = 45) achieved an ORR of 73.3% (95% CI, 58.1%-85.4%), including 15.6% of patients having a CR, regardless of PD-L1 expression level. The median OS was 26.1 months (95% CI, 15.7 -NR) at a median follow-up of 24.9 months.¹⁰ 

“This is probably the most impressive data that we’ve seen with any combination therapy,” Petrylak said. “These [data] need further confirmation; there are randomized trials ongoing looking at this combination of neoadjuvant therapy, as well as this combination up front compared with cisplatin- or carboplatin-based chemotherapy.”

Subsequently, data from the phase 3 EV-301 trial (NCT03474107) supported the FDA approval of enfortumab vedotin as second-line treatment of patients with metastatic urothelial cancer.11 The median OS for those who received enfortumab vedotin (n = 310) was 12.88 months (95% CI, 10.58-15.21) compared with 8.97 months (95% CI, 8.05-10.74) for those who received chemotherapy (n = 307; HR, 0.70; 95% CI, 0.56-0.89; P = .000412). The 6- and 12-month OS rates for enforutmab vedotin were 77.9% (95% CI, 72.74%-82.25%) and 51.5% (95% CI, 44.63%-58.03%), respectively. Among those who received chemotherapy, the 6- and 12-month OS rates were 69.5% (95% CI, 63.85%-74.38%) and 39.2% (95% CI, 32.60%-45.64%).

Further, in the response evaluable population, patients who received enfortumab vedotin (n = 288) had an ORR of 40.6% (95% CI, 34.90%-46.54%) compared with 17.9% (95% CI, 13.71%-22.76%) among those who received chemotherapy (n = 296). The disease control rates were 71.9% (95% CI, 66.30%-76.99%) and 53.4% (95% CI, 47.52%-59.17%), respectively.¹²

Another ADC, sacituzumab govitecan-hziy (Trodelvy), displayed efficacy as a second-line treatment option for patients with metastatic urothelial carcinoma in the phase 2 TROPHY U-01 trial (NCT03547973). “Sacituzumab govitecan has accelerated approval in patients who have received prior therapies,” Petrylak said.

Patients who progressed after prior chemotherapy and anti-PD-1/PD-L1 therapies treated with sacituzumab govitecan (n = 113) achieved an ORR of 27.4% (95% CI, 19.5%-36.6%), including 6 CRs. The median PFS was 5.4 months (95% CI, 3.5-7.2) and the median OS was 10.9 months (95% CI, 9.0-13.8).14 Perylak concluded by stating that future directions for the field include continued evaluation of combination checkpoint inhibition with targeted therapy.

_References

_{1. Petrylak DP. Metastatic bladder cancer: immunologic and targeted approaches. Presented at New York GU 14th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies; March 12-13, 2021; virtual. Accessed March 12, 2021.}

_{2. Roche provides update on Tecentriq US indication in prior-platinum treated metastatic bladder cancer. News release. Roche. March 8, 2021. Accessed March 11, 2022. https://www.roche.com/media/releases/med-cor-2021-03-08.htm}

_{3. Voluntary withdrawal of Imfinzi indication in advanced bladder cancer in the US. News release. AstraZeneca. Published February 22, 2021. Accessed March 11, 2022. https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2021/voluntary-withdrawal-imfinzi-us-bladder-indication.html}

_{4. Powles T, Park SH, Voog et al. Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis. J Clin Oncol. 2020;38(suppl 18):LBA21. doi:10.1200/JCO.2020.38.18_suppl.LBA1}

_{5. Galsky MD, Mortazavi A, Milowsky MI, et al. Randomized double-blind phase ii study of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients with metastatic urothelial cancer. J Clin Oncol. 2020;38(16):1797-1806. doi:10.1200/JCO.19.03091}

_{6. Balversa. Prescribing Information. Janssen Pharmaceuticals; 2019. Accessed March 11, 2022. bit.ly/2X67iEm}

_{7. Siefker-Radtke AO, Necchi A, Park SH, et al. First results from the primary analysis population of the phase 2 study of erdafitinib (ERDA; JNJ-42756493) in patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) and FGFR alterations (FGFRalt).J Clin Oncol. 2018;36(suppl 15):4503. doi:10.1200/JCO.2018.36.15_suppl.4503}

_{8. Lyou Y, Grivas P, Rosenberg JE, et al. Infigratinib and treatment response in advanced/unresectable or metastatic urothelial carcinoma in first-line and later-line treatment settings. J Clin Oncol. 2020;38(suppl 15):5038. doi:10.1200/JCO.2020.38.15_suppl.5038}

_{9. Balar AV, McGregor A, Rosenber JE, et al. EV-201 cohort 2: enfortumab vedotin in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors. J Clin Oncol. 2021;39(suppl 6):394. doi:10.1200/JCO.2021.39.6_suppl.394}

_{10. Rosenberg JE, Flaig TW, Friedlander TW, et al. Study EV-103: preliminary durability results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma. J Clin Oncol. 2020;38(suppl 6):441-441. doi:10.1200/JCO.2020.38.6_suppl.441}

_{11. FDA grants regular approval to enfortumab vedotin-ejfv for locally advanced or metastatic urothelial cancer. FDA. July 9, 2021. Accessed March 11, 2022. bit.ly/3i1zoNv}

_{12. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021;384(12):1125-1135. doi:10.1056/NEJMoa2035807}

_{13. Tagawa ST, Balar AV, Petrylak DP, et al. TROPHY-U-01: a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol. 2021;39(22):2474-2485. doi:10.1200/JCO.20.03489}