Raising the Bar for Precision Oncology and Clinical Research in a Community Practice Setting

Must patients choose between receiving cancer care close to home and gaining access to the most cutting-edge scientific advances?

The answer is a resounding no, according to physicians, other scientists, and administrative leaders at Florida Cancer Specialists & Research Institute (FCS), who on August 10, 2023, showcased how they have built a clinical trial and next-generation sequencing (NGS) infrastructure on par with traditional academic centers—while offering patients less travel time and lower costs.

Gordan

Heritage

Led by cochairs Lucio N. Gordan, MD, FCS president and managing physician, and Trevor Heritage, PhD, senior vice president and chief data officer, the speakers appeared in partnership with The American Journal of Managed Care at a session of the Institute for Value-Based Medicine. The group met in Tampa, Florida, a central location that allowed physicians and other practice leaders to gather from the nearly 100 clinics and research sites across the state. FCS’ extensive footprint means that 65% of Floridians live within 20 miles of a clinic in the practice, according to CEO Nathan H. Walcker, MBA, who welcomed the audience.

FCS, Walcker said, “has prioritized the integration of next-generation sequencing and clinical research to advance oncology care, not only within our practice but across the oncology ecosystem.”

Community oncology at FCS not only matches the best academic medical centers, he said, but often exceeds those capabilities.

Developing the Right Data: Comprehensive Genomic Profiling
Gordan then introduced an extended session on FCS’ resources in comprehensive genomic profiling (CGP), which allows the practice to determine patients’ eligibility for biomarker-driven therapies or clinical trials that require patients to have a certain mutational status. Bringing these services in-house was a major undertaking but a worthwhile one, because once a patient is diagnosed with cancer, time to the first treatment matters. And as Jennifer Gass, PhD, associate director, Genetics Laboratory, explained, the process of CGP is not simple, and there are good reasons results can take 12 to 14 days. CGP is an NGS approach that not only looks for all major types of variants but also detects signatures such as tumor mutational burden (TMB) and microsatellite instability (MSI).

Gass’ team, said Gordan, “oversees the interpretation and validation of molecular and genetics testing, enabling us oncologists and other providers at FCS to treat the patients with the best drug at the quickest time possible.”

In 2022, serving 100 sites translated into 1.3 million distinct visits and 91,000 new patients, he said. “So, we have an enormous amount of data in genomics at FCS. And with that, we will move the needle very significantly.”

Gass’ presentation occurred on the third anniversary of her arrival at FCS, which happened in the midst of the COVID-19 pandemic. Getting the right equipment and supplies was very difficult that first year—Gass was told some items would take up to 8 months to arrive. Then in September 2022, when it seemed the worst had passed, Hurricane Ian slammed into Southwest Florida, causing a round of losses when backup generators failed. But Gass’ team and the lab have bounced back, and she shared the process that allows comparatively speedy testing and interpretation of results.

The road to NGS. First, Gass reviewed key milestones in genetics and genomics, starting with the 1953 discovery of James Watson, Francis Crick, and Rosalind Franklin of the double helix of DNA,¹ through the discovery that a polymerase chain reaction allows amplification of DNA, and the monumental achievement of the first draft of the human genome, which was completed in 2001.²

“When we first started sequencing the human genome in 1990, it took 11 years, and that was [in] labs throughout the whole world,” Gass noted.³ Today, the fastest genome has been sequenced in 7 hours, 18 minutes. From there NGS testing began, which Gass described as “massive parallel sequencing,” which can reveal oncogenes, both hereditary mutations, such as BRCA1 or BRCA2, and somatic mutations, such as KRAS G12C. Use of NGS, as well as other elements of CGP, such as MSI and TMB, allows for a precision oncology approach, Gass explained. Treatments are more effective and less harmful to noncancerous cells with fewer adverse effects (AEs), leading to improved quality of life.

