By Dr. Benjamin Pradere
Once again, ASCO has lived up to its promise with its 2021 edition. The news in the field of bladder cancer was full and rich in information.
We have selected a part of the studies presented during the congress. As a result, news in all areas of bladder cancer is reported here for you: from new drugs to new combinations and news on all stages of bladder cancer, from BCG-unresponsive to first and second-line treatment for metastatic patients!
Bladder-sparing strategy, game changer in the making: is it ready for prime time?
Trimodal therapy is the new game changer in the making for the treatment of localised bladder cancer. Nevertheless, the optimal chemoradiation regimen has not been defined – although hypofractionated radiotherapy combined with gemcitabine has shown promising efficacy and safety (Watch this interview with Ass. Prof. Balar).
Given the potential synergy between CPI and chemotherapy, Balar et al. conducted a multicentre phase-2 clinical trial to assess the safety and efficacy of pembrolizumab added to standard trimodality bladder preservation therapy using gemcitabine and hypofractionated radiotherapy.
Patients were given pembrolizumab before TURB followed by a 4-week chemoradiation plus pembro. Response rates were assessed by TUR/biopsy of the tumour bed, urine cytology, and CT as well as MRI of the abdomen and pelvis. The results seem promising. At 12 weeks post-radiotherapy, a CR rate of 59% was measured in the overall cohort. Moreover, at a median follow-up of 14.6 months the 1-year estimated BIDFS rate was 88% in the efficacy cohort of 48 patients.
Another very interesting study designed to evaluate the potential role of a bladder-sparing strategy in the management of MIBC was presented by Dr. Galsky: the HCRN GU16-257 trial (Watch the interview with Dr. Galsky). In this study, patients received the association of Gem-Cis+Nivolumab, and, in case of clinical CR, it was proposed that they would continue with Nivolumab. The primary endpoint was the clinical complete response (cCR) defined as:
A co-primary endpoint was delineated as the ability of cCR to predict benefit defined as 2-year MFS in patients pursuing surveillance or as a pCR rate in patients who underwent RC. 76 patients enrolled, most of whom had cT2 disease (57%). 32% had cT3 disease. The cCR rate was 48%. 22 patients didn’t have any recurrence, and all patients with cCR remained alive at least until follow-up. Only one patient with cCR showed evidence of metastatic disease. Of note, a high tumour mutational burden (> 10 Muts/Mb) and the presence of an ERCC2 mutation were significantly associated with clinical response.
The phase-2 IMMUNOPRESERVE-SOGUG trial combined immunotherapy with durvalumab, tremelimumab, and radiotherapy as a chemotherapy-free strategy for bladder preservation in MIBC. The primary endpoint of the study was complete response defined as less than or equal to pT1 disease at biopsy. 26 patients (81%) met this endpoint, with 25 having a pathologic complete response. Two patients had residual MIBC. The median disease-free survival rate at 12 months was 76%, and the median overall survival rate at 12 months was 87%. Therefore, combined immunotherapy (durvalumab and tremelimumab) and concurrent radiotherapy is safe and has a high-rate of clinical response and bladder preservation, at least at 12-month follow-up.
The DUART trial investigated the combination of radiation therapy and the checkpoint inhibitor durvalumab in T2-T4 M0 patients unfit for surgery or cisplatin-ineligible. The primary endpoints were progression-free survival at 1 year and a specific disease control rate following post-adjuvant durvalumab. The 1-year probability of PFS was 73% (95% CI 56.4%, 94.4%) with a median PFS of 18.5 months. The 1-year OS probability was 83.8% (95% CI 70.4%, 99.7%) with a two-year OS probability of 76.8 (95% CI 60.2%, 98%). Median OS has not been reached yet. There was no correlation between clinical outcomes and baseline tumour PD-L1 expression.
