ESMO Updates Clinical Practice Guidelines for Urothelial Cancer

Joaquim Bellmunt, MD, PhD

In November 2021, the European Society for Medical Oncology (ESMO) updated their clinical guidelines for the diagnosis and treatment of urothelial carcinoma (UC) to accommodate recent advances in therapeutic options.

ESMO Guidelines Primer

Much has changed in the understanding and treatment of UC, including the development and availability of pembrolizumab (Keytruda) and nivolumab (Opdivo) for UC, atezolizumab (Tecentriq) for advanced or metastatic UC, and the antibody-drug conjugate enfortumab vedotin-ejfv (Padcev),¹ indicated for adult patients with locally advanced or metastatic UC (mUC). The strength of recommendation is guided by the supporting data (FIGURE2) and is in brackets at the end of the sentence to which it pertains.

Joaquim Bellmunt, MD, PhD, director of the Bladder Cancer Program at Beth Israel Deaconess Medical Center and associate professor of medicine at Harvard Medical School in Boston, Massachusetts, and one of the lead authors of the guidelines addressed the overall changes.

Treatment of Non–Muscle-Invasive Bladder Cancer

Complete removal of all visible lesions in the bladder via transurethral resection of the bladder tumor (TURBT) followed by intravesical instillation remains the optimal treatment of non–muscle-invasive bladder cancer (NMIBC) [I, A]. Patients with very high-risk disease should be considered for early radical cystectomy [RC; I, A]. The 2021 updated guidelines provide further detailed recommendations for low-, intermediate-, and high-risk NMIBC.²

BCG Failure

The updated guidelines contain recommendations for patients who experience failure on intravesical BCG therapy for intermediate- and high-risk disease.

"Including information on BCG in the way that has been adapted by other urological guidelines is important because bladder cancer needs to be approached in a multidisciplinary way,” Bellmunt said in an interview with Targeted Thera-pies in Oncology^TM.

BCG failure is further broken down into 4 categories to properly identify patients who will no longer benefit from BCG therapy.³

1. BCG refractory—persistent high-grade (HG) disease at 6 months after adequate BCG treatment or T1/Ta HG at 3 months or stage progression at 3 months after proper BCG induction.
2. 
   BCG relapsing—HG disease recurrence after achieving disease-free status within 12 months of adequate BCG
3. 
   BCG intolerant–toxicity prevents the patient from receiving adequate BCG
4. 
   BCG unresponsive–a combination of BCG-refractory and BCG-relapsing within 6 months of the last BCG.

For HG tumors unresponsive to BCG, RC should be pursued [III,B]. Thermochemotherapy and BCG reinduction are options only for patients unwilling or unable to pursue radiotherapy.⁴

According to investigators, thermochemotherapy has been shown to achieve a 47% 2-year disease-free survival (DFS) rate, although BCG reinduction achieved similar disease control in a randomized trial [II, B].^5,6

A newly included option for BCG-unresponsive patients who are unable or refuse to pursue RC is the use of pembrolizumab [III, C].

The single-arm phase 2 KEYNOTE-057 trial (NCT02625961) showed a complete response (CR) rate of 41% (95% CI, 30.7%-51.1%) in 96 patients with BCG-unresponsive carcinoma in situ receiving intravenous pembrolizumab.⁷

Nadofaragene firadenovec intravesical therapy has also been evaluated in patients with BCG-unresponsive NMIBC in a phase 3 study (NCT02773849). A total of 103 patients were included in the trial, and the CR at 3 months was 53% and 24% at 12 months.⁸ These data suggest that nadofaragene firadenovec could be an alternative to pembrolizumab; however, it is not yet approved by the FDA or European Medicines Agency [III, C].

Due to the nature of the studies and lack of approvals for both pembrolizumab and nadofaragene firadenovec, further robust data are required before stronger recommendations can be made for their use.³

Treatment of MIBC

Radical Cystectomy

Optimal management of MIBC should include multidisciplinary care involving tumor board discussions and/or direct consultations with a medical oncologist, radiation oncologist, and urologist [IV, B]. RC with pelvic lymph node dissection remains the standard of care for MIBC cT2-T4aN0M0 [I, A].⁹

Organ-preservation

For patients unable to undergo RC or desiring an alternative, organ-preservation therapy is an option [II, B].³ Trimodal therapy incorporating a combination of TURBT, radiotherapy, and chemotherapy is recommended (II,B). Cisplatin when administered with radiotherapy improved local control rates (HR, 0.50; 90% CI, 0.29-0.86) (II,B).¹⁰

Neoadjuvant and Adjuvant Therapy

A meta-analysis of 11 randomized trials including 3005 patients indicates a surviv- al benefit associated with cisplatin-based neoadjuvant chemotherapy regimens (HR, 0.86; 95% CI, 0.77-0.95). This equates to a 5% absolute increase in 5-year overall survival and a 9% absolute increase in 5-year DFS versus RC alone.¹¹

Three to 4 cycles of cisplatin-based neoadjuvant chemotherapy is recommended; however, the optimal regimen is still unknown. A recent, randomized phase 3 trial comparing dose-dense MVAC to gemcitabine and cisplatin in patients with MIBC indicates a higher local control rate (complete pathological response, tumor downstaging, or organ confined) with the use of MVAC (P = .021).¹² However, progression-free survival (PFS) data are pending, and previous retrospective studies are mixed regarding advantages of MVAC versus cisplatin/gemcitabine.^13,14

In patients unfit for cisplatin, adjuvant chemotherapy is not recommended [I, D]. An overall survival benefit (HR, 0.77; 95% CI, 0.59-0.99) and DFS benefit (HR, 0.66; 95% CI, 0.45-0.91) for patients receiving cisplatin-based adjuvant chemotherapy versus observation were shown in a meta-analysis of 9 randomized trials including 945 patients [II, B].¹⁵ However, no randomized phase 3 data are available at this time.