Considerations for NGS. “When you want to implement an NGS test, there’s a lot of different considerations to take,” Gass said. Factors include the following:

• Is testing for research and discovery or clinical purposes? If clinical, is testing diagnostic, prognostic, or for therapeutic use?
• Is the test of a gene panel, the whole exome (protein regions), or whole genome, which is seen more often with discovery?
• Is the patient population adult or pediatric? Is the test being used to examine a rare disease?
• Will the practice be reimbursed? Gass shared advice she received: “The best test you can run is a test that you’re going to get paid for.”

The testing process. Gass then outlined the how NGS works at the practice—both what testing covers and the steps involved. The comprehensive solid tumor panel includes 523 genes, DNA and RNA, DNA variants, fusions, MSI and TMB; testing covers dozens of mutations across cancers including lung, breast, colon, ovarian, gastric, bladder, melanoma, and sarcoma.

Gass offered a precise timeline of how long each step takes—up to a full week is needed just for gaining insurance approvals and collecting a good tissue sample. From there, things move quickly: a day each for creating slides and for isolating the tumor tissue and DNA/RNA, 1-3 days for creating the product for sequencing in the NGS library, a day for NGS bioinformatics, and up to 5 hours for NGS reporting.

Pathologists and variant scientists report variants based on consensus recommendations from the American Society of Clinical Oncology (ASCO), the Association for Molecular Pathology, and the College of American Pathologists; tier I variants, such as KRAS G12C, for which there is known clinical significance, and tier II variants have potential clinical significance. Tier III are variants of unknown significance.⁴ A final report lists variants, possible therapies, TMB and MSI scores, and other items found. “We also list any clinical trials that we might have out there for these patients, and we try to tailor trials to local trials within Florida, even South Georgia or Alabama,” Gass said.

“NGS is a powerful tool for oncology practices. It allows us to standardize patient results in our oncology practice as well as decrease that turnaround time, in hopes for better personalized treatment for our patients, as well as those trials.”

Use of bioinformatics. Next, Heritage explained what happens after the test—when data are used to drive both individual treatment plans and real-world evidence.

According to Gordan, Heritage has shaped FCS’ use of data from top to bottom. “Trevor has spearheaded initiatives to establish improved utilization of data, enhancing precision medicine, clinical research, matching the clinical decision support, value-based care, quality improvement—if you name it, there’s data.”

Heritage described bioinformatics as “the necessary evil” behind NGS, which has emerged over the last 10 to 15 years following the completion of multiple sequences of the human genome. In the early years, this science stayed in the walls of academia; as the need for applications arose, bioinformatics centers arose, including one funded at the McDonnell Genome Institute at Washington University in St Louis, Missouri, where Heritage worked. Heritage’s role at FCS is not only to create the information technology and decision support to build data sets and interpret what’s coming from Gass’ laboratory but also to help clinicians ask the right questions, order the right tests, and interpret the results when the tests are complete.

Creating the right infrastructure requires significant investment, Heritage said. “You’re getting into environments where you’re going to have high demands on compute power, storage, network bandwidth—these files are huge, [and] just manipulating them presents challenges that you haven’t previously had,” he said.

Operating systems such as Linux are new to many. Bioinformatics codes require specialized expertise, and as Gass discussed, FCS has hired clinical variant scientists—specialists who understand what the codes mean. Then there are variations across testing companies, Heritage said, which would be challenging for physicians to understand without help.
“What we’ve built out…is really the capability to give our physicians more or less real-time support,” Heritage said.

He emphasized that the bioinformatics team is there to ensure physicians understand the options, not to make decisions. “We don’t tell them what to do, because they’re the physicians. They decide what to do—we just outline some of the options, and then try to make [them] easier to execute.”

Implementing such a system requires not only enormous computing power but also the ability to integrate the steps into a busy practice environment. “One of the unfortunate things in bioinformatics is that almost all of the steps assume that there’s going to be people who know what to do, manually intervening all along the way,” Heritage said. “So, in order to get to the turnaround times that we expect as a practice, we have to figure out how we’re going to automate—to remove those manual steps.”

The bioinformatics team works with the pathology lab to develop the report that filters through all the data and isolates those variants associated with a diagnosis and finally those that are pathogenic. Flexibility and collaboration are critical as the need for testing expands, he said.

