From the Desk of Evan Yu: PD-1 or PD-L1 Inhibition for Front-Line Metastatic Urothelial Cancer.

With the recent regulatory approvals of PD-1 and PD-L1 antibodies for patients with metastatic urothelial cancer, we have significantly expanded treatment options for this patient population.  Atezolizumab is a PD-L1 antibody that not only demonstrated significant responses but has also shown durability of response and clinical benefit through stable disease in a substantial proportion of patients in the post-platinum treated setting, leading to FDA approval in May 2016.1 

Nivolumab is a PD-1 antibody that also has demonstrated such efficacy results in a similar patient population, with FDA approval achieved in February 2017. Pembrolizumab is another PD-1 antibody that has already demonstrated an overall survival benefit in this post-platinum setting when compared to taxane chemotherapy.3  Finally, both durvalumab and avelumab are PD-L1 antibodies in active development for patients with urothelial carcinoma with early signs of significant clinical activity.4, 5  It is now clear that the principle of inhibiting the PD-1/PD-L1 checkpoint is augmenting an individual’s adaptive cell mediated immune system to create meaningful clinical benefit.

Not surprisingly, initial development of any novel class of agents usually takes place in a later, unmet need, disease state.  However, now that we have firmly ingrained PD-1/PD-L1 therapy in the second-line after platinum-based chemotherapy for patients with metastatic urothelial carcinoma, the next obvious developmental strategy is to import these agents into the first-line setting.  Fortunately, we have already seen clinical activity in a couple reported trials in this setting for patients considered to be cisplatin-ineligible due to poor ECOG performance status, renal dysfunction, peripheral neuropathy, or hearing problems.  Both atezolizumab and pembrolizumab have reported promising data for this patient population,6,7 and we await regulatory review to see whether this first-line patient population, a significant unmet need due to patient comorbidity, will soon have commercial access to such active therapy.

There remains of large subset of patients who are eligible for cisplatin-based chemotherapy in the first-line, and a valid question is whether patients might benefit from receipt of PD-1/PD-L1 antibody therapy in this setting either alone or in combination with chemotherapy.  This is the goal of two large randomized phase 3 trials with very similar designs.  The first, NCT02853305, randomizes patients with locally unresectable or metastatic urothelial carcinoma to gemcitabine/cisplatin vs. gemcitabine/cisplatin plus pembrolizumab vs. pembrolizumab alone for patients eligible for cisplatin.  For those patients who are cisplatin ineligible, carboplatin may serve as a replacement.  Another trial with a similar design evaluates gemcitabine/cisplatin vs. gemcitabine/cisplatin plus atezolizumab vs. atezolizumab alone (NCT02807636).  Both of these trials utilize the dual primary endpoints progression-free and overall survival.  Although these trials could discover PD-1/PD-L1 therapy to offer improved progression-free and/or overall survival outcomes in the first-line setting, one must recognize that response rates with immuno-oncology agents alone are not apt to be as robust as with chemotherapy.  Whereas, response rates range in the 15-20% range for PD-1/PD-L1 therapy, cisplatin-based combinations offer an approximate 50% response rate.8  Although response is generally short-lived with cytotoxic chemotherapy, the value of such a response cannot be easily dismissed for a patient with rapidly progressive symptomatic disease, especially one with a visceral crisis.  These patients may have one opportunity for response, so choosing a therapeutic regimen with high response rates in the first-line could be optimal over choosing a less toxic and durable checkpoint inhibitor.

One interesting strategy in the first-line setting is to study combination immuno-oncology therapy.  The trial of durvalumab plus tremelimumab, a CTLA4 antibody, vs. durvalumab alone (NCT02516241) is primarily evaluating progression-free and overall survival, but it has promise to provide insight on whether combination immuno-oncology strategies might offer improved response rates.  Another important trial that will directly test the question of combination immuno-oncology agents vs. chemotherapy in this first-line setting compares nivolumab plus ipilumumab versus standard of care gemcitabine/platinum chemotherapy (NCT03036098).  It is with the promise of this type of strategy that has patients and clinicians alike excited about the future of immuno-oncology agents in the first-line metastatic setting.

With all these high yield trials ongoing, it is likely that you have access to at least one of the above first-line trials with immuno-oncology agents in your vicinity.  Only through enrollment of patients into clinical trials of this sort will we be able to move promising agents earlier in the treatment paradigm where there is promise for even greater impact.  Naturally, a future letter from my desk will focus on even earlier use in the high-risk adjuvant setting.  The theme of immuno-oncology early and often for this disease continues.

Highlighted First-line Metastatic Urothelial Cancer Trials:
  1. Rosenberg JE et al.  Lancet 2016; 387:1909-20.
  2. Sharma P et al.  Lancet Oncol 2017; 18:312-22.
  3. Bellmunt J et al.  N Engl J Med 2017; 376:1015-26.
  4. Massard C et al.  J Clin Oncol 2016; 34:3119-25.
  5. Apolo A et al.  J Clin Oncol 2016; 34 (suppl; abstr4514)
  6. Balar A et al.  Lancet 2017; 389:67-76.
  7. Balar A et al.  ESMO 2016; LBA32_PR.
  8. von der Maase et al.  J Clin Oncol 2000; 18:3068-77.