If Not 1st Line, How About Creating a 1.5 Line Therapy for Metastatic Urothelial Carcinoma?

PD-1/PD-L1 antibodies are being studied in every disease state imaginable for patients with urothelial carcinoma.  Atezolizumab, nivolumab, durvalumab and avelumab are all regulatory approved for patients with metastatic disease in the post-platinum chemotherapy setting.1-4  Pembrolizumab is also approved and is the only agent to have demonstrated an overall survival benefit to date when compared to taxane chemotherapy in the post-platinum setting.5  Additionally, atezolizumab and pembrolizumab are approved for patients who are ineligible for cisplatin chemotherapy in the 1st-line. 6,7  This can be due to poor ECOG performance status, renal dysfunction, peripheral neuropathy, or hearing problems. As I’ve previously discussed in a Clinical Trials Portal article, much work with checkpoint inhibitors is ongoing in the 1st-line disease space.9  Please refer to that previous article for a summary of that work and highlighted ongoing clinical trials.

As a practicing clinician, I am still using platinum combination chemotherapy in the 1st line when a patient can tolerate it.  Although response rates range in the 15-20% range for PD-1/PD-L1 therapy, cisplatin-based combinations offer an approximate 50% response rate.10  The downside is that cisplatin-based combinations do not offer the same level of durability of response or stable disease that is seen with PD-1/PD-L1 therapy.  One approach is to try to combine both PD-1/PD-L1 therapy with platinum chemotherapy, and that rational combination is ongoing already and previously described.9  However, another approach is to recognize that patients who receive many cycles of platinum-chemotherapy, suffer from fatigue, neuropathy, and multiple other potential toxicities.  These toxicities eventually become treatment limiting, and it is rare for patients to be treated beyond 6 cycles of therapy.  In non-small lung cancer, it has even been established that there is no benefit to 6 cycles of platinum chemotherapy when compared to fewer cycles.11

Taken together, a unique approach to introduce PD-1/PD-L1 therapy earlier in the metastatic disease paradigm, without either combination in the 1st line setting or compromising response rate with single agent use, is to create a new disease state.  Patients that have received prior platinum therapy for metastatic urothelial carcinoma, who obtain a response or stable disease, are great candidates for maintenance therapy with PD-1/PD-L1 therapy.  As a result, this is neither 1st line or 2nd line therapy.  Many in the field have informally termed this the “1.5 line” of therapy.  In addition to being a unique regulatory niche, this approach is pragmatic. By introducing lower toxicity agents to patients who may be suffering from significant chemotherapy-associated toxicities, patients may preserve quality of life with potentially improved efficacy outcomes.  This kind of maintenance or consolidative approach justifies the designation of this new disease state.

In regards to ongoing trials in this space, avelumab is being tested in a phase 3 trial with the goal of improvement in overall survival for patients who do not progress after receipt of 4-6 cycles of prior platinum-based chemotherapy.  Patients (n=668) are being randomized between avelumab and best supportive care.  Best supportive care is very acceptable in this disease state, as most patients will practically take a chemotherapy break after 4-6 cycles of platinum-based chemotherapy.  Meanwhile, the Hoosier Cancer Research Network has a 200 patient randomized phase 2 trial, using 6-month progression-free survival as the primary endpoint.  Although this endpoint may not be viewed as noteworthy as overall survival, prolonging progression-free survival with pembrolizumab over placebo in this setting is still clinically meaningful, given the cumulative toxicities of chronic chemotherapy.

In conclusion, creating a new disease state for novel therapeutic testing is pertinent to our goals as clinicians if the endpoints and impact are of importance.  In this situation, thoughtful consideration has gone into the development of the above-mentioned trials to ensure that patient needs are being met.  Hence, we should wholeheartedly support these efforts by accruing and referring patients for these trials. 

Highlighted 1.5 Line Metastatic Urothelial Cancer Trials

Written by: Evan Yu, MD 


  1. Rosenberg JE et al.  Lancet 2016; 387:1909-20.
  2. Sharma P et al.  Lancet Oncol 2017; 18:312-22.
  3. Massard C et al.  J Clin Oncol 2016; 34:3119-25.
  4. Apolo A et al.  J Clin Oncol 2016; 34 (suppl; abstr4514)
  5. Bellmunt J et al.  N Engl J Med 2017; 376:1015-26.
  6. Balar A et al.  Lancet 2017; 389:67-76.
  7. Balar A et al.  Lancet Oncol 2017; 18:1483-92.
  8. Galsky MD et al.  J Clin Oncol 2011; 29:2432-8.
  9. Yu EY.  UroToday Clinical Trials Portal; April 11, 2017.
  10. von der Maase et al.  J Clin Oncol 2000; 18:3068-77.
  11. Ross A et al.  Lancet Oncol 2014; 15:1254-62.
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