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— TRENDS AND CHALLENGES IN IMMUNO-ONCOLOGY TRIALSby Beth Kiernan

Immuno-oncology (I/O) is changing the way that we approach cancer therapy. As precision medicine comes to the forefront, clinical researchers are beginning to home in on tumors with targeted therapies, focusing on those that have been previously resistant to treatment. This has been accomplished with chemical agents in small cancer subsets; however, immunotherapy seeks to harness the mechanisms of our own immune system to target cancer and its pathways.

INTRODUCTIONAlthough a relatively new approach, I/O has developers eager for the possibilities – monoclonal antibodies, checkpoint inhibitors, therapeutic cancer vaccines, cytokines, and other classes of immunotherapy drug candidates are filling the pipelines of biopharma at a rapid pace. Uncharted territories, however, come with challenges, and immuno-oncology is seeing its fair share. Researchers are struggling to identify biomarkers that can predict drug response, while regulatory bodies scramble to keep up with the I/O momentum.

Looking at more than 2,500 active and commercially relevant I/O trials in CortellisTM Clinical Trials Intelligence (greater than 1/3 of the current neoplasm trials), we can see that 33% of the clinical space is comprised of two innovative classes of immunotherapies: therapeutic cancer vaccines and checkpoint inhibitors (Fig. 1). Although therapeutic cancer vaccine trials have steadily trended downward in the past five years, particularly in the noncommercial space, checkpoint inhibitors experienced a twenty-fold increase in the number of commercially relevant trials started in 2015 as compared to 2010.

Fig. 1. Active and commercially relevant immuno-oncology trials by class. Cortellis Clinical Trials Intelligence, February 2, 2016.

THERAPEUTIC CANCER VACCINESWhile therapeutic vaccine candidates have been on the clinical scene for decades, studies have not always been rewarding. The goal of eliciting an active immune response against malignant cells is often thwarted by the complexity of the immune system itself; a fact that may not reveal itself until in-patient trials. Cancer cells, too, have mechanisms in place to remain undetected by T-cells, adding a layer of difficulty to the preclinical process. Although there are currently three cancer prevention vaccines that have been approved by the FDA, only one cancer treatment vaccine, Dendreon’s Provenge (sipuleucel-T) for prostate

cancer, has been approved thus far. However, clinical researchers are identifying novel ways to overcome previous roadblocks. Diverse vaccine strategies and modalities are being employed across clinical development to follow up on the success of Provenge.

There are currently 347 active, commercial clinical trials for therapeutic cancer vaccines. At an average of 1.85 trials per sponsor, it is apparent that vaccine development comes at a cost. But small to medium specialized biotech companies and research institutions are taking the risk (Fig. 2).

ACTIVE, COMMERCIAL IMMUNO-ONCOLOGY TRIALS

67+19+1414%

19%

67%

Monoclonal Antibodies

Therapeutic Cancer Vaccines

Checkpoint Inhibitors

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While most cancer therapy vaccine trials are still in early development, indicating continued interest by biopharma, approximately 10 percent have progressed successfully to late stage trials (Fig. 3).

Despite the long-awaited success of a therapeutic cancer vaccine with Provenge in 2010, developers are still facing limitations in designing trials. This is true especially when it comes to patient selection. Since vaccines are an active form of immunotherapy, they require a healthy immune system to work. However, patients who have previously been treated with chemotherapy and/or other agents often lack the ability to produce

a strong immune response due to a suppressed system. Adding to that, cancer cells themselves inherently suppress the immune system – a mechanism that ensures their survival. So how are researchers working around this? Adjuvants and delivery vehicles are being employed to both boost and control the immune response to the antigen. Silently introducing them into the system, however, can be tricky. In the case of a study that measured the response of mice injected with a gp100 melanoma peptide, the popular water-in-oil emulsion method for vaccination worked against the intended cause, as T-cells were directed to the injection site instead of the tumor.1

Fig. 2. Top 10 sponsors for active, commercially relevant trials for therapeutic cancer vaccines. Cortellis Clinical Trials Intelligence, February 2, 2016.

Fig. 3. Active, commercially relevant therapeutic cancer vaccine trials by phase (postmarketing studies and unreported phases are not shown). Cortellis Clinical Trials Intelligence, February 2, 2016.

TRIALS BY PHASE 33+3+10+1+32+21Phase 0

Phase 1

Phase 1/2

Phase 2

Phase 2/3

Phase 3

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CHECKPOINT INHIBITORSCheckpoint inhibitors have been garnering much-earned attention in the I/O space. While cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) has been targeted for immunotherapies for some time, two relatively new targets have developers upping their enthusiasm for the class: programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1). Like CTLA-4, PD-1 is a receptor on T-cells. It binds ligands PD-L1 and PD-L2 to downregulate the immune system by preventing the activation of T-cells. In certain neoplasms, these proteins are upregulated, thereby suppressing an immune response to cancer cells. Checkpoint inhibitors block this mechanism, allowing the immune system to “see” cancer cells and launch an attack.

Big pharma and specialized biotech companies are active in the space, with Bristol-Myers Squibb (BMS) leading the way (Fig. 4). Following the success of both Yervoy (CTLA-4) and Opdivo (PD-1), BMS is working to expand their approved use for other cancer types. They are also studying KIR and LAG3 inhibitors as part of their I/O pipeline, with lirilumab (anti-KIR) in phase 1 trials and BMS-986016 (LAG3) having begun a phase 1 study in 2013. Roche’s pipeline is made up by PD-L1 and IDO inhibitors (RG-7446 and RG-6078, respectively), while AstraZeneca focuses on CTLA-4 and PD-1/PD-L1, as reported in a PharmaTimes article by Charlotte Jago of Thomson Reuters.2

Fig. 4. Active, commercially relevant trials for cancer checkpoint inhibitors by sponsor. Cortellis Clinical Trials Intelligence, February 2, 2016.

