Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Why the 21st Century Cures Act is a Good Thing

A Q&A with Mary Woolley, President and CEO of Research!America
Q: You attended the December 2016 signing by President Obama of the 21st Century Cures Act and are recognized to be a strong supporter. Yet harsh criticism of it has quickly appeared in JAMA, BMJ, a variety of other venues, as well as on these pages. Please tell our readers why this is good legislation and how the public health will be protected from exploitation in this very different regulatory world.
A: The bi-partisan 21st Century Cures Act is grounded in a commitment to assuring that our nation’s research ecosystem has the capacity to accelerate the pace at which safe and effective medical advances reach patients. The Act will expand the efficiency, reach and impact of medical discovery in a manner that sustains crucial safeguards against unsafe or ineffective products. The law finances more research, helps to reduce the administrative cost surrounding basic research, and takes additional steps to overcome challenges the Food and Drug Administration (FDA) faces. Patient groups, health care professionals, academic leaders, industry leaders and the FDA and the National Institutes of Health (NIH) were frequently consulted regarding provisions of this bipartisan bill, and their insights were incorporated. We at Research!America were closely involved throughout development of the bill, and are pleased that it crossed the finish line last December.
After years of automatic spending cuts and flat-funding, researchers have been stressed as they work to find solutions to deadly and complex diseases. The 21st Century Cures provides some relief in that regard with an initial $352 million in FY17 to support the NIH Precision Medicine, BRAIN, and Cancer Moonshot initiatives. In FY18, Congress released another $496 million in 21st Century Cures funds for NIH. Congress recognizes that these dollars are targeted and temporary; they do not supplant the need to grow NIH’s annual budget. As reflected in surveys that Research!America commissions regularly, Americans recognize the importance of federally-funded research and support streamlining the pursuit of medical research and innovation.
The FDA, which has for years been underfunded, is authorized to receive a total of $500 million under the 21st Century Cures law. In FY17 FDA received $20 million and in FY18 $60 million from this mandatory funding stream. This new funding, in combination with other provisions of the law, is particularly meaningful as it will give the FDA more flexibility to recruit additional experts needed to assure that our regulatory system can properly evaluate rapidly evolving science in areas such as immunology and regenerative medicine.
One important example of rapidly evolving science is the potential to diversify the evidence base used to evaluate the safety and efficacy of medical advances by leveraging “real world evidence” (RWE). The Cures Act defines real world evidence as “data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than randomized clinical trials.” While concerns have been raised that the RWE provisions would force the FDA to relax critical safety and efficacy standards, these provisions were developed with agency input. This section of the law is designed to empower, not require, the FDA to capitalize on real world data. Real world data will be used when — and only when — it is appropriate to do so.
Faster medical progress saves lives. The 21st Century Cures Act will fuel faster progress. It’s incumbent upon research advocates to engage elected officials to build on the Cures Act, and ensure that adequate funding is provided to make the promise of science and innovation a reality in our lifetime.
An earlier version of this post was published Feb. 8, 2017.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

How to Initiate Treatment for Chronic Myelogenous Leukemia

Jerald P. Radich, MD, Director of the Molecular Oncology Lab at the Fred Hutchinson Cancer Research Center, and Professor of Medicine at the University of Washington School of Medicine

Q: What is your basic approach to handling a middle aged adult patient in good general health who is referred to you with a new diagnosis of Chronic Myelogenous Leukemia?
A: First off, the treatment of choice for chronic phase CML is a tyrosine kinase inhibitor (TKI). Currently there are three approved TKIs in the front line setting, imatinib and the second generation TKIs, nilotinib and dasatinib. There have been three randomized trials comparing imatinib to either nilotinib or dasatinib, and all three show remarkably similar results. The second generation TKIs have better short term efficacy (cytogenetic and molecular responses at 12 months), and fewer progressions to advanced phase disease, yet surprisingly, overall survival seem similar between imatinib and the newer agents. This is especially relevant since imatinib may soon become generic.
All of the TKIs are well tolerated, and each have specific toxicities. For example, nilotinib can cause elevations in metabolic syndrome manifestations (lipids, glucose), while dasatinib can cause pleural effusions and in rare occasions, pulmonary hypertension.
In choosing a TKI, a few things are important to consider, and they revolve around the goals of therapy, which should be different for different patients. One important consideration is risk of progression at the time of diagnosis. There are several clinical prognostic scores available (Sokal, Hasford, EUTOS) that correlated with outcome. Patients with low risk disease can safely be treated with any TKI, while if a patient has a clinical presentation at high risk, it might be better to start with a more potent second generation TKI. Secondly, it is now becoming clear that some patients who achieve an outstanding disease response can discontinue therapy and not relapse. Thus, for a younger patient who might be facing decades of TKI therapy, or who may wish to have children, a second generation may be a good starting point, since the chance to achieve a complete molecular response is greater than with imatinib. However for the lion’s share of patients, starting with imatinib is a fine choice, particularly in older patients, or those with higher risk of cardiovascular complications, since imatinib seems relatively free of these complications compared to the more potent TKIs.
Lastly, if generic imatinib becomes far cheaper than other TKIs, there are some solid medical economic arguments that might compel one to start therapy with imatinib.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Making NGS Work for Oncologists

