Future Oncol. 2015;11(16):2299-306.

Anti-PD-1 and PD-L1 therapy for bladder cancer: what is on the horizon?

 

Sundararajan S1, Vogelzang NJ2.

  • 1University of Arizona, Tucson, AZ 85721, USA.
  • 2University of Nevada School of Medicine & US Oncology/Comprehensive Cancer Centers of Nevada, Las Vegas, NV 89014, USA.

 

Abstract

Oncologic therapeutics has evolved enormously as we entered the 21st century. Unfortunately, the treatment of advanced urothelial cancer has remained unchanged over the last two decades despite a better understanding of the genetic alterations in bladder cancer. Pathways such as the PI3K/AKT3/mTOR and FGFR have been implicated in urothelial bladder cancer. However, targeted therapies have not shown proven benefit yet and are still considered investigational. Recently, researchers have been successful in manipulating the systemic immune response to mount antitumor effects in melanoma, lung cancer and lymphoma. Historically, intravesical Bacillus Calmette-Guérin immunotherapy has been highly active in nonmuscle invasive bladder cancer. Early data suggest that immune checkpoint inhibitors will soon prove to be another cornerstone in the treatment armamentarium of advanced bladder cancer.

KEYWORDS: PD-1; PD-L1; bladder cancer; immunotherapy

PMID: 26260808

 

Supplements

Q: What is the rationale and role of immunotherapy in bladder cancer at this point?

Answer: Cancer cells survive and grow by evading of our body’s natural immune system. Our immune system is designed to identify and attack any foreign material (bacteria, viruses, cancer cells) in our body. Cancers cells attach to specific immune checkpoints such as cytotoxic T lymphocyte associated protein – 4 (CTLA-4), programmed cell death protein -1 (PD-1) and turn off the switch that would trigger a response against them. Bladder cancers cells have been known to express PD-L1 (a ligand for PD-1) and hence using a PD-1 or PD-L1 inhibitor would be a perfect rationale to treat them.

 

Q: What is your observation about anti-PD-1 or PD-L1 therapy in bladder cancer?

Answer: Anti PD-1 and PD-L1 therapy has shown promising results in phase 1 and 2 trials so far. In the phase 1/ 2 study of Atezolizumab by Powles et al1, a PD-L1 inhibitor that included patients with varying degree of PD-L1 expression, about two-fifth of patients with strong expression of PD-L1 responded to this drug and 2 patients had complete response of cancer. This is remarkable considering that these patients were heavily pre-treated and had poor prognostic factors. Similar findings were noted in the IMvigor 210 phase 2 study2 that was recently presented at European Society of Medical Oncology Meeting in Sept 2015. Pembrolizumab, a PD-1 inhibitor has been evaluated in a phase 1 trial3 with 33 patients. About ¼ of patients responded to this therapy and about 3 patients had complete response of cancer.

 

Q: What is your comment about the biomarker cutoff for PD-1/PD-L1 therapy?

Answer: A notable aspect in the above trials is that, a modest response was noted to this therapy even in patients who did not have PD-L1 expression. However this was less than the PD-L1 positive group. At this point, it is clear that PD-L1 positivity certainly enhances response to these therapies. However we would need standardization of PD-L1 assessment to improve response to therapy since different trials have used different cut off values4.

 

Q: What is the future of Anti- PD-1/PD-L1 in bladder cancer?

Answer: Larger phase 3 trials are underway evaluating these drugs as second line therapy in bladder cancer. Also phase 2 trials combining anti PD-1/PD-L1 therapy with chemotherapy in first line setting are ongoing as well. In my opinion, these drugs are going to an important treatment modality in bladder cancer both in relapsed/refractory setting and front line setting.

 

References

  1. Powles T, Eder JP, Fine GD et al. MPDL3280A (anti-PD-L1) treatment leads toclinical activity in metastatic bladder cancer.Nature 515(7528), 558–562 (2014).
  2. Rosenberg J, Petrylak C, Abidoye O, et al. Atezolizumab in patients with locally-advanced or metastatic urothelial carcinoma: Results from a pivotal multicenter phase II study (IMvigor 210). Abstract 21LBA, European Society of Medical Oncology, 2105.
  3. Plimack ER, Bellmunt J, Gupta S, et al. Pembrolizumab (MK-3475) for advanced urothelial cancer: Updated results and biomarker analysis from KEYNOTE-012. J Clin Oncol 33, 2015 (suppl; abstr 4502).
  4. Sundararajan S, Vogelzang N. Anti-PD-1 and PD-L1 therapy for bladder cancer: what is on the horizon? Future Oncol. 2015;11(16):2299-306. doi: 10.2217/fon.15.162.

 

Contact:

Srinath Sundararajan, MD

Ssundararajan@email.arizona.edu.

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