SIU 2017: SIU-ICUD Joint Consultation on Bladder Cancer - Systemic Therapy for Metastatic Urothelial Carcinoma

Lisbon, Portugal (  Dr. Merseburger, along with Dr. Sternberg, were the co-chairs for this chapter. There has been a lot of development in this space in the past 5 years, so they highlighted some of the key changes along the way. However, the final published chapter will have the most up to date recommendations. 

There were 5 general sections for this chapter:
  1. First-line treatments, doublet-therapy and triplet drug combination with cisplatin therapy
  2. Cisplatin-ineligible patients
  3. Second-line treatments/Salvage chemotherapy monotherapy/combination therapy
  4. Targeted agents and biomarker driven strategies
  5. Immunotherapy of bladder cancer
First-line treatments, doublet-therapy and triplet drug combination with cisplatin therapy
Over the years, there have been better patient selection, better supportive care, earlier diagnosis and screening:
  • Dose-dense MVAC vs. MVAC (2006 Sternberg) – at 2 years, there was a 10% survival improvement with ddMVAC
           o   Decreased the toxicity and increased efficacy
           o   EORTC randomized study confirmed these findings
           o   Level 1 evidence, Grade A recommendation

  • Important to remember that cisplatin chemotherapy is still the SOC first line therapy
           o   Produced a 72% ORR in patients with metastatic UCC

  • Doublet therapy (Gem-Cis) is accepted as a SOC first line therapy as well
           o   Decreased rate of mucositis and neutropenia, but higher rate of thrombocytopenia
           o   Many have dropped the day 15 gemcitabine resulting in more tolerable 3 week course (Level 1b evidence)

Cisplatin-ineligible patients
  • Approximately 50% of MIBC are ineligible for cisplatin therapy
  • Carboplatin based doublet therapy has traditionally filled this space, with ORR 36% (LOE 2)
  • More recently, immune checkpoint blockage has been introduced into this field
           o   Pembrolizumab (ORR 29%) and Atezolizumab (ORR 23%) are now approved
           o   Level 2 evidence
           o   Median OS was 15.9 months (9.3 months for carbo based doublets)

  • Gemcitabine triplet therapies 
            o   Gem/Cis/Paclitaxel – ORR 43%
            o   Gem/Paclitaxel/doxorubicin – ORR 56% - Level 2 evidence

Second-line treatments/Salvage chemotherapy monotherapy/combination therapy
  • Vinflunine phase III trial monotherapy
           o   OS benefit compared to best supportive care, but was not an ITT analysis
           o   LOE 1b, Grade B

  • Taxanes – limited activity
            o   LOE 2, Grade B

  • Premetrexed – limited activity
  • VEGFR TKI’s – no role in second line therapy
  • More recently, RANGE study (Petrylak et al, Lancet, Sept 2017) demonstrated prolonged PFS (OS not available yet) with ramicirumab with docetaxel vs. docetaxel alone
           o   Promising but not yet enough to make a recommendation

  • At this time, no clear benefit for the use of combination therapy (LOE 2, Grade B)
Targeted agents and biomarker driven strategies
Targeted agents were discussed extensively in earlier sessions, and the concept of precision medicine was already covered. As such, he did not spend much time on this topic. The group’s guidelines were as follows:
  • Enroll in biomarkers based clinical trials
  • Biopsies at the time of progression or ctDNA profiling
  • Level 2 evidence for:
           o   Sunitinib, ramicirumab with docetaxel, afatinib for patients with Her2/Her3 somatic alterations
           o   Enfortumab or  multiple FGFR3 inhibitors for patients with FGFR3 activating mutations
           o   Everolimus for patients with TSC1/2 somatic mutations or inactivating mutations

Immunotherapy of bladder cancer
These novel therapies are revolutionizing the field of systemic therapy for bladder cancer

5 have been approved by the FDA so far – a few of phase 1 trials alone!
  • Therefore, there is some room for improvement in the selection of patients who respond best
  • Patients with high mutational load and MSI seem to respond best
  • However, as discussed previously, identifying good biomarkers has been difficult
Several are now even in trial for the adjuvant setting after RC for high-risk MIBC.

Despite a quick overview of the topic, it was very well received. The full guidelines will expand further on the recommendations.

Presented by: Axel Merseburger 

Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 37th Congress of Société Internationale d’Urologie - October 19-22, 2017- Lisbon, Portugal
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