Trials are Treatments

Greg Simon, the outgoing head of Cancer Moonshot, gave the last “Fireside Chat” at JP Morgan’s healthcare conference in San Francisco last week.

Greg is a wise systems thinker with unique experience. One of his key insights is both critically important and actionable, and helps us to understand why new oncology therapies present such a difficult challenge to doctors and to the established clinical trial methodologies. Until these challenges are resolved, many patients will be affected in serious and even fatal ways.

Oncologists must now address the fact that, for a significant and growing number of patients, the best available treatment may be a therapy that is only available in a clinical trial, when compared to the best available drug in the Standard of Care. Simon pointed out that this creates a new ethical stress on regulators and clinicians. In the “old days,” the ethical imperative was to ensure patients were warned that trials quite likely would not work, were not to be considered as treatment alternatives, and represented a kind of gift to the patient’s fellow man. Today, a powerful imperative exists to ensure patients know that alternative therapies, available only in clinical trials, may well be dramatically superior to the Standard of Care — while acknowledging the very real risks that still pertain.

What makes this dilemma more pointed is the reality that multiple lines of standard chemo will effectively rule out many clinical trial options for the patient — previous treatment is often an “exclusion criterion” for new therapies. Thus, failing to secure an appropriate trial for an early-stage patient with a difficult prognosis may actually block positive options later. This situation will only increase as immunotherapies move forward inevitably in the treatment sequence.

Yet finding an appropriate trial is extraordinarily difficult for doctors and often impossible for patients on their own.

This is not a new problem, and it is not limited to oncology. As Dr. Vince DaVita documents in “The Death of Cancer,” this kind of dilemma occurs naturally whenever a major new therapy begins to demonstrate superior results. Decades ago, doctors had to decide to add chemotherapy to surgery-only, which was then the Standard of Care; later they had to consider combination chemotherapy when monotherapy was the approved approach.

These were difficult struggles in their day. But today’s challenge creates a new level of stress and threatens to slow what should be an unprecedented leap forward in cancer care. People are dying in the meantime.

Since the sequencing of the human genome fifteen years ago, there has been a flood of investment, new molecular science, drug discovery and therapeutic development. The range of solutions coming to clinical trial is impressive in sheer volume, in the encouraging nature of initial trial data, and in the variety of “mechanisms of action” being pursued. Scientists have also unveiled substantial complexity and differentiation even in diseases that were previously indistinguishable. Most important, there is tantalizing evidence that many of these therapies may offer better clinical results, better quality-of-life, and fewer adverse side effects than conventional chemo.

Even if these new therapies functioned as conventional monotherapies, where one drug could be used to treat one disease, the sheer volume of new and dynamic science underlying the new drugs would make it difficult for treating physicians to keep up with the best available therapy for the individual patient. Yet there is another powerful complicating factor — biology is complicated and messy, and for the first time the biopharma industry is producing an array of therapies that begin to match up with the multiplistic and dynamic nature of biologic dysfunction.

The scientists Robert Weinberg and Douglas Hanahan famously identified the “hallmarks of all cancer cells” as “sustained proliferative signaling; evasion of growth suppressors; resistance to cell death; avoidance of immune destruction; the ability to induce angiogenesis; the deregulation of cellular energetics; the ability to enable replicative immortality; and the activation of invasion and metastases.”

Therapies are now emerging to target each of these dysfunctions, while paying increasing attention to the dynamics of the overall cancer “system.” With learnings, it becomes ever clearer that doctors need to deploy a multifaceted toolset to treat many cancers, often delivered according to personalized dosing strategies and tightly coupled to the cadences of cancer growth. Thus, many new therapies depend on the availability of complementary drugs, applied according to time-based protocols. As Vince DaVita writes in The Death of Cancer: “Some very good and relatively safe cancer drugs show no evidence of effectiveness when used alone. Herceptin and Erbitux, or the new kinase inhibitors, such as vemurafenib, attack very specific targets, but many have little activity when used alone. They work by enhancing the action of other drugs…”

Classical clinical trials are built on a gold standard — the scientific method. Develop a hypothesis, define and randomize a population, control for a single variable, implement double-blind, and test. This works great for monotherapies, although it typically takes a long time to get definitive, statistically significant results. For drugs, this has typically meant seven years on top of the ten years it takes to get a drug to trial in the first place.

17 years is unacceptably long for a monotherapy, but completely unworkable for complex multifaceted protocols.

There isn’t really anyone to blame for all this. The scientists at NCI, the FDA, the biopharma industry, and the teaching hospitals understood the challenge many years ago, and they are working hard to encourage and regulate new approaches. These include new and modified clinical trial types (e.g., basket, umbrella, adaptive, multi-ARM, off-label, “N-of-1”) and new techniques applied to classical types (retrospective “virtual” trials based on big data analysis, Bayesian math, etc.)

When neoadjuvant and adjuvant chemotherapy first emerged and allowed doctors to reduce the necessity for radical and disfiguring cancer surgeries, resulting in much smaller and less invasive procedures, doctors varied in how quickly they moved to the use of the new techniques during the clinical trial phase.

Today we face an analogous situation. Conventional chemotherapies have been successful, have been blended into ever better combinations, and their side effects have been variably mitigated. Yet at the core they are toxins engaged in a war “to kill the cancer cells before they kill the patient.”

The treatments are difficult to tolerate, often address a modest percentage of an affected population, sometimes deliver a small or temporary effect, and routinely tear down the immune system. As Patrick Soon-Shiong noted at JP Morgan, high-dose chemo may even have a role in promoting metastasis.

While raw and early-stage, the emerging therapies of the new molecular biology offer the promise of a better answer — a systemic approach that will make use of optimized surgical and radiological techniques, build on comprehensive “omic” analyses, boost rather than deplete the immune system, apply targeted rather than “broad-spectrum” molecular agents, and deploy multiple molecular agents to address the dynamic and evolutionary behavior of the cancer dysfunction. We will see drugs used together, each intended to build on insights based on new understanding of the genome, transcriptome, proteome, biome, signal pathways, acquired resistance, angiogenesis, T cells, NK cells, et. al.

The hope is that these approaches can be tailored to the particular indication, and eventually personalized fully to the individual patient. This will take time, and full enrollment in worthy clinical trials is emerging as a critical gating factor. We need trial success and acceleration to advance the evidence of efficacy.

Our existing industry, clinical, and regulatory frameworks are not optimal to drive this acceleration. As a community, we need to focus on improving and maturing the new clinical trial methodologies with real urgency and cooperation. Critically, we need new tools and better data to match patients to the best available trial when the patients are optimally ready, willing, and able. This will require patients to push for “omic” testing and trial evaluation, and physicians to think about trials earlier in the cancer journey. Industry and academic institutions will need to provide much better information to doctors, more quickly, more usably, and with appropriate tools for trial discovery, evaluation, and enrollment.