“You need to think about the overall design of the workflow to support the diversity of tests,” Heritage said. “This is a really rapidly changing area.”

Applications in precision oncology. Once data are available, the question becomes: How can they drive decisions? As Heritage explained, the data program at FCS has many elements, as follows:

• database of 37,000 unique patients, with 200,000 clinically significant variants, going back to 2013;
• a proprietary precision oncology platform, called FCS Precise, that allows clinicians to search and filter patient data by gene and mutation to gain insights about NGS results;
• real-time deliverables for physicians that NGS results have returned, including actionable variants, matches for targeted therapies, and potential clinical trial matches for the patient;
• weekly reports for research physicians and coordinators on patients for whom the practice has NGS results; and
• a service, FCS Molecular Help, which offers an email address staffed by the bioinformatics scientists and geneticists to answer physician questions.

Heritage said the practice is just beginning to tap the potential of FCS Precise, which launched in July 2022.⁵ “One of the interesting things that we’re working on is something that we call the FCS Precise treatment map,” he said. “For a group of patients with a given diagnosis, we ask, ‘What are the first-line, second-line, third-line treatment options that are available for that patient? What did the journey of previous patients with a given genomic profile look like? What were the outcomes for those patients?’ Then, we are trying to use that information to influence decisions that may be made for future patients.”

Heritage said FCS is also mapping where patients live—and where testing was done—relative to its clinical trial locations, to “get some indication if they would be willing to travel that distance on an ongoing basis.”

“The FCS Precise platform gives us organization-wide visibility to NGS data across the whole practice, which we’re actively using both for clinical purposes as well as internal research purposes—and to drive our real-world evidence program,” Heritage said. “The ability to map particular combinations of genetic variants to practice-preferred, and potentially payer-preferred, therapies is really helpful to physicians in quickly identifying the appropriate therapy for their patient.”

“We are currently at the beginning of intelligent matching of patients to trials,” he said. “It’s more of a rules-based approach right now, but we are also looking at AI [artificial intelligence]-driven approaches. This [FCS] Molecular Help service that we’re providing...is really a critical component for our physicians to help them answer some of the questions that they have around NGS results.”

Taking the Lead in Research: Clinical Trials in the Community
New cancer drugs are not approved without clinical trials, and clinical trials do not happen without patients. Yet, studies show that less than 5% of patients take part in a trial⁶—a share that oncologists would like to increase.

As senior director for Clinical Research Administration at FCS, John Musser handles the business side of making trials available and easier to access. He shared data on the research landscape at the practice: FCS offers more than 150 trials through 37 research location in 21 counties, including 3 phase 1 drug development units located in Sarasota, Lake Mary, and Lake Nona. The research operation involves 160 staff, and more than 600 FCS patients are treated on a trial each year. Today, Musser said, when the FDA approves a new cancer therapy, the drug was most likely studied at FCS.

As Musser explained, there are still trials that are not well designed for the community setting, but that’s changing. “I had a wonderful talk with a pharma company today, and they want to build [a] study for the community setting only. That was absolutely wonderful to hear; they want to bring those types of trials directly to the patients,” he said.
With the FDA now requiring drug sponsors to recruit more diverse clinical trial populations, research centers are insisting on less restrictive eligibility criteria. If the study criteria are too strict, “they’re unable to get enough patients on study to be meaningful,” Musser said.

He also shared information from his colleagues about the things that keep patients out of trials. Besides travel time and costs, there’s fear: Will there be adverse effects? Will I get a placebo? What if I want to change my treatment plan? Addressing those concerns, through patient education, is an ongoing process.

“It takes a very dedicated team to assure these patients that you’re not just a guinea pig, you’re not just getting a placebo; you’re going to receive the same type of care that you would if you were on standard of care,” he said. “That is something we continue to work through.”

