Guest Commentary: Planning successful oncology trials amid a rapidly shifting treatment landscape

 

By Dr. James Kyle Bryan & Dr. Andrew Zupnick of Novella Clinical

 

The field of clinical oncology appears to be entering a new Golden Age, owing to better targeted therapies and a wave of new immunotherapies. This progress is all spurred by an evolving understanding of the biology of cancer, more accessible technologies and regulatory agencies’ commitment to getting breakthrough therapies to doctors and patients faster.

 

These paradigm shifts present complex challenges for sponsors looking to design successful clinical trials for their investigational new drugs. Drug developers will not only need to stay abreast of the rapidly evolving and competitive landscape, but also remain flexible and innovative in responding to these changes.

 

 

The latest generation of oncology drugs is driven by key insights into cancer biology made possible by decades of scientific research and improvements in technology such as tumor imaging and genomic sequencing. These insights allow for the development of precision drugs that target genetic aberrations that are inherited (e.g., the BRCA1 or BRCA2 genetic mutations) or, more commonly, develop over time (e.g., the BCR-ABL1 gene fusion as is common in chronic myelogenous leukemia or the ALK, EGFR or KRAS aberrations as found in subsets of lung cancers).

 

For precision medicines, technologies such as next-generation sequencing (NGS) and custom genetic assays have caught up to science and our understanding of the drivers of cancer. These improvements have given researchers the tools necessary to exploit new cancer-implicated molecular pathways. Moreover, the cost of NGS has come down, enabling physicians to use the technology to assess appropriate treatment. Only a decade ago, it cost about $1,000 to sequence a million base pairs. Today, it costs less than $0.10. Before NGS’ emergence in 2008, it cost more than $9 million to sequence an entire human genome, but today some companies claim to be able to do it for $1,000. Because of the increasing accessibility of genetic data, many leading cancer hospitals are performing NGS on new cancer patients upon initial diagnosis to help guide treatment decisions.

 

The genomic data captured by this new technology can be used in companion diagnostic tests to inform which patients are most likely to benefit from a certain therapeutic intervention. The approval of precision medicines is frequently happening in tandem with the approval of companion diagnostics, most recently the regular approval of Zykadia (ceritinib) for certain lung cancers which showed evidence of ALK-rearrangement via an FDA-approved test.

 

In addition to precision medicine that targets genetic alterations, the field is seeing tremendous advances in immunotherapy agents that activate the immune system to manipulate cancer cells. Scientific breakthroughs in this area have translated to therapies that demonstrate unprecedented efficacy in a broad range of cancers.

 

Former U.S. President Jimmy Carter, for example, was successfully treated for melanoma with Keytruda (pembrolizumab), an immunotherapy drug that inhibits the PD-L1 checkpoint and has been shown to successfully shrink tumors. There are currently five PD-1/PD-L1 checkpoint inhibitors on the market. Remarkable results with new immunotherapies can also be found in B cell lymphoma, where treatment with chimeric antigen receptor (CAR)-modified T cells showed an impressive overall and complete response in a small group of patients.

 

 

As scientific discoveries continue to fuel ever more powerful and promising new drugs, the regulatory landscape has likewise gone through some changes. In response to the early success of precision medicines and immunotherapies, drug approvals are occurring faster and more frequently. In late 2013 we saw the first approval for an oncology product (ibrutinib) under the FDA’s new (at the time) Breakthrough Therapy designation, which can significantly reduce review times and overall time to market. In 2014, all but one of the new oncology drug approvals had some form of expedited designation, and 2015 set a record for FDA approvals in oncology with 33 (versus 22 and 19 in 2014 and 2013, respectively). Further, with more drugs entering the market, the standard of care has changed for cancer at an unprecedented rate. For example, the National Comprehensive Cancer Network has updated its 2017 clinical practice guidelines for lung cancer five times since it was issued in late 2016, based on new clinical data.

 

The startling efficacy of both targeted therapies and immunotherapies is motivating the FDA to accelerate approval timelines. Special classifications such as Breakthrough Therapy, Priority Review, Fast Track and Orphan Drug statuses and designations reflect the agency’s commitment to getting new therapies to market which may confer a significant benefit or address a particularly unmet need, allowing drug developers to move through the review process quickly and sometimes skip the traditional randomized Phase 3 altogether.

 

With the advent of more targeted agents, toxicities are more manageable, patients are receiving more lines of therapy and clinical efficacy is more broadly determined. As a result, the FDA has also become more accepting of surrogate endpoints that weigh response and the duration of response more heavily than the standard survival endpoints to demonstrate a drug’s safety and effectiveness in clinical trials. For example, ceritinib was approved from a Phase 2 trial after more than half of patients showed an overall response rate that lasted seven months.

 

Furthermore, approvals are sometimes granted based on single-arm cohorts of larger Phase 1 or Phase 2 trials. The recently FDA-approved immunotherapy Imfinzi (durvalumab) was approved based on a 182-patient single-arm bladder cancer cohort from a larger Phase 1/2 multi-arm trial.

