OncologyLive® is the flagship publication of OncLive®. Each issue delivers expert insights and clinical oncology news and updates, which impact the day-to-day clinical practice of oncology professionals who work tirelessly to help improve patient outcomes.

On September 20, 2023, with the goal of improving care, the American Oncology Network (AON) announced the completion of its business combination with Digital Transformation Opportunities Corp (DTOC) to become a publicly traded entity. The combined company was dubbed “American Oncology Network, Inc,” and its common stock began trading on the Nasdaq Stock Market under the ticker symbol AONC. Representatives from the new company rang the closing bell at the Nasdaq to commemorate the first day of trading on September 21, 2023.

“The platform [of] AON provides physicians and nurse practitioners the ability to escalate their level of care and function at a level that would be on par with any academic center from the standpoint of services provided, but [it] keeps that care closer to home for patients,” Stephen “Fred” Divers, MD, chief medical officer at AON and a medical oncologist at the Genesis Cancer and Blood Institute in Hot Springs, Arkansas, said in an interview with 

. “We had a desire to create this network and expand it nationally so that oncologists in the community would have access to a more sophisticated level of practicing medicine. We [experienced] rapid growth over the subsequent 5 years, and an opportunity came forward where we would be able to bring the company public. [We feel] that it afforded the capital and the opportunity to grow our footprint nationally; we expect significant growth going forward.”

The definitive business combination between AON and DTOC was first announced in October 2022.

 AON also received a strategic investment from AEA Growth of $65 million in April 2023 with the goal of further supporting community oncology practices.

The final approval for the business combination was given by the stockholders of DTOC at a special meeting on September 19, 2023. The network noted that the partnership and strategic investment would be utilized to help further AON’s goals by adding new providers to the network, scaling ancillary services, introducing new service offerings, and expanding existing services.

Founded in 2018, AON is a network of community oncology practices headquartered in Fort Myers, Florida. To date, the network is comprised of more than 200 providers from more than 75 clinics in 19 states. The organization is led by a team of physicians and other health care leaders, leveraging their expertise to aid in the longterm success of community oncology practices. The network provides member institutions with access to fully integrated, centralized services in areas including specialty pharmacy, laboratory and pathology, radiation therapy, and imaging. AON also offers electronic medical records services, a care management team, and several financial assistance programs to its members.

Divers explained that the business combination and the decision to bring AON public will lead to enhanced care for patients being treated in the community setting. “Being part of Nasdaq should resonate with all of our customers and patients throughout the country as we expand this network to improve access, quality, and cost efficiency [of care]; care delivered in the community is typically more cost-effective and associated with higher patient satisfaction scores,” he said.

Prior data have demonstrated that community oncology care has typically been less cost prohibitive for patients compared with care administered at larger institutions. In a 2018 matched-claims analysis of patients with breast, colorectal, and lung cancers published in the 

, findings presented by Gordan et al showed that patients treated at hospital-based clinics experienced significantly increased costs of care compared with those treated at community-based clinics.

To conduct their analysis, investigators obtained cost data for 6675 patients identified from the IMS LifeLink database who had at least 1 medical chemotherapy claim between July 1, 2010, and June 30, 2015. In terms of cost per patient per month, patients treated at a community practice (n = 4450) experienced a mean cost of $12,548 (standard deviation [SD], $10,507) vs $20,060 (SD, $16,555) for those treated at a hospital-based practice (n = 2225; 

 < .001). The mean monthly chemotherapy cost was $4933 (SD, $4983) for patients treated at a community-based practice vs $8443 (SD, $10,391) for those treated at a hospital-based practice (

In addition to potentially lessening the cost of care, joining a larger network such as AON could afford community oncology practices the ability to offer better quality care for patients in historically hard-to-reach demographics, such as patients in rural areas, according to Divers. As much as 19% of the US population lives in what could be defined as a rural area. Although the combined incidence rates for cancer are higher in urban areas, the death rates from the disease have been found to be higher in rural areas.

This gap in cancer-related outcomes between rural and urban patients has been attributed to several factors, including older age, higher rates of obesity, disability, lower quality of health education, lack of trust in the health care system, and, particularly, difficulty in accessing high-quality cancer care due to geographic barriers. Only 15% of US oncologists work in rural settings, and US counties without an oncologist represent approximately 60% of the total land area. Metropolitan counties are also much more likely to have an oncologist compared with nonmetropolitan counties (66.5% vs 33.9%, respectively) and have far more oncologists by land area (11.5 oncologists vs 0.5 oncologists per 1000 square miles).