Promising data but much more to come
In the neoadjuvant setting, a phase-2 trial assessed Atezolizumab with Gemcitabine and Cisplatin in MIBC patients. The primary endpoint was the proportion of patients with < pT2N0, secondary endpoints involved the proportion of patients with pT0N0, recurrence-free survival, and safety. 39 patients were evaluated, the primary endpoint was met by 27 patients (69%) < pT2N0 at radical cystectomy, including 17 (44%) pT0N0. The median RFS has not been reached yet with a median follow-up of 16.7 months.
In the adjuvant setting, the first results from the phase-3 CheckMate 274 trial were presented. This trial investigated adjuvant nivolumab vs placebo in patients who underwent radical surgery for HR-MIBC. Over a median follow-up of 20 months, median disease-free survival was significantly longer in patients receiving nivolumab (21 months) compared to placebo (11 months). The authors demonstrated that adjuvant nivolumab is associated with both statistically significant and clinically meaningful improvement in DFS compared to placebo both in ITT patients and patients with PD-L1 ≥ 1%.
Metastatic Urothelial Carcinoma: new drugs are coming
In locally advanced and metastatic UC, a randomised phase-2 study comparing Cisplatin-Gemcitabine with or without berzosertib was presented by Dr. Pal. Berzosertib is an ATR inhibitor, the ATR (ataxia telangiectasia and Rad3-related) gene responds to DNA single-strand breaks. The primary objective of the study was to assess whether berzosertib improves the PFS. Unfortunately, the study did not meet its primary endpoint of improved progression-free survival with berzosertib. The median PFS in both arms was measured at approximately 8 months, and almost 20% of the patients in the study arm required dose reduction of berzosertib, and more patients required growth factor support.
For the first-line treatment setting for Cis-ineligible patients, action according to the Keynote-052 results was proposed as these results showed a durable anti-tumour activity after 5 years, with a response rate of 28.9%, a median duration of response of 33.4 months, and a median overall survival of 11.3 months. Patients with high PD-L1 expression were more likely to respond and have longer responses. This supports the role of pembrolizumab as first-line therapy for cisplatin-ineligible patients with advanced urothelial carcinoma.
Dr. Powles presented the results of EV-301, a phase-3 trial of enfortumab vedotin versus chemotherapy in patients with previously treated, locally advanced or metastatic urothelial carcinoma. Patients were randomised to receive enfortumab vedotin or an investigator choice of standard (docetaxel, paclitaxel, or vinflunine). The primary endpoint was OS, and secondary EP included PFS, OR rate, and disease control as well as safety and tolerability. After 11.1 months of follow-up, median OS was prolonged by 3.9 months with enfortumab (median OS: 12.9 vs 9.0 months, respectively; HR 0.70, 95% CI 0.56-0.89, 1-sided p = 0.00142). PFS was also improved with enfortumab vedotin (5.6 months) versus chemotherapy (3.7 months). Both ORR (40.6% vs 17.9%) and disease control rate (71.9% vs 53.4%) were significantly higher with enfortumab vedotin. Enfortumab vedotin is the first drug beyond chemotherapy and immunotherapy to show a significant survival advantage in previously treated advanced urothelial carcinoma.
The inducible T-cell co-stimulator (ICOS) protein is a member of the CD28 immunoglobulin receptor superfamily, which is the same receptor superfamily that CTLA-4 and PD-1 belong to. It has been shown in other cancers (melanomas) that tumours which show a high level of ICOS exhibit a better response and thus the chances of survival increase. The INDUCE-1 study, an open-label, first-in-humans, phase-1 study in advanced solid tumours, including urothelial cancers, was presented at ASCO. It investigated the potential for ICOS agonist feladilimab in combination with PD-1. The results included the safety profile of this new drug: there were no grade-5 treatment-related adverse events, and the majority of events were grade 1 or 2. Feladilimab mono- or combination therapy with pembrolizumab had a manageable safety profile, and ICOS agonism demonstrated evidence of clinical activity with some durable responses, especially in patients whose tumours expressed PD-L1 or ICOS.
In conclusion, the bladder cancer field is experiencing a fantastic boom more than ever. We hope that we gave you enough food for thought and that you are now as excited as we are to improve the patient care management of our patients with bladder cancer.