President Barack Obama signed the 21st Century Cures Act into law today, earmarking $6.3 billion over 10 years for advancements in precision medicine development, brain research, heroin and prescription drug abuse prevention, and mental health.

Two years in the making, the legislation includes $1.8 billion for Vice President Joe Biden’s Cancer Moonshot program, now renamed for his son, Beau Biden, who died of a brain tumor last year. "I believe that the United States of America should be the country that ends cancer once and for all,” Obama said.

The breakdown includes $1 billion for fighting the opioid epidemic; $1.5 billion for the BRAIN Initiative to find new ways to treat, cure and prevent brain disorders such as Alzheimer’s and epilepsy; $1.5 billion over 10 years for the Precision Medicine Initiative; and $500 million to the FDA over 10 years to speed up drug approvals and access to medical devices for patients. It also includes bipartisan mental health reforms.

“The Cures Act brings us one step closer to breakthroughs on some of the biggest health challenges of our time,” Obama added.

Obama and Biden stressed the bipartisan cooperation that led to the overwhelming House and Senate votes to approve in the past two weeks.

Biden said, “This is going to give hope. Every day, millions are praying—praying for hope, praying for time. This will accelerate the kinds of efforts we can make right now, to extend life.”

Although the White House praised the Cures Act, it has also been criticized for potentially weakening the FDA’s ability to scrutinize new drug applications and regulate medical devices. The bill includes provisions that would reduce the amount of data drug developers must supply the FDA for purposes of drug review. Patient advocacy groups, eager to speed up the development and marketing of life-saving medicines, and a battalion of pharmaceutical industry lobbyists argued for passage of the bill.

Obama has stated that the legislative package represents a compromise that will lead to essential advances in medicine and social health conditions.

The brain initiative, he said, would “revolutionize” understanding of Alzheimer’s, traumatic brain injury, and epilepsy. The precision medicine component would improve the targeting of drugs, and the mental health element would ensure that insurance companies treat substance abuse disorders fairly, while improving the screening of potential inmates to determine whether mental illness treatment would be better for them than incarceration. The act includes provisions for improvement of clinical trials.

ASCO President Daniel Hayes, MD, has praised the Cures Act as “landmark legislation [that] will spur development and delivery of promising new treatments for patients.”

The bill is the last piece of legislation that Obama will sign into law. He reflected on what the Cures Act means for him. “It’s not always easy to remember, but being able to honor those we lost in this way, and to know we may be able to prevent other families from feeling that loss—that makes it a good day.”

Articles

President Obama Signs 21st Century Cures Act

Researchers are hoping that a proposed phase II study exploring use of the Optune system in patients with recurrent grade III malignant glioma will expand the indications for the tumor treating fields (TTFields) device beyond its current FDA-approved use in recurrent grade IV glioblastoma.

Daniel O’Connell, MD, a neuro-oncologist at UCLA’s Geffen School of Medicine, discussed his proposal with 

 at the 21st Annual Scientific Meeting of the Society of Neuro-Oncology (SNO) being held November 17-20, 2016 in Scottsdale, Arizona.

Patients with grade III progressive or recurrent anaplastic glioma represent an unmet clinical need, O’Connell noted in his presentation at SNO. These patients have poor median survival despite available chemotherapy, and when they recur after temozolomide, no standard of care options are currently available to them. Choice of therapy is up to the physician, but most often the regimen includes bevacizumab, he added.

O’Connell and his colleagues will evaluate whether TTFields may provide a new option for these patients. It is a noninvasive, regional, antimitotic treatment that delivers low-intensity, intermediate-frequency, alternating electric fields to tumors through transducer arrays placed on the scalp. He cited the “buildup of evidence in favor of the use of tumor treating fields,” both with respect to the system’s better side-effect profile and accumulating evidence favoring prolonged survival.

The study’s primary objective is to determine the efficacy of Optune in patients with recurrent malignant glioma based on 6-month progression-free survival (PFS). Secondary objectives include evaluating the safety and efficacy of Optune in this group of patients and to determine if the treatment has a significant impact on their quality of life using the Functional Assessment of Cancer Therapy (FACT) questionnaires—FACT-Brain and FACT-Cognitive Function.

With currently no known biomarker to signal which patients may have a better response to Optune technology, another secondary aim of the study is to determine whether the presence of the 

 mutation in tumor specimens improves treatment response. The investigators will also use CytoScan analysis to explore whether the presence of proneural or mesenchymal phenotype yields a better response to the device, and they will assess 

 sensitivity of the glioma cells in each patient’s tumor samples before and after TTFields to see if there is a correlation with treatment response.

O’Connell plans to enroll at least 26 patients, with a maximum of 36, who have had no prior treatment with bevacizumab or any experimental agents. TTFields will be administered with a monthly adherence rate goal of 

75% of therapy over a 4-week cycle. MRIs will assess patients for tumor response and disease progression using RANO 2010 criteria to evaluate radiographic response rate, PFS, and overall survival.

“We want to keep our patients naïve for the purpose of the TTFields,” said O’Connell. “This is a different modality than immunotherapy, targeted therapy, and traditional chemotherapy, in that it utilizes a novel mechanism; it is not ionizing radiation, and it is distinct from radiation therapy.”