Biopsy requirements climb. Gustavo A. Fonseca, MD, FACP, medical director for the Clinical Research Program, next explained a review that FCS undertook to understand why fewer patients were enrolling in trials. James Reeves, MD, examined 200 patient records—from 2012 and 2022—that highlighted how requirements to have a biopsy and NGS available were becoming more common before patients enrolled in a study. For many patients, the biopsy is done as part of standard of care, and the NGS is in the archive. But for some, this could be a barrier to enrolling in a trial.

“We analyzed this from 2 perspectives—we analyzed it from the patient’s perspective as well as from the [perspective of] the clinical trials,” Fonseca said. FCS leaders saw that from the patients’ viewpoint, requirements for NGS had climbed from 3% of patients in 2012 to 48% of patients by 2022. The analysis also showed that 76% of the patients did not need an extra biopsy to enroll in a trial, compared with 95% in 2012.

“So, we are seeing the trend—it is very clear, but it’s not really the majority of the patients,” Fonseca said.

As precision oncology takes hold, the percentage of clinical trials that don’t have targets has dropped dramatically over the past decade. And most patients are receptive to the idea of being on a clinical trial, Fonseca said. “But we also know we have had patients who withdraw consent. And sometimes the doctor says, ‘You know what, it’s going to take too long for you to go for that biopsy. We’ll just go ahead and do the standard of care.’”

Fonseca said clinical trial coordinators are familiar with this phenomenon—as well as the give-and-take with the pathology lab when the trial team needs 20 slides, and Gass reports that the patient’s tissue cannot be exhausted.

Fonseca sees this issue continuing as medicine moves forward—with more targeted therapies, antibody-drug conjugates, and immunotherapy that requires TMB assessment. “We’ve heard about NGS and the ways that we can make sure that that information is utilized,” he said. “Now, will this become an issue for patients? While we hope not, my point…was to bring this to [your] attention.”

The new look of phase 1. Director of Drug Development Manish Patel, MD, whose research is based at the Sarasota location, started with a review of the evolution of phase 1 clinical trials: In the past, these were small studies with 20 to 30 patients to establish a dose before research moved into phase 2.

“Now, the phase 1 trials are much more complicated. They often have hundreds, if not thousands of patients, because we’re answering a lot of questions up front,” he said. “They’ve become monster trials,” sometimes with different combinations, biomarkers, or settings. Thus, phase 2 studies may be less involved, because phase 1 may lead to an expansion cohort once there’s an established dose—or even straight to approval.

The reason: Project Optimus, the FDA’s effort to overhaul dose optimization and selection in oncology, leading to greater collaboration among academia, pharmaceutical sponsors, patient groups, and regulators—with a focus on early and frequent meetings to set expectations.⁷

In the past, Patel explained, a drug would move through development and approval, and physicians would start using it, wondering, “Are we really using the right dose here? You always wonder [if] it wasn’t done right when it was being studied.”

“For that reason, in the phase 1 trials now, instead of just going with 1 dose and moving forward, now we’re going to be requiring multiple doses to be looked at in the expansion phases. So, the phase 1 trials will be bigger, with a need for more patients to get these drugs through,” he said.

Patel acknowledged the approach has pros and cons. “I think it’s good overall for the field and patients to get the doses right,” he said. It’s also allowed many smaller biotech companies to grow. Patel cited IQVIA data showing 68% of the new products are from these small companies and 72% of these emerging biopharma companies are developing a single drug.

Drug development at FCS. Patel said 44% of the drug development unit trials involve targeted therapies. “That tells you about the importance of precision medicine,” Patel said. Another 37% involve immunotherapy, and 11% are for antibody-drug conjugates.

Just the PD-1 and PD-L1 area accounted for 5683 trials in 2022, according to a review.⁸ Combinations beget trials—pembrolizumab accounted for 1500 alone in 2021,⁸ and that number has only climbed, Patel said. He rattled off the different drug classes being studied: monoclonal antibodies, bispecific antibodies, trispecific antibodies, bispecific T-cell engagers.

“And of course, we can’t talk about oncology right now without talking about CAR [T-cell] therapy,” he said. “It’s a really exciting field.”
Despite cytokine release syndrome (CRS) events in the range of 20% to 25%, the CAR T-cell story is balanced by overall response rates of 80% to 90%. “At certain centers who do it well, it’s a great therapy, and it is evolving. But because of their success, bispecific antibodies are really taking off,” he said.