Divers hopes the expansion of AON will better equip these smaller community practices located in rural areas with the necessary resources to treat patients more effectively. “[My institution] joined AON in 2018 because of a desire to be part of something bigger and to make sure that we were providing the highest level of care possible for our patients,” he explained. “[We are located] in a relatively rural area in Arkansas, and there were not always opportunities to have access to elite-level care, so being part of a larger organization provided us with the ability to escalate the level of care through the AON platform.”

Studies performed on a smaller scale have shown the benefit in terms of quality of care of community oncology practices joining a larger network. In a 2021 retrospective study published in 

, Tucker et al examined the impact of community practices in largely rural areas of Kentucky joining the Markey Cancer Center Affiliate Network (MCCAN). The MCCAN is a statewide network developed by the National Cancer Institute–designated University of Kentucky Markey Cancer Center with the stated purpose of enhancing access to high-quality cancer services and programs for patients with cancer treated in community hospitals.

The study included 13 MCCAN hospitals who were members of the network for a minimum of 3 years prior to 2018. Each MCCAN hospital was matched a control hospital for comparison purposes; MCCAN hospitals were also divided into 2 groups: those from the primarily rural Appalachian area of Kentucky (n = 7) and those located in the non-Appalachian portions of the state (n = 6).

Compliance with care quality measures for MCCAN institutions was assessed vs control hospitals for the 3 years prior to joining the network (T1) and the 3 years after joining (T2). Investigators selected 4 evidence-based cancer care quality measures for MCCAN hospitals and a matched set of control hospitals that were established at least 3 years prior to first hospital joining MCCAN and stayed in place through 2017. They included the administration of radiation therapy within 1 year of diagnosis for women under age 70 receiving breast-conserving surgery for breast cancer (BCSRT); radiation therapy being recommended or administered following any mastectomy within 1 year of diagnosis of breast cancer for women with at least 4 positive regional lymph nodes (MASTRT); the recommendation or administration of adjuvant chemotherapy within 4 months for patients aged less than 80 years with stage III colon cancer (ACT); and the removal and pathological examination of at least 12 regional lymph nodes for patients with resected colon cancer (12RLN).

Findings from the study demonstrated that MCCAN member hospitals achieved a significant increase in compliance in terms of BCSRT (

 < .0001) from T1 to T2. Additionally, during T2, MCAAN members had significantly higher compliance rates regarding BRSRT (

 = .03) compared with the nonmember controls.

According to the 2023 edition of the Community Oncology Services Global Market Report, the global community oncology market size is projected to grow from $47.95 billion in 2022 to $53.79 billion in 2023 at a compound annual growth rate of 12.2%. Additionally, the market is expected to grow at a compound annual growth rate of 10.9%.

 AON is also heavily involved in oncology pharmaceuticals, a market that is expected to grow from a $177 billion industry in 2021 to approximately $313.7 billion by 2026, at a compound annual growth rate of 12.1%.

From 2019 through June 2022, AON produced compounded annual revenue growth exceeding 60% and continues to operate at a profit.

 Moreover, the network generated more than $1.1 billion in revenue in 2022, demonstrating year-over-year growth of approximately 20%.

The network is expected to leverage its newfound publicly traded status to further capitalize on the growing community oncology market, Divers said. “Since we joined AON, it’s also been a huge success from the standpoint of our business—our volumes have increased significantly, both on the patient side and [in terms of] provider volume,” he noted. “Recruitment has increased, our footprint coverage has increased, and patient satisfaction has increased.”

“There’s an addressable market that’s out there. The oncology community is somewhat large and fragmented between academic institutions and community settings. Our vision and mission are to be patient-centric and to provide the necessary tools and resources for our providers to deliver the highest quality of care possible for our patients regardless of their location, whether that be rural or in the larger metropolitan areas.”