 

Changes to protocol designs are also influencing how quickly enough evidence can be generated for the FDA to grant approval. For example, one can test a new therapy across a variety of tumor types by conducting a “basket trial,” enrolling patients with specific genetic mutations as opposed to common tumor histology. This concept was validated via the FDA’s recent approval (May 23, 2017) of pembrolizumab in microsatellite instability-high or mismatch repair deficient solid tumors, the first such approval which was “based on a common biomarker rather than the location in the body where the tumor originated.” In another innovative design, “umbrella trials” allow an investigator to test multiple therapies in a given indication using a single protocol. Subjects are assigned to a therapeutic arm based on the molecular characteristics of their cancer. These approaches can be complex, but have been successful because they link protocol design to personalized medicine/biomarker approaches, make it possible to explore multiple indications with similar genotypes at once and specifically look for large effects in small populations.

 

As tempting as it is to speed up the clinical trial with an innovative, aggressive study design, there are risks and trade-offs in this strategy. Designing an overly complex clinical trial could lead to the study being underpowered statistically, and require additional studies to convincingly demonstrate efficacy. There is, of course, additional cost in trial implementation and burden for the clinical sites and their staff which also need to be weighed. Above all, ensuring the safest possible use of drugs is paramount; building appropriate safety measures into any clinical trial may avoid time-consuming questions/clinical holds or even rejection from regulatory agencies.

 

 

Competition is fierce in the oncology space, with small and large drug companies working at a feverish pace to bring new therapies to market. Time is of the essence because once published, scientific data is not proprietary. In 2013, the U.S. Supreme Court ruled that DNA is a “product of nature” and thus determined genes and proteins cannot be patented. Scientists can design antibodies for different epitopes and create drugs that have a different chemical design with the same targeted, inhibitory effect, though. For example, many drugs have been developed that target the BRCA1 and BRCA2 gene mutations.

 

The stakes are high, with the company that has a first-in-class product approved gaining an inherent jump on the market. Earlier this year, Agios and Celgene received priority review by the FDA for enasidenib, a first-in-class leukemia drug that targets the IDH2 mutation, while a number of other companies are also pursuing IDH inhibitors. Several companies are locked in a race to be the first to successfully commercialize a CAR-T cell therapy, and there are a number of companies pursuing next-generation ALK inhibitors, where ceritinib recently won an expanded use in first-line treatment. For small or mid-sized biopharma, competing in this space against much larger and highly resourced companies can be increasingly difficult.

 

 

For sponsors planning clinical trials, keeping pace with the standard of care and predicting which drugs are next to hit the market can be daunting, as can anticipating the newest efficacy data to use when deriving statistical models. In order to track upcoming approvals and monitor competitive intelligence, companies can use proprietary databases/services and solicit feedback from active investigators. Sponsors often leverage an advisory board or individual key opinion leaders to provide their insights on the non-confidential information available on competitive agents and trials reported at conferences or published in the literature.

 

In order to preserve that all-important competitive edge, sponsors have the ability to maintain secrecy until required by regulatory bodies to disclose their clinical research. The FDA will allow for delay of release of final study data for products which are still under development and not yet approved for marketing. The rules vary depending on when submission of the marketing application is anticipated but are intended to allow for remaining in stealth mode during development.

 

There is a limit to how far into the future sponsors are able to forecast, and as such, they may wish to consider designing protocols with a degree of adaptability. For example, adjusting language to be less strict in inclusion/exclusion criteria will allow investigators to cast a wider net and aid patient recruitment. However, the downside is that this might result in a more heterogeneous population with ramifications to data quality and a higher threshold to demonstrate statistical efficacy.

 

In some indications, there is no single accepted standard of care or there may be a pending approval which may shift the standard. Therefore in trials where a new drug is combined or compared with the existing standard of care, researchers may need to consider allowing an investigator to choose from a menu of comparators. Again, the statistical and logistic implications must be carefully considered as well as the timeline. It may be that the approval of an agent in an indication may not be followed by rapid adoption of the new “standard.”

 

Depending on the stage of one’s clinical trial, it may be possible to complete crucial portions of the study before the new therapy is generally available or reimbursed. While no one has a crystal ball to guide choices, advance planning may save a lot of trouble later in the process. Sponsors always have the option of making critical amendments to their protocols; however, amendments during the course of a clinical study are time-consuming and expensive and must be used judiciously.

 

Many sponsors are adding multiple arms to their trials. Novella Clinical recently worked with a sponsor that added an arm to study its drug candidate as a second-line of therapy after realizing a competitor was likely pursuing first-line approval. While first-to-market would be ideal, the sponsor took advantage of a potential gap in therapeutic options, removing the chance of directly competing for a rare patient population and speeding the potential time-to-market as approved second-line therapies are minimal, all while leaving the window open to compete for first-line use later in a head-to-head comparison.

 

 

In this new age of drug development, it’s exciting to bear witness to the promising therapies that will change the course of cancer treatment and have the potential to improve lives. There are more than 800 cancer drugs in development and more than 14,000 active cancer clinical trials, all competing for the attention of a finite number of experienced investigators and top-notch sites. The successes seen in oncology in recent years guarantee that clinical practice will continue to change at a rapid pace, making it more important than ever for sponsors to plan accordingly. There are many ways to conduct clinical trials and remain viable in this rapidly changing treatment landscape. Partnering with an experienced, oncology-focused clinical research organization can provide the insight and guidance needed to bring new cancer therapies to market successfully.

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James Kyle Bryan, M.D., is chief medical officer of Novella Clinical. Andrew Zupnick, Ph.D., is vice president of oncology strategy of Novella Clinical. Novella Clinical is a full-service contract research organization specializing in oncology clinical trials for small and mid-sized sponsors.