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Research Advocates, Leading Docs to Expand Precision Medicine Access With Decentralized Model


NEW YORK – Although precision oncology advances have benefitted patients with some of the most commonly occurring tumor types, such as lung and breast cancer, rare cancers have not seen the same level of impact.

Difficulties accruing patients to clinical studies and securing funding for translational research have contributed to disparities in treatment options for patients with rare cancers, who collectively have significantly lower five-year survival rates than patients with more prevalent cancers.

Research advocacy group TargetCancer Foundation, oncologists at leading cancer centers, and genomic profiling firm Foundation Medicine recently teamed up to address this gap through a prospective study that will employ a decentralized model in the hopes of expanding access to molecular testing and personalized treatments to more patients around the country.

In the Target Rare Cancer Knowledge (TRACK) study, which Bayer is also supporting, investigators are focusing on cancers that affect fewer than six in 100,000 people per year. They aim to enroll 100 patients with cholangiocarcinoma, 100 patients with cancers of unknown primary origin, and 200 patients with other types of rare cancers.

The primary goal of the study is to match patients to personalized treatments based on molecular markers identified from next-generation sequencing. These "matched" drugs can be approved agents, off-label therapies, or investigational treatments in clinical trials. Researchers are primarily interested in tracking the percentage of patients who receive molecularly targeted matched treatment and how long they live without their cancer progressing while on these drugs.

"Rare cancers are individually rare, but altogether, they're roughly 25 percent of the cancer burden," said Razelle Kurzrock of University of California, San Diego, the TRACK study's principal investigator. "As a group, they're very important. A lot of rare cancers don't have an FDA-approved treatment, and if they do have an FDA-approved treatment, it might be one treatment and there is nothing really beyond that."

Kurzrock expects that some of the anticipated 400 patients recruited to TRACK will come from the Rare Tumor Clinic she directs at UC San Diego, but she hopes that most patients will come from community oncology settings in remote parts of the country.

At first glance, the general design of the TRACK study doesn't sound all that different than other basket or umbrella trials, which have been used to elucidate the value of precision medicine: patients enrolled in the trial receive NGS tumor profiling, and if they harbor any of the biomarkers of interest, they're assigned to one of several biomarker-drug arms. Trials like these are often seen as being mutually beneficial for patients, who receive access to targeted treatments that otherwise may not have been an option, and for researchers, who glean valuable information from the NGS results and patients' outcomes on matched therapies.

Within TRACK, the access and research aims are much the same. However, unlike typical umbrella and basket trials, which have certain centralized design and protocol elements, TRACK takes a decentralized approach to try to mitigate the barriers rare cancer patients face in trying to join such studies.

Even though the trial's main sites are MD Anderson Cancer Center and UC San Diego, patients can enroll from anywhere in the US, and are not required to physically travel to one of these sites. Instead, patients can complete their consent process remotely and continue to visit their original cancer center and receive care from their treating physician.

While the requirement that patients travel to major academic cancer centers to partake in a precision oncology study presents a barrier to patients with all types of cancer, such requirements exacerbate existing enrollment challenges in rare cancer clinical trials, in which it is difficult enough to identify a sufficient number of eligible patients.

In addition to not having to travel to one of the main study sites, patients enrolled in TRACK can have their local care providers send a tumor tissue or blood sample to Foundation Medicine for NGS analysis on its FoundationOne CDx assay and its FoundationOne Liquid blood-based test. The results will be sent to the TRACK study's virtual molecular tumor board for review. The virtual molecular tumor board, which includes the study's lead investigators and a handful of other rare cancer experts, will then generate treatment recommendations based on the NGS results and share those recommendations with the patients' treating physicians.

"The envelope of the study stops at the treatment recommendation," Jim Palma, executive director of TargetCancer Foundation, explained. "We're not directly putting patients on specific medications the way that some studies would do by having a treatment arm." For example, the protocol for the American Society of Clinical Oncology's TAPUR basket trial allows any CLIA-certified, College of American Pathologists-accredited lab to screen patients, but patients must match to one of the study's therapeutic arms in order to receive treatment within the trial. 

In TRACK, the patients and their local treating physicians will decide whether to follow the molecular tumor board's recommendations. According to Kurzrock, this element of the study design is crucial, allowing for personalization based on patients' preferences. "Physicians are more willing to participate when they are reassured that the decision will ultimately be theirs," she said.

This was one of the lessons that Kurzrock gleaned from the i-PREDICT study at UC San Diego, which was not unique to rare cancers, but which employed a similar study design in that it provided patients with treatment recommendations based on NGS but left the final decision in the hands of the patients' treating oncologists. Indeed, Kurzrock said that much of the TRACK study's design is modeled off of i-PREDICT.