Adjuvant nivolumab showed promising results in the CheckMate 274 trial (NCT02632409), producing an improved DFS rate in the overall study population compared with placebo (74.9% vs 60.3%; HR, 0.70; 98.22% CI, 0.55-0.90) as well as in PD-L1–positive patients (74.5% vs 55.7%, respectively; HR, 0.53; 98.72% CI, 0.35-0.85) [I, D].¹⁶

Nivolumab is approved in the adjuvant setting in patients who show resistance to platinum-based chemotherapy but is not yet recommended because we do not yet have survival data,” Bellmunt said. “We need to wait for survival data for adjuvant chemotherapy.”

Management of Advanced/Metastatic Disease

Cisplatin-based Chemotherapy

The most widely used and accepted cisplatin chemotherapy regimen is gemcitabine-cis- platin for patients fit enough to tolerate it [I, A]. Alternative regimens include dose-dense MVAC [I, B]; MVAC with granulocyte colo- ny-stimulating factor [I, B]; and gemcitabine, cisplatin, and paclitaxel (Abraxane) [I, C].

Similar results are reported with these regimens, although gemcitabine-cisplatin has a more favorable safety profile and tolerability across studies.^17-19

Other regimens expanding the gemcitabine-cisplatin combination are not recommended because studies show no statistical improvement in outcomes or improvement in overall survival.^20,21

Some patients are deemed unfit for cispla- tin-based chemotherapy based on predefined criteria established by consensus in 2011.²²

For these patients, carboplatin-based chemo- therapy is recommended [I, A], with the preferred combination of carboplatin and gemcitabine.²³

Atezolizumab and pembrolizumab are potential alternative first-line choices for PD-L–positive patients not eligible for cisplatin-based therapy, but current data do not show a superior response with immune checkpoint inhibitors (ICIs) vs chemotherapy [III, B].^24,25

Bellmunt noted the importance of establishing PD-L1–positive status based on scoring prior to initiating therapy with pembrolizumab or atezolizumab, unless the patient is entirely chemotherapy ineligible.

Enfortumab Vedotin-ejfv and Pembrolizumab

A study evaluating the combination of enfortumab vedotin-ejfv and pembrolizumab in the first-line setting for cisplatin-ineligible patients (NCT03288545) produced an objective response rate (ORR) of 73.3% (95% CI, 58.1%-85.4%). However, due to the small sample size, no recommendations for use can be made at this time.²⁶

The most important data within advanced and metastatic disease is from JAVELIN Bladder 100 trial [NCT02603432], where maintenance immunotherapy with avelumab [Bavencio] has provided survival benefit for patients who are not progressing after receiving chemotherapy,” Bellmunt said.

Within 10 weeks of first-line platinum-based chemotherapy, avelumab should be initiated. Patients without disease progression after 4 to 6 cycles of gemcitabine with cisplatin or carboplatin have an overall survival (OS) advantage compared with best supportive care (HR, 0.69; 95% CI, 0.56-0.86) [I, A].²⁷

“Unlike with other cancers, the combination of immunotherapy and chemotherapy has failed in [UC] trials compared to standard-of-care...chemotherapy. So for metastatic patients, we still recommend platinum-based chemotherapy first,” Bellmunt said.

"For patients who have no progression on chemotherapy, we recommend they switch to maintenance avelumab, which has shown a substantial survival advantage.”

Relapsed Advanced/Metastatic UC

For patients with progression after platinum-based chemotherapy, pembrolizumab is recommended based on a significant survival advantage compared to chemotherapy observed in the KEYNOTE-045 trial (NCT02256436) [I, A]. Compared with chemotherapy, pembrolizumab showed a higher overall response rate (21% vs 11%) and longer median DOR (29.7 months vs 4.4 months) in the second-line setting.^28,29

Chemotherapy and Immunotherapy-relapsed disease
Patients with progression after chemotherapy and maintenance avelumab should be given enfortumab vedotin-ejfv due to its superiority to chemotherapy (vinflunine or taxanes) [I, A]. Superior overall response rate (40.6% vs 17.9%), PFS (HR, 0.62; 95% CI, 0.51- 0.75), and OS (HR, 0.70; 95% CI 0.56-0.89; 12.8 vs 9.0) were observed with enfortumab vedotin-ejfv versus chemotherapy.³⁰

Bellmunt noted the lack of approval for enfortumab vedotin-ejfv in many countries in Europe but added that “there was a survival advantage for these patients [from EV-301] in the second-line setting. We are now extrapolating these data to patients who are progressing after maintenance, and enfortumab vedotin-ejfv is approved in the United States.”

There is greater evidence for enfortumab vedotin-ejfv than erdafitinib (Balversa). Erdafitinib showed an objective response rate of 40% among all patients and 59% among patients who had previously undergone immunotherapy in a phase 2 trial that evaluated 22 patients with fibroblast growth receptor (FGFR) mutations.31,32 Further, a median PFS of 5.52 months (95% CI, 4.2-6.0), and median OS of 11.3. months (95% CI, 8.0-21.1) were also observed. For the FGFR-selected population, erdafitinib is also recommended, though with less robust evidence [III,B].

Final Thoughts

To conclude, Bellmunt addressed the guidelines as a whole and noted a consideration.

“These guidelines provide evidence-based medicine recommendations, but these recommendations need to be adapted country by country, especially based on reimbursement policies.”

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