American Oncology Network and Digital Transformation Opportunities Corp. announce completion of business combination. News release. American Oncology Network. September 20, 2023. Accessed September 25, 2023. https://www.aoncology.com/2023/09/20/american-oncology-network-digital-transformation-opportunities-announce-completion-business-combination/

American Oncology Network, a rapidly growing network of community-based oncology practices, to go public through business combination with Digital Transformation Opportunities Corp. News release. American Oncology Network. October 6, 2022. Accessed September 25, 2023. https://www.aoncology.com/2022/10/06/american-oncology-network-to-go-public-through-business-combination-with-digital-transformation-opportunities-corp/

American Oncology Network, a rapidly growing network of community-based oncology practices, receives strategic investment from AEA Growth. News release. American Oncology Network. April 28, 2023. Accessed September 25, 2023. https://www.aoncology.com/2023/04/28/american-oncology-network-receives-strategic-investment-from-aea-growth/

Who we are. American Oncology Network. Accessed September 25, 2023. https://www.aoncology.com/who-we-are/

Gordon L, Blazer M, Saundankar V, Kazzaz D, Weidner S, Eaddy M. Cost differences associated with oncology care delivered in a community setting versus a hospital setting: a matched-claims analysis of patients with breast, colorectal, and lung cancers. J Onc Pract. 2018;14(12):e729-e738. doi:10.1200/JOP.17.00040

Levit LA, Byatt L, Lyss AP, et al. Closing the rural cancer care gap: three institutional approaches. JCO Oncol Pract. 2020;16(7):422- 430. doi:10.1200/OP.20.00174

Tucker TC, Charlton ME, Schroeder MC, et al. Improving the quality of cancer care in community hospitals. Ann Surg Oncol. 2021;28(2):632-638. doi:10.1245/s10434-020-08867-y

The Business Research Company. Community oncology services global market report. Accessed September 25, 2023. https://www.thebusinessresearchcompany.com/report/community-oncology-services-global-market-report

Insights on the $177.4 billion oncology pharmaceuticals global market to 2026 - ResearchAndMarkets.com. News release. Business-Wire. October 6, 2021. Accessed September 26, 2023.

Articles

On September 20, 2023, with the goal of improving care, the American Oncology Network announced the completion of its business combination with Digital Transformation Opportunities Corp to become a publicly traded entity.

AON Goes Public, Aims to Leverage Increased Resources Into Improved Patient Care

The cancer care landscape is experiencing dynamic forces impacting providers’ ability to meet growing demand for patient care services. Cancer risk increases with age, so cancer cases will continue to rise in the United States, driven by an aging population.

 An estimated 18 million individuals in the United States with a history of cancer were still alive on January 1, 2022,

 and many require follow-up care, putting even more pressure on providers.

Beyond the growing number of patients requiring care, there is a looming shortage of oncologists. According to the American Society of Clinical Oncology (ASCO), there were 12,940 oncologists in the US workforce in 2020.

 Unfortunately, almost 20% were nearing retirement age, and only 15.6% were early career oncologists younger than 40 years.

Oncology practices must develop innovative strategies to optimize their services to meet increasing demand. A closer look at some of the approaches being used across The US Oncology Network (The Network—a network of independent, physician-owned community-based practices—to improve patient access can provide helpful insight into how practices can meet the growing need for their services.

The Anxiety of Prolonged Waiting Times for Patients

There are important reasons why new patients with cancer should be seen quickly. Most have a long wait before arriving on the oncologist’s doorstep, given the journey from a referring physician to an oncologist and the additional time that may have been spent undergoing screening. During that time, anxiety builds in patients over whether they really have cancer and, if so, what the path forward looks like.

Certain cancers progress quickly, so seeing patients as soon as possible is critical. The priorities at this stage are to care for patients by reducing their anxieties and by promptly creating a treatment plan that moves their care forward.

Maximizing the Care Team to Support Increased Volume 

Given the declining number of oncologists and the increasing demand for services, practices must find effective ways to offset some of the work oncologists handle, and identify strategies to optimize existing patient services. This will enable more patients to be seen in a timely manner. Here are a few approaches being used across The Network to enhance patient access:

Integrate advanced practice providers (APPs) into the care model. 

Effectively using APPs maximizes oncologists’ time, enabling them to see more new patients. Consequently, there is a growing trend to form care teams with APPs. With this model, oncologists oversee new patients or acute changes in therapy, whereas APPs perform follow-ups, help with initial intake, and manage less severe cancer types and patients having repeat infusions. For instance, practices often receive referrals for those with hematological and benign conditions. These individuals can receive a high level of care from the care team and an APP, as opposed to an oncologist. APPs can also support palliative care conversations.

Incorporating oncology-focused pharmacists.

 The number of oral products in cancer care is growing rapidly. From 2019 to 2021, the FDA approved 44 new cancer therapies, of which 27, or 61%, were oral anticancer agents.

Oncology-focused pharmacists can play an important role in managing care for patients on oral therapies. With pharmacists monitoring dosing and collaborating with oncologists, more oncologists’ time can be freed for other tasks that only they can perform.

