Targeted Therapies Offer Fresh Options in Urothelial Carcinoma

Jason Harris

Daniel P. Petrylak, MD
Daniel P. Petrylak, MD
Oncologists looking for options beyond immuno-oncology (I/O) for treating patients with metastatic urothelial carcinoma (mUC) may soon have a range of targeted therapy choices, according to Daniel P. Petrylak, MD.

Petrylak, a professor of medicine and urology at Yale School of Medicine in New Haven, Connecticut, discussed the growing potential for targeted therapies in mUC at the New York GU™: 12th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies meeting.

In April, the FDA granted an accelerated approval to erdafitinib (Balversa), an oral pan-fibroblast growth factor receptor (FGFR) inhibitor that is the first targeted therapy approved for mUC.

“This is a very exciting area,” Petrylak said. “There are multiple targets we can pursue in UC. These include TSC1, Trop-2, Nectin, AKT/ PI3K, and FGFR, and there are other drugs that are now being developed.”

Petrylak, a 2017 Giants of Cancer Care® award winner for genitourinary cancer, noted that immunotherapy is not appropriate for every patient with mUC. Only a subset of patients, roughly 25%, derive benefit from I/O; some develop resistance to immunotherapy agents, and some progress after initial treatment. Furthermore, some patients are ineligible for cisplatin-based chemotherapy, eliminating another potential treatment option.

“How can we use some of the targeted therapy approaches to improve treatment of mUC?” Petrylak asked. “Multiple pathways are altered in mUC, but there isn’t [a single] dominant pathway.”

Petrylak said these factors make it necessary to carefully select patients for treatments.

Investigators are exploring treatment targeting the TSC1 gene following results from a phase I trial of everolimus (Afinitor) plus pazopanib (Votrient). The response rate was low overall (11.1%), but 1 patient who had mUC with a TSC1 mutation had a complete response (CR) lasting 14 months.1 Furthermore, in vitro evaluation showed that TSC1 sensitizes UC cells to mTOR inhibition.2

Investigators are assessing FGFR inhibitors and anti-FGFR antibody–drug conjugates (ADCs) for advanced UC in multiple ongoing and upcoming trials. FGFRs are membranebased tyrosine kinase receptors involved in cellular proliferation, differentiation, and steroid biosynthesis. In addition to the presence of activating mutations, FGFR overexpression has been implicated in UC.

Erdafitinib, an FGFR-targeting ADC, was approved based on findings from the phase II BLC2001 trial (NCT02365597). It is indicated for the treatment of adult patients with locally advanced or metastatic bladder cancer with an FGFR2 or FGFR3 alteration that has progressed on platinum-containing chemotherapy.

In results presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, erdafitinib induced an overall response rate (ORR) of 40.4% (95% CI, 30.7-50.1), with a CR of 3.0% and a partial response (PR) of 37.4%.3 All patients in the study (N = 99) had FGFR alterations. Seventy-five (76%) patients treated with 8 mg of continuous erdafitinib experienced a reduction in tumor size.

Erdafitinib induced an ORR of 32.2% in patients with FGFR2/FGFR3-positive, locally advanced or metastatic bladder cancer, including a CR of 2.3% and a PR of 29.9%. Among 64 patients with an FGFR3 point mutation, the ORR was 40.6% (95% CI, 28.6-52.7) compared with 11.1% (95% CI, 0-25.6) among 18 patients with an FGFR3 fusion. There were no confirmed responses among the 6 patients with an FGFR2 fusion.4

Responders included patients who had been unresponsive to anti–PD-1/PD-L1 treatment.

The median progression-free survival (PFS) was 5.5 months (95% CI, 4.2-6.0), and the median overall survival (OS) was 13.8 months. After 11 months of follow-up, 21.2% of patients remained on treatment.

“This is actually pretty impressive,” Petrylak said, comparing the results with findings from previous studies that showed a control group survival of 7 to 8 months. “But it’s a select group of patients.”

In results for a study of continuous versus intermittent dosing of erdafitinib first presented at the 2018 Genitourinary Cancers Symposium, the ORR was 42% in patients with FGFR2/ FGFR3-positive locally advanced or metastatic UC who received 8 mg of continuous erdafitinib. The CR rate was 5%, and the PR rate was 37%.5

Enfortumab vedotin, an ADC consisting of an anti–Nectin-4 monoclonal antibody attached to the microtubule-disrupting agent monomethyl auristatin E, has also demonstrated positive activity in mUC. Results from the phase I EV-101 trial (NCT02091999) were first presented at the 2016 ASCO Annual Meeting and updated at the 2017 meeting. At the April 28, 2017, data cutoff, 81 patients had received enfortumab vedotin at study sites in the United States and Canada, including 21 in dose-escalation cohorts and 60 in doseexpansion cohorts.6,7

Among 71 evaluable patients across the entire cohort, the ORR was 41% (95% CI, 29.3- 53.2), including 3 (4%) CRs and 26 (37%) PRs.