Patel explained the bispecific antibody structure: As the name suggests, it has 2 targets; one arm targets CD3 on the outside of the T cell, and the other arm targets the antigen on the tumor cell. “When those attach, it allows the T cells to be in close proximity to the tumor cells,” he said, creating a more powerful attack on the cancer with a less potent CRS reaction.

“Clearly, the advantage is that this [is] right off the shelf,” Patel said. “The financial toxicity is less; the safety profile is a little cleaner. And there’s a lot more you can do with this,” he said. “Obviously, with the CAR [T-cell therapy], the duration of responses and the one-time dose do have some advantages as well. But this field is constantly moving.”
Patel then reviewed several recent studies involving FCS, including the following:

• With Janssen, there has been a phase 1b study of the bispecific JNJ-78278343, described as “a T cell-redirecting agent targeting human kallikrein 2 (KLK2),” paired with PD-1 inhibitor cetrelimab to treat metastatic castration-resistant prostate cancer (NCT05818683).
• With Boehringer Ingelheim, there has been a first-in-human, phase 1 dose-escalation trial of BI-765049 and BI-65049 + ezabenlimab, given to patients with solid tumors expressing B7-H6 (NCT04752215). Patel said the goal is to convert a “cold tumor” that typically does not respond to immunotherapy to a “hot tumor.”
• With Moderna, there has been a study on the cancer vaccine mRNA-4157 with and without pembrolizumab (NCT03313778); results presented this spring showed a 44% reduction in the risk of recurrence or death for those with late-stage, high-risk melanoma.⁹ “We put the second patient ever on this therapy,” Patel said. The mechanism involves using tumor tissue to make a vaccine that mimics B-cell and T-cell responses. Having the cancer vaccine platform ready helped Moderna respond quickly to COVID-19, Patel said. The FDA granted the treatment breakthrough designation in February 2023, and a phase 3 trial is underway.^10,11
• With Eli Lilly, there has been work on the first phase 1 trial for third-generation Bruton tyrosine kinase inhibitor pirtobrutinib (Jaypirca), which led to approval to treat relapsed/refractory (R/R) mantle cell lymphoma in January 2023.¹² Patel was a coauthor for the phase 1/2 BRUIN study (NCT03740529) appearing in the Lancet.¹³
• Patel reviewed early data previously presented for revumenib (SNDX-5613) in R/R KMT2Ar acute leukemia and couldn’t hide his sense of big things to come. He described this patient population as very hard to treat and was encouraged by positive response rates seen to that point. “I hope this drug makes it—it will be really exciting for our group,” he said. On October 2, 2023, Syndax announced that the pivotal AUGMENT-101 trial for revumenib had met its primary end point and would be stopped early.¹⁴
  A trial drawing on knowledge from the FCS database involves the oral select RET inhibitor KL590586 (NCT05265091), which the practice had just opened. “I think we can really lead this in the country,” Patel said. Another is from Tango Therapeutics and involves an oral HDAC1 inhibitor to target STK11, which Patel said has shown up in NGS reports and is a known driver of immune evasion. It’s an important trial for FCS to do, he said, “because we’ll find these patients.”

Patel concluded with a discussion of antibody-drug conjugates (ADCs), walking the audience through the mechanism of action and the description of the ADC payload. “It’s a huge field, and our group has been working on these for a long time,” he said. Two were highlighted:

• Raludotatug deruxtecan (DS-6000), from Daiichi Sankyo, is being studied in phase 1 in advanced renal cell carcinoma (RCC) and ovarian cancer, with an estimated trial end date of October 2024 (NCT04707248). Of the 30 patients in the multicenter study, at the data cutoff on February 25, 2022, 17 patients (56.7%) were still on treatment: 12 patients with ovarian cancer and 5 patients with RCC.
• SGN-B6A, from Seagen, is an integrin beta-6 targeted ADC being studied in patients with advanced solid tumors; an update from the phase 1 study (NCT04389632) reported at ASCO showed efficacy results in dose escalation and expansion for non–small cell lung cancer, esophageal cancer, and squamous cell carcinoma of head and neck had a 30% overall response rate. FCS is currently enrolling patients on study for the ADC, both first line and R/R, in combination with pembrolizumab.
  