 Based on a 2020 report by the US Census Bureau, the rural population represents 20% of the nation’s total population,

 and according to an ASCO report, 66% of rural counties have no oncologist.

 This disparity creates a significant challenge in ensuring individuals in rural communities can get the care they need.

Telehealth, which grew tremendously during the COVID-19 pandemic, provides a viable solution for delivering a wide range of cancer care services to rural dwellers who face obstacles in gaining access to care. Many practices have focused on telehealth and become very competent in its use. The technology is especially suited for follow-ups, long-term monitoring, and survivorship care. It also saves significant time for patients and providers. A recent study found telehealth visits saved patients an average of 2.9 hours of driving time (round trip) and 1.2 hours of in-clinic time per visit,

 some of which may be freed for the care team to perform other tasks.

Provide patients access to financial counselors.

 Cancer care is expensive, and unfortunately, many health insurers and employers are moving into high-deductible health plans that can create severe financial burden for patients. Many practices are investing in financial counselors to help patients understand early in their cancer journey what their out-of-pocket expenses are and what resources they can utilize to help cover costs. There are several different funds for patients, and counselors can help them maximize opportunities for assistance, lowering the financial burden they face. This assistance enables patients to access care they otherwise might not be able to afford, as patients facing financial difficulties sometimes forego treatment altogether.

The Network, supported by McKesson, is providing practices expertise, data, and innovative tools to advance their efforts to meet the increasing need for their services. By examining what is happening across The Network in large cities and small rural areas, best methods and valuable data are being compiled and shared to help practices better understand who is referring to them, how long it takes new patients to be seen, and ways to solve patient access challenges.

Following are a few useful strategies being employed and shared across practices in The Network:

Care teams are building centralized contact centers to provide the best possible patient experience across all locations, from the patient’s initial contact until treatment ends.

Practices are being educated on new technologies and customer care methods for contact centers to ensure patients have the best possible interaction, via phone or text messaging.

The digital experience is being enhanced so patients can utilize portals to securely submit forms, pay bills, and communicate with their care team. Best practices are also being shared, providing ways to leverage APPs so they can communicate with patients online.

Integrating precision medicine data into the physician’s electronic health record to quickly determine the best personalized treatment plan and potential clinical trial opportunities optimizes the practice workflow and, most importantly, provides the patient with timely access to the best treatments, close to home.

A team has also been created within The Network to visit and assess practices to identify specific issues that inhibit timely access to care. The team examines workflow issues, such as scheduling, new patient intake, lab processes, and other key functions. The focus is on developing improvements that enable new patients to be seen within 48 hours.

Timely Access: a Vital Part of the Mission

The US Oncology Network is composed of independent community oncologists and care teams dedicated to delivering high-quality care that provides the best outcomes for patients, close to home. They take great pride in offering patients innovative treatments and superior care in their local communities. A critical part of this mission is ensuring that patients who are referred to a practice are seen quickly, so they receive care as soon as possible during a difficult time. The Network is committed to supporting practices in their efforts to achieve this important goal, empowering them with the resources and tools necessary to provide patients timely access to the services they need.

Devon Womack is the SVP and COO of The US Oncology Network.

Age and cancer risk. National Cancer Institute. March 5, 2021. Accessed online August 24, 2023. https://www.cancer.gov/about-cancer/causes-prevention/risk/age

American Cancer Society. Cancer Treatment & Survivorship Facts & Figures 2022-2024. 2022. Accessed online August 24, 2023. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/cancer-treatment-and-survivorship-facts-and-figures/2022-cancertreatment-and-survivorship-fandf-acs.pdf

Physician Compare Datasets. Centers for Medicare & Medicaid Services. Accessed August 24, 2023. https://old-prod.asco.org/sites/new-www.asco.org/files/content-files/practice-and-guidelines/documents/2020-workforce-information-system.pdf

AMA Physician Masterfile. American Medical Association. Updated July 3, 2023. Accessed August 24, 2023. https://www.ama-assn.org/practice-management/masterfile/ama-physician-masterfile

Blinder VS, Garrett-Mayer E, Jacobsen PB, et al. Oral chemotherapy metric performance in quality oncology practice initiative practices: updated trends and analysis. 

