The field of immunotherapy has historically caused controversies in oncology, with many physicians initially skeptical of the approach. However, the approval of the first immune checkpoint inhibitor ipilimumab (Bristol-Myers Squibb’s, Yervoy) at the beginning of this decade marked a turning point and a new era in treatment strategy. In bladder cancer, where immunotherapy development has stalled for decades, this represents an exciting opportunity to breathe new life into this treatment approach. Once again, immunotherapy stole the show at a major oncology conference, this time it was the turn of the ECCO-ESMO (2015) annual congress.

Bladder Cancer Treatment Comes Full Circle: A cutting-edge therapy builds on an age-old discovery

In many respects, bladder cancer led the way in the development of the field of immuno-oncology, as it was the one of the first targets of immunotherapy in oncology and it was the first indication for which an immunotherapy (BCG vaccine) was granted approval by the FDA in 1990. However, since the approval of the BCG vaccine for non-muscle-invasive bladder cancer, the development of immunotherapies for the indication has remained stagnant. Due to the new found faith in immune checkpoint inhibitors it is perhaps unsurprising that this drug class is once again gaining momentum in bladder cancer, with physician interests piqued by the approval of PD-1 inhibitors, including Bristol-Myers Squibb’s nivolumab (Opdivo) and Merck & Co.’s pembrolizumab (Keytruda), in malignant melanoma and non-small-cell lung cancer (NSCLC).

Immune Checkpoint Inhibitors are Set to Breathe New Life into Bladder Cancer Treatment

Bladder cancer is one of the ten most common cancers worldwide that can afflict both genders and is the 13th most common cause of death associated with cancer (Stewart BW, 2014). A mixture of immunotherapy (BCG vaccine), chemotherapies, and surgery are currently used to treat bladder cancer. The management of early-stage bladder cancer contributes to a significant healthcare burden due to the high risk of recurrence, frequent monitoring of the disease and high treatment costs. Few new agents have been approved for bladder cancer in the past 20 years, thus the competitive barriers to entry remain much lower in bladder cancer than in some other cancer markets.

Bladder cancer is associated with a high mutational burden (Lawrence MS, 2013), which provides a genetic basis for clinical response to checkpoint pathway inhibition and formed the basis for immunotherapy trials in invasive and metastatic bladder cancers. Currently, a number of immunotherapies, as well as targeted therapies, are in development for this disease. Early studies of PD-L1 inhibition in bladder cancer presented at the 2014 ASCO Annual Meeting showed promise, raising expectations of this class in the indication. Final data from the IMvigor 210 trial of Roche/Genentech’s atezolizumab in patients with locally-advanced or metastatic bladder presented at ECCO-ESMO 2015 continues to validate this approach (Rosenberg J, 2015).

Evidence from the ECCO-ESMO 2015 annual conference: Is Atezolizumab a Game Changer for Bladder Cancer?

Following the approval of the BCG vaccine for bladder cancer, the immunotherapy drug classes experienced decades of silence in the indication, with no further regulatory approvals in this class (see, ‘History of Immunotherapy in Bladder Cancer’). According to a number of medical oncologists presenting at the ECCO-ESMO conference, this is all about to change. Atezolizumab, an engineered, human MAb against PD-L1, being developed by Roche and Genentech is the first product to receive breakthrough therapy designation by the FDA for the treatment of bladder cancer. Compelling results of the pivotal Phase II IMvigor 210, evaluating atezolizumab in refractory advanced/metastatic bladder cancer patients featured in a late-breaking abstract were presented by Dr Jonathan Rosenberg, from the Memorial Kettering Sloan Cancer Center, at the ECCO-ESMO European Cancer Congress 2015 (Rosenberg J, 2015, Abstract 21LBA):