Smruti Vidwans, PhD, Chief Science Officer at CollabRx

Q: Your group has recently described an Actionability Framework for designing treatment strategies for cancers that are characterized by mutations. What is the basis and rationale for such an approach?
A: As Next Generation Sequencing (NGS) is increasingly adopted into clinical practice, physicians are faced with the daunting task of identifying variants that are clinically actionable – those that can help them select potential treatment options. In oncology, NGS technologies are used to profile tumor or liquid biopsies and identify variants in cancer-related genes. Cancer gene panels range in size from a handful of genes to several hundred. Depending on the size of the panel, many variants may be observed in tumors.
Genes in cancer panels can broadly be classified into three groups. The first group includes genes (e.g. BRAF, EGFR) that are validated for use in clinical decision-making based on related drug approvals, inclusion in treatment guidelines and a large body of supporting clinical data. The second group includes genes with ‘emerging’ data supporting actionability. Lastly, the vast majority of genes in large panels have limited data supporting use in the clinic and are primarily used for research purposes.
Clinical actionability of NGS data is context-dependent. Relevant factors include diagnosis, nature of observed variants, targetability of variants by one or more drugs, strength of evidence linking variants to therapies, potential interactions between variants within a sample etc.. There is another set of considerations, having to do with the patient as an individual, that is key for clinical actionability. Even when the molecular profile of a patient’s tumor clearly identifies one or more treatment options (e.g. when observed variants are in clinically validated genes such as BRAF), acting upon these treatment options is dependent on patient physiology, disease burden, history, patient goals and wishes and many others factors. For example, inclusion of a BRAF inhibitor in the next course of treatment will be influenced by whether the patient has already been treated with one and whether they have derived or are deriving clinical benefit from it. In the case of a treatment-naive patient with a BRAF mutation, the choice between a BRAF inhibitor and an immunotherapy will likely be influenced by factors such as burden of disease. Patient context becomes even more important if observed variants are in genes in the second group, for which treatment guidelines are not established, or for which clinical data are emerging.
The goal of NGS testing is to aid oncologists choose treatments most likely to help their patients based on molecular characteristics of their tumors. However, when NGS test results are not deeply integrated with other patient information, there is a real danger that they will become just another set of data that oncologists are confronted with, and are unable to derive benefit from, in the limited time they are able to spend with each patient. This is a shame for the patient, an impediment to achieving the promise of precision oncology, and will ultimately limit adoption of this technology in the clinic.
We’ve made great strides in providing oncologists with information linking molecular information to a variety of treatment options. Now we need to equip them with tools beyond the genetic test report that will enable them to find the most appropriate treatment choices for their patient at any given time.
For reference, download the poster from the Molecular Med Tri-Con 2016:
Download PDF of Poster
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Treating Metastatic Malignant Melanoma

Keith Flaherty, MD, Associate Professor of Medicine, Harvard Medical School; Director of Developmental Therapeutics, Cancer Center, Massachusetts General Hospital.

Q: What is your basic approach to handling a new young adult patient in good general health who is referred to you with a diagnosis of Malignant Melanoma, metastatic to liver or lung? The primary cutaneous melanoma, 1.5 mm in thickness, was diagnosed in Maine 5 years ago and was of skin on the forearm; treated there by wide resection with clear margins and no lymph node dissection. There was no molecular/genomic testing of the primary.
A: In a case like this, there are a few additional elements of data that I always try to obtain:

  1. Brain MRI
  2. Serum LDH
  3. V600 BRAF mutation status (younger patients are significantly more likely than older patients to have a V600 BRAF mutation), so it’s likely that this patient has one
  4. Presence or absence of disease-related symptoms
  5. Prior scans that might allow the pace of disease progression to be ascertained (not always possible in a very recently diagnosed patient; but even if 4-6 weeks have passed since the first assessment prior to me seeing the patient, I’ll consider repeating imaging of the lungs and liver to glean the pace of progression.

The factors above go into determining disease burden and pace of disease progression. Presence of brain metastases does not necessarily impact choice of first-line systemic therapy, but certainly informs the need for resection (for single large metastases) or stereotactic radiation for one or several small metastases in parallel with pursuing systemic therapy. The presence of numerous brain metastases would push me to select BRAF/MEK combination therapy if a V600 BRAF mutation were found. Elevated serum LDH, the presence of disease-related symptoms, or evidence of rapid disease progression each push me toward considering of BRAF/MEK combination therapy (presuming BRAF mutant), and certainly two or three of these three factors would force that decision. In the absence of any of these factors, first-line immunotherapy is generally my approach. For most patients that means single-agent PD-1 antibody therapy. But, for young patients who are not deterred by a high rate of severe toxicity and for patients with any of the three “aggressive’ disease warning signs indicated above, I would favor combined CTLA-4/PD-1 antibody therapy. This is based on the higher initial response-rate and short-term ability to control the disease with the combination compared to PD-1 antibody monotherapy. We do not yet know that this combination improves overall survival compared to sequential therapy with PD-1, CTLA-4 and/or BRAF/MEK inhibition. In the absence of that data, I favor PD-1 monotherapy first-line for most patients. If a patient progresses on first-line PD-1 antibody therapy, then I reassess the same warning sign factors as above, now informed by the rate of progression evident on follow-up scans. Modest evidence of progression pushes me to consider CTLA-4 antibody therapy as the second-line approach versus BRAF/MEK combination therapy for more aggressive evidence of disease progression. Recent evidence that the same strategy will soon be an option with MEK inhibitor monotherapy in NRAS mutant melanoma patients. These decision points for selecting first, second and even third line therapy are currently informed by clinical factors. However, we know that each treatment approach can produce years-long remissions as first-line treatment. Thus, it is imperative that we continue to conduct clinical research to develop additional diagnostic methods for identifying those patients predicted to achieve long-term benefit from each of therapies and relay on these for navigating among these multiple treatment options.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.