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Nation’s urban and rural populations shift following 2020 census. News release. United States Census Bureau. December 29, 2022. Accessed August 28, 2023. https://www.census.gov/newsroom/press-releases/2022/urban-rural-populations.html

Torres L. Health challenges facing minority communities. US Department of Veterans Affairs. April 21, 2023. Accessed August 28, 2023. https://news.va.gov/118294/health-challenges-facingminority-communities/

Winstead E. Telehealth can save people with cancer time, travel, and money. National Cancer Institute. February 16, 2023. Accessed September 8, 2023. https://www.cancer.gov/news-events/cancer-currents-blog/2023/telehealth-cancer-care-saves-time-money#:~:text=Estimated%20Savings%20in%20Context&text=At%20Moffitt%20Cancer%20Center,%20the,of%20time%20in%20the%20clinic

A closer look at some of the approaches being used across The US Oncology Network to improve patient access can provide helpful insight into how practices can meet the growing need for their services.

Providing Timely Cancer Care Access Is Crucial Amid Growing Patient Volume

Despite the discovery of protein arginine methyltransferase 5 (PRMT5) more than 20 years ago, interest in the potential oncogene as a treatment target for patients with hematologic and solid malignancies has increased in recent years with the advancement of multiple novel agents through preclinical and early-phase studies.

PRMT5 is the major type II arginine methyltransferase and has a hand in several key biological processes, including the regulation of cell growth and migration. It is capable of methylating histone and non-histone substrates and can also undergo methylation. The gene is also involved in the cell cycle and embryonic development.

Direct arginine methylation by PRMT5 has been shown to affect the activity of multiple proteins that are essential to the growth factor signaling pathway that plays a role in the proliferation, differentiation, and survival of cancer cells. Studies have demonstrated that PRMT5 is upregulated in lymphomas, breast cancer, lung cancer, colorectal cancer, and glioblastoma, leading investigators to believe that it has the potential to be a promising treatment target.

Investigators have hypothesized that PRMT5 inhibition could represent a novel therapeutic strategy to address cancer-initiating cells. Inhibition of PRMT5 could disable mechanisms protecting tumor cells from DNA damage caused by radiotherapy and chemotherapy. Preclinical study has shown that PRMT5 depletion or inhibition sensitizes tumor cells to agents that induce the DNA damage response, such as PARP and topoisomerase inhibitors.

Early-Phase Studies of PRMT5 Inhibitors Display Mixed Results

To date, no PRMT5 inhibitors have gained FDA approval for the treatment of patients with cancer.

 However, several novel agents are currently being developed for patients with hematologic malignancies, solid tumors, and historically hard-to-treat malignancies (

During the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Ahnert et al presented findings from a phase 1 dose-escalation study (NCT03854227) examining the PRMT5 inhibitor PF-06939999. The study enrolled patients with solid tumors, including endometrial cancer, head and neck squamous cell carcinoma (HNSCC), non–small cell lung cancer (NSCLC), urothelial cancer, cervical cancer, and esophageal cancer.

PF-06939999 was administered at a dose of 0.5 mg to 12 mg daily. Two of 28 efficacy-evaluable patients who were treated with the agent achieved a partial response (PR), 1 with HNSCC and 1 with NSCLC. Safety findings showed that there were no treatment-related deaths or discontinuations due to treatment-related toxicities in the safety population. Dose-limiting toxicities (DLTs) consisted of thrombocytopenia (n = 2), anemia (n = 1), and neutropenia (n = 1). Any-grade treatment-related adverse effects (TRAEs) occurred in 86% of patients and included anemia (43%), thrombocytopenia (32%), dysgeusia (29%), and nausea (29%).

Investigators concluded that PF-06939999 displayed dose-dependent and manageable toxicities and selected 6 mg daily as the recommended dose for the dose-expansion portion of the study. However, in April 2022, Pfizer, the manufacturer of PF-06939999, announced that the phase 1 trial would be terminated based on a strategic evaluation within its current oncology portfolio. Pfizer noted that the decision was not due to safety concerns or requests from regulators.

Another PRMT5 inhibitor, the selective and reversible agent GSK3326595, was first evaluated for the treatment of patients with myeloid malignancies in the phase 1/2 trial Study 208809 (NCT03614728). Part of the mechanism of action of GSK3326595 involves inhibiting cellular mRNA splicing and upregulation of tumor suppressor function. Mutations in splicing factors are present in approximately 40% of patients with myelodysplastic syndrome (MDS) and more than 60% of patients with chronic myelomonocytic leukemia (CMML). Therefore investigators hypothesized that treatment with GSK3326595 could lead to a synthetic lethal phenotype in splicing mutant disease.