“The longest responder is a woman who is more than 2 years out now, who initially failed a checkpoint inhibitor—she was actually one of the worst cases of UC I’ve seen,” Petrylak said.

The patient received neoadjuvant chemotherapy for a renal pelvis tumor and had 28 positive lymph nodes at the time of surgery. The disease spread to her liver within a month, and she failed on ipilimumab/ nivolumab (Yervoy/Opdivo) before going on enfortumab vedotin.

“She had a complete response,” Petrylak added. “And she’s working, and she’s active. She’s doing extremely well.”

In March 2018, based on findings from the EV-101 trial, the FDA issued a breakthrough therapy designation to enfortumab vedotin for the treatment of patients with locally advanced or metastatic UC who progressed after receiving a PD-1 or PD-L1 inhibitor. Seattle Genetics and Astellas, manufacturers of the ADC, issued topline results from the pivotal phase II EV-201 trial in March 2019. Enfortumab vedotin induced a 44% ORR per independent review. The duration of response was comparable to that observed in EV-101.8

Another ADC showing promise in this patient population is sacituzumab govitecan, which is directed against Trop-2. In findings presented at the 2019 Genitourinary Cancers Symposium, sacituzumab govitecan exhibited significant clinical activity in patients with heavily pretreated, relapsed/refractory mUC in the open-label, single-arm phase I/II IMMU 132-01 basket study (NCT01631552).9

The ORR was 31.1% (14 of 45) at a median follow-up of 15.7 months. The median PFS was 7.3 months (95% CI, 5.0-10.7), and the median OS was 16.3 months (95% CI, 9.0-31.0). The median number of treatment cycles was 8, with a relative dose intensity of 95.2%. Three of the 5 patients still on treatment at the time of data cutoff had ongoing responses.

Two patients (4%) had CRs, and 12 (27%) had PRs. The median duration of response was 12.9 months.

The activity of sacituzumab govitecan in the study extended to the post–checkpoint inhibitor setting. The ORR was 23.5% (4 of 17) among patients who received prior checkpoint inhibition. Further, the ORR was 33.3% (5 of 15) among patients with liver involvement at study entry.

Based on the results, investigators have initiated the international, single-arm, open-label phase II TROPHY U-01 study (NCT03547973). Investigators will assess sacituzumab govitecan in 100 patients with UC that has progressed despite prior platinum therapy and immune checkpoint inhibition. The study includes a cohort of 40 patients who are unfit for platinum-based therapy and who progressed after immune checkpoint therapy.

References

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  2. Iyer G, Hanrahan AJ, Milowsky MI, et al. Genome sequencing identifies a basis for everolimus sensitivity. Science. 2012;338(6104):221. doi: 10.1126/science.1226344.
  3. 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(15):4503. doi: 10.1200/JCO.2018.36.15_suppl.4503.
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  6. Rosenberg JE, Heath EI, Van Veldhuizen PJ, et al. Anti-tumor activity, safety and pharmacokinetics (PK) of ASG-22CE (ASG-22ME; enfortumab vedotin) in a phase I dose escalation trial in patients (Pts) with metastatic urothelial cancer (mUC). J Clin Oncol. 2016;34(15):4533. doi: 10.1200/JCO.2016.34.15_suppl.4533.
  7. Petrylak DP, Perez RP, Zhang J, et al. A phase I study of enfortumab vedotin: updated analysis of patients with metastatic urothelial cancer. J Clin Oncol. 2017;35(15):106. doi: 10.1200/JCO.2017.35.15_suppl.106.
  8. Seattle Genetics and Astellas announce positive topline results from pivotal trial of enfortumab vedotin in locally advanced or metastatic urothelial cancer [news release]. Bothell, WA, and Tokyo, Japan: Seattle Genetics and Astellas Pharma; March 28, 2019. bit.ly/2OuyERy. Accessed April 25, 2019.
  9. Tagawa S, Faltas BM, Lam ET, et al. Sacituzumab govitecan (IMMU- 132) in patients with previously treated metastatic urothelial cancer (mUC): results from a phase I/II study. J Clin Oncol. 2019;37(7):354. doi: 10.1200/JCO.2019.37.7_suppl.354.
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