January 2016 Edition Vol.11, Issue 1

2016 Forecast Series – Perspective on Precision Medicine with Jennifer Carter, MD, MPH, Founder and Chief Medical Officer, N-of-One

2016 Forecast Series—Jennifer Levin Carter, MD, MPH, Founder and Chief Medical Officer, N-of-One

OBR: You have told us before that community oncologists are expressing a growing interest in next generation sequencing (NGS). Is NGS becoming more commonplace for community oncologists, and how do they use it to screen patients?

JC: Novel therapies are beginning to transform cancer care. In 2015 alone, 14 new oncology drugs received FDA approval. Many of these therapies are targeted therapies directed at the tumor of patients identified to have particular molecular alterations.1  Data are growing demonstrating improved response when patients are matched to targeted therapies based on their molecular profile. Thus, over the last year, despite reimbursement challenges, there has been growing utilization of NGS testing by oncologists outside of academic centers. Hospital networks and physicians practicing in the community are implementing or exploring precision medicine programs with the goal of retaining patients in an increasingly competitive environment by providing more cost-effective, cutting-edge care.

For example, Intermountain Healthcare, a leading provider in the field of genomic medicine, has conducted two exciting studies that demonstrate the value of this approach. In these initial studies, armed with the necessary interpretation, physicians changed treatment management in more than 60% of cases where molecular testing linked to highly analyzed therapeutic strategies was available.2,3

OBR: How does an oncologist sort through the different sizes and types of NGS panels?

JCIn order to address the evolving needs of the market, a number of companies are developing different size gene panels for NGS testing. Illumina, for example, has launched TruSight 15. This panel includes 15 genes that are commonly mutated in solid tumors such as EGFR, BRAF, MET, and other genes that are associated with FDA-approved targeted therapies. Illumina is seeking FDA approval for this panel to offer physicians an alternative to testing patients with single gene tests which, in order to test more than one target, are more expensive and utilize more tumor tissue.

In addition, while many labs continue to provide 50-100 gene panels, there is also a trend toward the availability of larger panels testing up to several hundred genes. These panels allow physicians to receive a broader evaluation of a patient’s tumor by testing for mutations that may be associated with FDA-approved drugs on-label, off-label, and in clinical trials.

OBR: Why is NGS valuable to community oncologists?

JCDepending on reimbursement and stage of disease, it is likely that patients may have their tumor tested more than once. It is possible, that a patient’s tumor may be initially sequenced at the time of presentation on a smaller gene panel to evaluate for on-label, FDA-approved therapeutic options. Upon recurrence or progression, the tumor could be re-sequenced on a larger gene panel to evaluate for resistant mutations or additional alterations that might lead to a clinical trial.

In addition, other molecular tests are starting to become a more essential part of the diagnostic paradigm. Data suggest that copy number alterations are critical drivers in many cancer types.4 Assessment of gene fusions, translocations, and protein expression is becoming essential as more targeted therapies are available that are directed at these types of alterations in specific genes. The first FDA-approved test for an immunotherapy, PD-L1, is assessed by immunohistochemistry.

With the availability of multiple size and types of tests, an integrated analysis of the results of all of these tests enable physicians to make the best therapeutic decisions for patients in the context of each patient’s specific cancer type.

OBR: Regarding NGS, as the technology grows doesn’t that sometimes make things more confusing for oncologists?

JC: Based on the results of molecular testing, oncologists have unprecedented access to many new FDA-approved targeted therapies that are included in NCCN guidelines. The new therapies are demonstrating improved response rates for patients with many different tumor types. With access to the growing amount of molecular data, clinicians are looking for ways to gain the insight needed to select relevant therapeutic strategies for each of their patients. 

For example, a melanoma patient with a BRAF V600E mutation could benefit from the FDA-approved drug vemurafenib, but clinical trials have demonstrated that a colorectal cancer patient with the same mutation is not likely to benefit from this drug as a single agent. Furthermore, a patient with colorectal cancer and a BRAF D594G mutation which inactivates BRAF yet activates MEK through RAF1 could potentially benefit from yet another therapeutic approach such as regorafenib. This challenge is compounded both by the rapid growth in the number of therapies available and the number of increasingly complex clinical trial designs.

Meanwhile, physicians can effectively utilize molecular data to develop patient-specific therapeutic strategies through the scientific evidence that links the data to relevant therapeutic options. Assessing a patient’s clinically relevant molecular alterations at the gene variant level as well as the combination of these alterations in the context of each patient’s cancer subtype can enable the physician to efficiently develop the most relevant therapeutic strategy.

Treatment strategies can include FDA-approved on-label or off-label therapies, and therapies in clinical trials. Many of the therapies identified through this analysis are only available through clinical trials. Thus, access to knowledge on patient-specific clinical trials at the point of care can enable physicians to extract the full treatment potential from assessing a patient’s molecular profile.

OBR: With the proliferation of genetic tests and biomarkers, are we seeing better clinical trial design and outcomes thanks to clinical trial matching?