  • Following treatment with atezolizumab, 15% of the overall patient population (n=311) achieved a response, increasing up to 27% in patients with the highest levels of PD-L1 expression, assessed using the VENTANA PD-L1 (SP142) CDX assay which prospectively measured tumor-infiltrating immune cell PD-L1 expression based on 3 IHC scoring levels (IC1, IC2 and IC3). Commenting on the significance of the results, Dr Rosenberg stressed that such levels of response have never been seen in patients with refractory heavily pretreated bladder cancer.
  • Metastatic bladder cancer patients currently face a median overall survival (OS) of only 6-8 months, due to the lack of effective therapeutic choices (Sonpavde G, 2015). Although the OS from the IMvigor 210 trial are not yet mature the median OS for the patients with the highest levels of PD-L1 expression the interim analysis was over 10 months.
  • While the immature OS data for atezolizumab, displays early signs of a positive correlation between PD-L1 expression and MOS, the same cannot be said of the PFS data. Interestingly, the PFS was 2.1 months for all patients in this trial, irrespective of the level of PD-L1 expression. These data raise the important question, of which patients should receive atezolizumab?
  • Atezolizumab’s toxicity profile was similar to that observed in NSCLC, with the most common drug-related adverse events being fatigue (29%), Nausea (13%), pruritus (10%), and decreased appetite (11%). Treatment related grade 3/4 adverse events were observed in 15%.
  • Dr Rosenberg concluded the proffered paper session at ECCO-ESMO 2015 by stating that he believed atezolizumab has the potential to change the standard of care in metastatic bladder cancer, although he caveated the importance of validating these findings in Phase III.

Roche have announced that the data from IMvigor 210 will be submitted to global health authorities and are expected to support regulatory filing with the FDA in combination with atezolizumab’s Breakthrough Therapy Designation in this market (Roche Press Release, September 27 2015). While atezolizumab is poised to become the first immune checkpoint inhibitor to gain regulatory approval in bladder cancer and enjoy first-to-market status, it is not expected to enjoy this solace for long, with strong competition forecast from other immunotherapies, the two PD-1 inhibitors that are already approved for other oncology indications: nivolumab and pembrolizumab. DRG explore the bladder cancer market dynamics in much greater depth in the published report entitled: Niche Markets and Rare Diseases; Bladder Cancer (published in August 2015).

Missing pieces of the Immunotherapy Puzzle

There was no escaping immunotherapy at the ECCO-ESMO 2015 annual conference. With the unprecedented coverage of immunotherapies it was easy to jump on the immunotherapy bandwagon, however while the clinical benefit of immune checkpoint inhibitors is unquestionable, a number of crucial questions remain unanswered;

  • Which patients should receive a PD-1/PD-L1 inhibitor? Is PD-L1 a good target but a bad biomarker?
  • What is the optimal dosing schedule for checkpoint inhibitors? Do the agents need to be administered until progression? Is there a potential to adopt a vaccine approach?
  • What is the maximum tolerated dose?

Further optimization of the agents and their role in the field of oncology is therefore essential if the checkpoint inhibitors to reach their full potential. During Presidential Session III, the keynote speaker Dr Jean-Charles Soria stressed the importance of addressing these questions before the next wave of immunotherapies reach the clinics. For more discussion of these topics please refer to the blog from G. McConnell entitled, “The Immune Checkpoint Inhibitor Can of Worms: New Developments but More Questions”., written by Gemma McConnell, a Principle Business Insights Analyst at DRG.

The Evolving Role of Immunotherapy in Oncology

Whilst immunotherapy has undergone a remarkable and rapid rebirth in recent years, it remains in its infancy, with many key questions unanswered and indications unexplored. Without a doubt, immunotherapy looks set to remain the buzzword of oncology conferences for many years to come, as the field continues to evolve and bring new hope to a multitude of oncology indications.

Bibliography

Soria JC. Keynote Lecture: Revolution in clinical trials in early drug development. Proceedings of the ECCO-ESMO 2015 annual conference; Presidential Session III. 2015, September 28.

Couzin-Frankel et al. Breakthrough of the year 2013. Cancer immunotherapy. Science. 2013. 20; 342(6165).

Lawrence MS, Stojanov P, Polak P, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature.2013; 499:214-218.

McConnell G. “The Immune Checkpoint Inhibitor Can of Worms: New Developments but More Questions”   DRugwatch.2015.

Rosenberg J et al. Atezolizumab in patients (pts) with locally adavacned or metastatic urothelial carcinoma (mUC): Results from a pivotal multicentre Phase II stufy (IMvigor 210). ESMO 2015 annual meeting.

Sonpavde G et al. Future directions and targeted therapies in bladder cancer. Hematolological Oncology Clinical North America. 2015; 29: 361-376

Stewart BW, Wild CP. World Cancer Report 2014. World Health Organization. ISBN 978-92-832-0429-9.

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