Challenges of decentralization

While the remote access features were built into the TRACK study design with the goal of enabling patient participation from anywhere in the country, there is no guarantee that the treatment recommendations patients receive will afford that same flexibility. There is the possibility that the best treatment recommendation for a patient based on their NGS results will be a clinical trial that does ultimately require some travel.

"That is absolutely a limitation of this trial," Kurzrock acknowledged. That said, even though the study does not provide or ensure access to interventional treatments, Palma explained that the patients enrolled in the trial will be able to leverage the services that the TargetCancer Foundation provides outside of the TRACK study, including help with overcoming clinical trial access barriers.

Part of the TargetCancer Foundation's mission "is to help patients navigate clinical trials and potential issues," he said. "While it's not an immediate part of our protocol in this research study, we will be helping people actually access the trials and treatments that are recommended to them if they want to pursue them."

The TargetCancer Foundation has close relationships with community organizations, foundations, and nonprofits focused on rare cancers, Palma said, and he anticipates working closely with them to conduct outreach and recruitment for the study and to help patients navigate access difficulties.

In cases where patients receive off-label treatment recommendations from the TRACK molecular tumor board, Palma and Kurzrock both acknowledged that local treating physicians may need assistance securing access to drugs from manufacturers and advocating for patients with insurers.

"What we're trying to accomplish with the study is really … to get people the information they need and the feedback from the expert molecular tumor boards to find the best treatment possible," Palma said. "But, we also want to make sure that patients have access to those treatments, so we are looking to fill that gap as well."

Kurzrock said that while it is not yet set in stone, she is working with TargetCancer Foundation and others involved in the TRACK study to bring a team of dedicated medication acquisition specialists onto the study. UC San Diego already employs a team of these specialists, who were essential in the i-PREDICT study. In that trial, 149 patients consented to participate and out of 83 patients who underwent treatment, 73 received molecularly informed therapies, resulting in an overall match rate of 49 percent — significantly higher than other precision oncology trials with match rates in the single or low-double digits. 

Kurzrock hopes that these medication acquisition specialists will be able to increase matched treatment access in the same way within the TRACK study. "It's a lot of paperwork that many of the patients' treating physicians realistically won't have the [bandwidth] to do on their own," Kurzrock said of the process of securing access to molecular tumor board-recommended, off-label drugs.

NGS testing, patient follow up

While access to clinical trials and off-label drugs is not necessarily guaranteed within TRACK, the study ensures all patients will have access to NGS testing through Foundation Medicine, which is provided to those enrolled at no cost. The FoundationOne Liquid test will be conducted several times during the course of the study to evaluate any changes in circulating tumor DNA from baseline after patients receive matched treatment.  

Patients' results and treatment outcomes collected over the study's one-year follow-up period will be reported to researchers, who will leverage the data to better understand the molecular makeup of these under-studied rare cancers. "We're going to be sequencing each of these patients, and that in and of itself will give us more information," Kurzrock said. "We will be able to better understand the underlying biology as reflected by the sequencing."

At the study's conclusion, the researchers will publish their findings. "We're generating data in a group of cancers that aren't typically aggregated together and don't get as much attention," Palma said. "We think we have a lot of value to add by making this data public once we have a chance to put it all together and analyze it."

The primary outcomes assessed in the TRACK study will include the percentage of patients matched to treatment and their subsequent progression-free survival, but the study will also measure response rate, rate of stable disease, time-to-treatment failure, overall survival, and the ratio of the progression-free survival on matched therapy compared with progression-free survival on prior treatment.

In the i-PREDICT trial, researchers employed a match score — calculated based on the number of mutations in patients' tumors that matched to the drugs they were given, divided by their total number of genomic alterations in their tumors. Patients with high matching scores in the study tended to have a better disease control rate, progression-free survival, and overall survival.

"With i-PREDICT, the better patients were matched to therapy, the better they did," Kurzrock said, adding that the TRACK study will be an opportunity to assess if the same is true on a national scale of patients with rare cancers.

Palma and Kurzrock highlighted that the COVID-19 pandemic has underscored the value of the study's decentralized approach, particularly since cancer patients are a vulnerable population. "Travel has always been a challenge for clinical trials, but now with COVID, it's been nearly impossible," Kurzrock said, referencing quarantine requirements and limitations on domestic travel in recent months.

To address these challenges during the pandemic and allow clinical trials to continue, the FDA and National Cancer Institute have recently made concessions, allowing for remote consent processes, telehealth appointments, and local lab use within trial protocols. According to Palma, these remote allowances were already a part of the TRACK study design prior to the pandemic, but they have become all the more important given the timing of the study's launch. Even patients who could have traveled to a study site like UC San Diego or MD Anderson may not be able to now due to COVID-19 restrictions and risks. 

"There are very few positive things about COVID, but it has definitely jumpstarted the conversation surrounding clinical trial access," Kurzrock said. "I can't predict the future, but I think remote access could be here to stay."