What are the challenges today? During a brief discussion following the presentations, Gordan discussed shortages and delays his practice works through to get patients what they need.

“There’s a huge bottleneck for bispecific and CAR T-cell therapy in the country,” Gordan said. “We went from 10 years ago, probably 70% of trials were with chemotherapy backbone and now it’s 2% of the trials. So that means that 5 years from now, 40% of our treatments will be bispecifics plus or minus CAR T [cells], and the other 40% will be even more targeted therapies. So, the world is changing super fast. And who knows what AI is going to bring as far as drug development as well.”

References
1. The discovery of the double helix, 1951-1953. National Library of Medicine. Accessed October 5, 2023. https://profiles.nlm.nih.gov/spotlight/sc/feature/doublehelix
2. Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome. Science. 2001;291(5507):1304-1351. doi:10.1126/science.1058040
3. Wosen J. Stanford scientist who broke genome sequencing record on what faster diagnoses mean for patients. STAT. March 22, 2023. Accessed October 5, 2023. https://bit.ly/3LRfWlX
4. Li MM, Datto M, Duncavage EJ, et al. Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn. 2017;19(1):4-23. doi:10.1016/j.jmoldx.2016.10.002
5. FCS adds new in-house precision oncology capabilities. News release. Florida Cancer Specialists and Research Institute. July 21, 2022. Accessed October 2, 2023. https://flcancer.com/articles/florida-cancer-specialists-adds-new-in-house-precision-oncology-c/
6. Murthy VH, Krumholz HM, Gross CP. Participation in cancer clinical trials: race-, sex-, and age-based disparities. JAMA. 2004;291(22):2720-2726. doi:10.1001/jama.291.22.2720
7. Project Optimus. Food and Drug Administration. Updated October 2, 2023. Accessed October 5, 2023. https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus
8. Upadhaya S, Neftelinov ST, Hodge J, Campbell J. Challenges and opportunities in the PD1/PDL1 inhibitor clinical trial landscape. Nat Rev Drug Discov. 2022;21(7):482-483. doi:10.1038/d41573-022-00030-4
9. Caffrey M. Moderna and Merck’s cancer vaccine cuts risk of recurrence or death 44% in late-stage, high-risk melanoma after resection. AJMC. April 16, 2023. Accessed October 5, 2023. https://bit.ly/3F38ikP
10. Moderna and Merck announce mRNA-4157/V940, an investigational personalized mRNA cancer vaccine, in combination with Keytruda (pembrolizumab), was granted breakthrough therapy designation by the FDA for adjuvant treatment of patients with high-risk of melanoma following complete resection. News release. Merck. February 22, 2023. Accessed October 5, 2023. https://bit.ly/3Q3WgxD
11. Carvalho T. Personalized anti-cancer vaccine combining mRNA and immunotherapy tested in melanoma trial. Nature Med. August 16, 2023. https://www.nature.com/articles/d41591-023-00072-0
12. US FDA approves Jaypirca (pirtobrutinib), the first and only non-covalent (reversible) BTK inhibitor for adult patients with relapsed or refractory mantle cell lymphoma after at least two lines of systemic therapy, including a BTK inhibitor. News release. Eli Lilly and Company. January 27, 2023. Accessed October 5, 2023. https://bit.ly/3LOKyo4
13. Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892-901. doi:10.1016/S0140-6736(21)00224-5
14. Syndax announces pivotal AUGMENT-101 trial of revumenib in relapsed/refractory KMT2Ar acute leukemia meets primary endpoint and stopped early for efficacy following protocol-defined interim analysis. News release. Yahoo Finance. October 2, 2023. Accessed October 5, 2023. https://finance.yahoo.com/news/syndax-announces-pivotal-augment-101-110000001.html