He said that he expects the FDA will give the go-ahead to use the TTFields system in the grade III setting in the next few months. After that, he would like to start enrolling patients in the single-arm trial, which already has funding and he anticipates will continue through 2020.

“We expect this trial to last for years because these patients, regardless of therapies, typically live about 5 to 7 years, so the use of this will hopefully push us over to that 9-year mark—that’s our hope, of course, for these patients.”

While the device is showing promise, O’Connell said that it is yet to be determined how things will go with the technology. He added that there are patients, especially younger patients, who are looking for different treatment options.

“It’s a work in progress in our community in neuro-oncology,” he said. “The data clearly suggest that there is a benefit with this device and therefore should be used in patients who are willing to use it.”

O’Connell D, Carrillo J, Kong XT, et al. A phase II, single arm study of Optune® in bevacizumab-naive subjects with recurrent who grade III malignant glioma. 

View more from the 2016 SNO Annual Meeting

Phase II Trial Looks to Study Optune's Efficacy in Grade III Recurrent Glioma

A phase I trial of the antibody drug conjugate ABT-414 has shown promising results for the treatment of patients with EGFR-amplified, recurrent glioblastoma (GBM).

Lead author Martin van den Bent, MD, PhD, of the Erasmus MC Cancer Center in Rotterdam, the Netherlands, is presenting the findings during the 21st Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology (SNO) being held November 17-20, 2016, in Scottsdale, Arizona.

, van den Bent discussed the trial’s significant findings, that agent’s toxicity profile, and what lies ahead for the investigational agent.

ABT-414 trial that you are presenting at SNO?

: ABT-414 is an antibody drug conjugate directed against the activated EGFR receptor, and attached to it is a very strong, very potent cytotoxic agent, monomethyl auristatin F (MMAF). This compound is not like what we have done in the past with erlotinib (Tarceva) or gefitinib (Iressa) to inhibit EGFR signaling, but rather, to use EGFR to activate the EGFR receptor to get a very strong potent toxic into the tumor cell.

We have been conducting a phase I study as part of a larger effort to evaluate the activity of this compound. What we are now reporting is the expansion phase of a group of recurrent GBM patients all with EGFR amplification, so all with targets present. What we are showing here is that if you treat these patients at first, second, or third relapse, we get a 6-month progression-free survival (PFS) rate, which is in the area of 35%, which is sizable, as we know that passing the 20% 6-month PFS rate typically implies that you are looking at something that is active and worthwhile for further investigation.

What is the mechanism of action for this drug?

In the past we have been using drugs like gefitinib, erlotinib, or rituximab (Rituxan), which were either small-molecule inhibitors targeting kinase inhibitors or monoclonal antibodies directed against the receptor. What we tried to do with those approaches is to inhibit the signaling, the downstream signaling of the EGFR receptor. All the trials, however, have been negative and there is no reason to assume that any of the other EGFR-inhibiting agents will yield a different result.

What else have you learned from this trial?

What we see in more detail is that we typically do not see a response rate in GBM. We don’t see a clear survival signal, which is not unanticipated as we know that only a minority of the patients seem to respond. But we do see a 25% 6-month PFS rate, and that’s of pivotal relevance here. We did a phase I study, an expansion cohort of a phase I study, and it shows that the signal that we see in this expansion cohort warrants further investigation. And we are actually doing that.

There is a trial ongoing in recurring GBM, and there is another trial ongoing in the frontline setting, in which the activity of ABT-414 is investigated in newly diagnosed patients. With these 2 studies together, we will get a clear readout of the activity of ABT-414 in this setting. But we have to be smart about giving it to EGFR-amplified patients. We have to understand which patients are responding to this treatment and who are resistant, since it is clear that not all patients are alike with this compound.

What about the safety profile? Is it any different from other known drugs in this class?

The toxicity profile is definitely different. There is eye toxicity of a type that we in neuro-oncology have rarely seen. One-third of patients get ocular toxicities, which comes down to a keratitis, an irritation of the eye. It feels like dry and burning eyes for the patient, and if severe, may even decrease vision, a toxicity which does not appear to be specific to the ABT-414 construct. That is really an issue. We have to make this drug acceptable for patients. We have to find ways of modifying the ocular toxicities; outside that, however, it is a very well-tolerated drug.

Does the risk of this toxicity outweigh the benefits

It would be better if we see less toxicities, so this is what we have to work on. The signal that we now see in patients with this drug clearly warrants further clinical investigation. And along those lines, other compounds with similar mode of action but less toxicity might be something that needs to be developed, but that is for the future.

It is important to realize that although a GBM patient often has 

 abnormalities, amplification, or mutations, these are all in the extracellular domain. And from the other tumor types we know that erlotinib, gefitinib work, in particular, with a completely different type of mutation. So using these agents to downregulate EGFR pathway signaling is not going to work. We need another approach. ABT-414 is a different approach as we are using a sort of Trojan horse concept to use the receptor to get the cytotoxic inside a tumor cell.

A phase I trial of the antibody drug conjugate ABT-414 has shown promising results for the treatment of patients with EGFR-amplified, recurrent glioblastoma.

Katie Kosko

Articles

President Obama Signs 21st Century Cures Act

Phase II Trial Looks to Study Optune's Efficacy in Grade III Recurrent Glioma

Expert Discusses Promising ABT-414 Trial Results in EGFR-Amplified, Recurrent GBM