JC: Clinical trials are rapidly becoming the most effective and rapid way for patients to access novel therapies that may be their “best” treatment option based on their molecular profile. This has led to a shift in clinical trial paradigm. Historically, patients were matched to clinical trials based on the organ of origin and histology of their cancer without consideration of molecular alterations that may be present in their tumors. A growing number of studies have demonstrated that using molecular markers to stratify patients into appropriate clinical trials can improve success rates of trials.

OBR: Can you give us an example of how clinical trial design is improved?  

JC: Two new trial methodologies have emerged in order to address this need: the Basket or Bucket trials and the Umbrella trials. In both of these designs, there are multiple study arms and patients are matched to a targeted therapy based on their biomarker status. The Basket trials, such as NCI-Match, match patients with different tumor types testing the effect of one drug or a combination of therapies on a specific mutation. Umbrella trials, like Lung-MAP, assess the effect of different targeted therapies on different mutations in one cancer type. In addition, adaptive trial designs enable researchers to amend the trial protocol based on emerging data at pre-specified time points during the trial.

The growing amount of the molecular data and novel trial design, however, is not well addressed by online and public listings of clinical trials. These resources generally do not provide the detailed analysis needed to help physicians and patients identify the targeted therapy trials for which they would be eligible based on their molecular profile.

OBR: Is clinical trial design only going to get better in the future?

JC: New ways of connecting patients and physicians to relevant clinical trials are emerging that enable physicians to efficiently match patients to the best clinical trials based on a detailed analysis of the results of NGS testing. The evidence of the implications of a patient’s molecular profile on drug sensitivity, drug resistance and combination therapies, and knowledge of the molecular features of a drug and each arm of a trial, enables physicians to more readily match their patients to relevant targeted therapy trials. 

Clinical Trial Matching can be enhanced when patients are also matched based on their location as they prefer generally to enroll in trials at the institutions where they are being treated—otherwise, at a hospital that is close to home. Additional services can assist patients and physicians to connect with these trials.

Because many of these trials struggle to find enough patients with the “right” molecular profile, many pharmaceutical and biotechnology companies are also responding by opening trials at an institution where a patient with a particular alteration is being treated, the "just-in-time” trial.  Hopefully, this will enable more patients outside of academic centers to have access to novel therapies and thus also help industry acquire the data needed to more rapidly move the drugs through the testing and FDA approval process.

OBR: Liquid biopsies were in the news a lot in 2015, and it feels like there is a lot of excitement about how liquid biopsies could become an integral part of precision medicine. Could you please explain the advantages of liquid biopsies in precision medicine, and do you think this technology could begin to transform precision medicine in 2016 or 2017?

JC: Liquid biopsies may transform the way patients with cancer can be treated. Through a blood draw, physicians can profile tumors that may otherwise not be accessible to biopsy. There are a number of different liquid biopsy methodologies including evaluating cell-free DNA, i.e., DNA shed from tumor cells (cfDNA), circulating tumor cells (CTCs), and exosomes. Each methodology has potential advantages and disadvantages which will likely play out as data continue to emerge.

Since samples are easy to obtain, a physician can profile the patient more frequently. This will enable the physician to evaluate for the emergence of new mutations that may indicate treatment failure, recurrence or development of resistance earlier and serially over time. Thus, based on this data, physicians can alter their therapeutic strategy to try to forestall recurrence and prevent resistance.

Liquid biopsies may also capture the heterogeneity of the tumor better than a tissue biopsy thus allowing for more informed combination therapy design. Liquid biopsies may enable a quantitative assessment of cfDNA or CTC levels that can be used to assess the presence of residual disease after resection of a tumor or the recurrence or progression of disease before obvious by imaging studies. There is emerging data to suggest that, in the future, liquid biopsies may even be able to be used as a screening test for cancer.

OBR: What else would you like our readers to know?

JC: The potential to access even more information can be a powerful resource for developing better therapeutic strategies. Widespread adoption and maximizing the clinical utility of a molecular test will require the ability to transform the increasingly complex data generated into knowledge that the physician can use at the point of care to better treat patients. Physicians will need the clinical and scientific evidence linking a patient’s molecular profile to therapeutic strategies. There will be a greater need to provide analysis of the patient’s full molecular profile in the context of the heterogeneity of the specific tumor type and over time after repeat biopsies. This will require an ability to analyze the implications of the emergence of novel mutations to lead to the use of combination targeted therapies more effectively at the beginning of treatment and evolve the choice of the combination of drugs, based on changes in the profile, to monitor for the effectiveness of the treatment regimen and thus to try to prevent resistance and progression.

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References

1. Forbes: Arlene Weintraub. Eight Milestones of 2015 in the War on Cancer, January 1, 2016

2. Nadauld et al., J. Clin. Oncol. 33, 2015 (ASCO Abstract e17647)

3. Nadauld et al., J. Clin. Oncol. 33, 2015 (ASCO Abstract e17641)

4. Ciriello et al. Emerging landscape of oncogenic signatures across human cancers, Nature Genetics, 45, Oct 2013

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