Looking at the 482 active, commercially relevant checkpoint inhibitor trials, there are approximately 3.52 trials per sponsor – almost twice that of therapeutic cancer vaccines. PD-1 trials are seeing an upswing following the positive results of Opdivo and Merck’s Keytruda and now comprise approximately 52 percent of current checkpoint inhibitor trials (Fig. 5).

In the PharmaTimes article, Jago shows that survival and overall response rates with Yervoy, Opdivo, and Keytruda were increased or high, compared to standard treatments. In fact, the author states that Merck’s Keytruda data was so promising that the drug was approved based on phase 1 results alone from the KEYNOTE-001 study for metastatic melanoma.2

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Checkpoint inhibitor trial phases are practically split down the middle, with approximately 52 percent in early phase and 48 percent in phase 2 and 3, indicating both an ongoing interest by biopharma and successful progression into later stage trials (Fig. 6).

Lung tumors have surpassed melanoma as the top cancer type being studied for commercial drug development of checkpoint inhibitors. Looking at the top patient segments in lung tumors, melanoma, and solid tumors, it is apparent that developers in the space have identified an unmet need – those with late-stage or treatment-resistant cancers, where other drugs have failed (Fig. 7).

Fig. 5. Active, commercially relevant checkpoint inhibitor trials by action. Cortellis Clinical Trials Intelligence, February 2, 2016.

Fig. 6. Active, commercially relevant checkpoint inhibitor trials by phase (postmarketing studies and unreported phases are not shown). Cortellis Clinical Trials Intelligence, February 2, 2016.

52+23+2525%

23%

52%

PD-1

CTLA-4

PD-L1

ACTIVE, COMMERCIAL CHECKPOINT INHIBITOR TRIALS

TRIALS BY PHASE 32+15+1+32+20Phase 0

Phase 1

Phase 1/2

Phase 2

Phase 3

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One caveat that researchers have discovered in bringing checkpoint inhibitor candidates to trial is that predictive and prognostic biomarkers, which are necessary for proving efficacy and identifying patient populations, are difficult to measure in terms of response. This is particularly seen in trials where PD-L1 is being reported as a biomarker (39 percent of all checkpoint inhibitor trials using biomarkers). Although high PD-L1 staining often does correlate with a high response rate, no staining does not necessarily mean that there will be no response rate. Physiological biomarkers, too, may have equal correlations. Looking at the current biomarkers used in checkpoint inhibitor

trials, there are 1.23 biomarkers per trial on average. PD-L1 is the most common biomarker used in the top three conditions of checkpoint inhibitor studies. Of those lung tumor studies that use biomarkers, PD-L1 is measured in 56 percent. Epidermal growth factor is measured in 44 percent, and ALK tyrosine kinase is measured in 31 percent (Fig. 8).

Another challenge Jago highlights in the immuno-oncology paradigm article is that guidance on studying two unapproved drug candidates in combination trials has only recently been published by the FDA (in 2010 and 2013).2

Fig. 7. Most common patient segments in top three conditions of active, commercially relevant cancer checkpoint inhibitor trials. Cortellis Clinical Trials Intelligence, February 2, 2016.

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CONCLUSIONAs immuno-oncology draws biopharma in with novel cancer therapies and staggeringly positive results, it becomes crucial to find an unsaturated niche within the space. Biotech companies have carved out their place in therapeutic cancer vaccines while big pharma invests heavily in checkpoint inhibitors, but what comes next? Immunotherapy and cross-class combinations are proving to be successful, but I/O is a constantly moving space. With the recent success of Amgen’s melanoma candidate T-vec (Talimogene

laherparepvec), the first oncolytic virus to be approved for marketing, it’s probable that the next go-to class of immunotherapies will move beyond T-cells. As we venture forth into immuno-oncology, it is becoming more of a reality that drug developers will outsmart cancer cells. Exploiting cancer pathways using our own immune system is not a novel approach, but approaching it in a novel way is key to staying one step ahead of both the disease and the competition.

Fig. 8. Most common biomarkers in top three conditions of active, commercially relevant cancer checkpoint inhibitor trials that use biomarkers. Cortellis Clinical Trials Intelligence, February 2, 2016.

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REFERENCES1 Hailemichael, Y. et al. Persistent antigen at vaccination sites induces tumor-specific CD8(+) T cell

sequestration, dysfunction and deletion. Nat. Med. 19, 465–472 (2013). http://www.nature.com/nm/journal/v19/n4/full/nm.3105.html?WT.ec_id=NM-201304

2 Jago, Charlotte. The Immuno-Oncology Paradigm. PharmaTimes (2015). http://edition.pagesuite-professional.co.uk//launch.aspx?eid=cd1122ab-5b80-428d-a3de-078a009af9c4

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AUTHOR

BETH KIERNAN

Beth Kiernan is a pharmaceutical research analyst – clinical trials at Thomson Reuters. In this role, Beth is responsible for analyzing the intelligence contained within Cortellis CTI, focusing on global clinical trial developments. Prior to joining Thomson Reuters in 2013, Beth worked as a research scientist and teaching assistant in the field of molecular biology and genetics. She holds a degree in biology from Rutgers University.

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