Investigators presented the trial design of Study 208809 at the 2019 American Society of Hematology Annual Meeting & Exposition. The trial aimed to enroll approximately 302 patients with relapsed/refractory MDS, CMML, or hypoproliferative acute myeloid leukemia (AML) that had evolved from an antecedent MDS. The study entailed a dose-finding phase, that could be expanded into 3 additional parts if prespecified criteria were met: a randomized comparison of GSK3326595 monotherapy with investigator’s choice of best available therapy in all patients, a single-arm investigation of safety and efficacy of GSK3326595 plus 5-azacitidine in participants with newly diagnosed high-risk MDS, and a single-arm evaluation of the safety and efficacy of GSK3326595 monotherapy in patients with relapsed/refractory AML with mutations in pre-RNA splicing machinery.

But, in February 2022, it was announced by the manufacturer, GSK, that Study 208809 would be terminated after the trial enrolled approximately 10% of its target enrollment. According to GSK, the removal of the program was due to, “prioritization within the synthetic lethal portfolio,” following its fourth-quarter results earning release.

Although the phase 1/2 trial of GSK3326595 in patients with hematologic malignancies was terminated, findings from the phase 1 METEOR-1 trial (NCT02783300) revealed that the agent displayed modest efficacy and safety signals in patients with advanced solid tumors. METEOR-1 was the first-in-human study of GSK3326595 in adult patients with advanced metastatic solid tumors or non-Hodgkin lymphoma (NHL). It enrolled patients with relapsed/refractory disease or disease with no standard of care, adequate organ function, and an ECOG performance status of 1 or 0.

Findings from METEOR-1 presented during the 2022 European Society for Medical Oncology Congress showed that the agent induced 3 confirmed PRs in patients with solid tumors: 2 in the cohort of patients with adenoid cystic carcinoma (ACC; n = 50) and 1 PR in a patient with estrogen receptor–positive breast cancer (n = 37). Additionally, patients with NHL (n = 29) experienced an overall response rate (ORR) of 10%; 1 patient with follicular lymphoma and 1 with diffuse large B-cell lymphoma experienced a complete response (CR). The duration of response (DOR) was 32.4 months and 3.4 months, respectively, in the 2 patients with a CR.

“The waterfall plot shows some regression among different tumor types,” Ulrik N. Lassen, MD, a clinical professor in the Department of Clinical Medicine at the University of Copenhagen in Denmark, said in an invited discussion of the findings after the presentation. “That was especially [true] in cystic carcinomas and NHL. The study drug was well tolerated, and the actual data corresponds to what was seen in the dose-escalation part [of the study].”

Regarding safety, TRAEs of any grade were reported in 95% of the 218-patient safety population. Grade 3 TRAEs occurred at a rate of 46%, grade 4 treatment-emergent adverse effects (TEAEs) were present in 7% of patients, and no grade 5 events related to study treatment were observed.

Any-grade serious TRAEs were seen in 19% of patients. Dose reduction due to any AE, treatment interruption or delay due to any AE, and treatment discontinuation due to any AE occurred at a rate of 56%, 70%, and 12%, respectively.

Investigators concluded that the observed tolerability and single-agent efficacy of GSK3326595 were consistent with those of other PRMT5 inhibitors with published data available. METEOR-1 is still active but is not recruiting additional patients.

Newer Data Show Promise in Effectively Targeting PRMT5

Despite early phase trials of PF-06939999 and GSK3326595 ending before data were fully mature, recent updates from other clinical trials evaluating PRMT5 inhibitors have displayed more promising results, with the agents examined in these studies poised to advance into later phases of development. During the 2023 ASCO Annual Meeting, findings were presented from a phase 1 clinical trial (NCT04089449) that examined the potent, selective PRMT5 inhibitor PRT811 in patients with advanced solid tumors, central nervous system lymphoma, and/or recurrent high-grade glioma.

“This is a very novel compound targeting PRMT5, which is highly expressed in patients with glioblastoma and high-grade glioma and also is active in patients whose tumors are splicing mutation positive,” Varun Monga, MD, clinical associate professor of internal medicine—hematology, oncology, and blood and marrow transplantation in the Department of Internal Medicine at the University of Iowa Carver College of Medicine in Iowa City, said in an interview with 

. “PRT811 is brain-penetrant. PRMT5 has a functionality of epigenetic regulation, it demethylates the protein substrates, and it controls these key cellular processes via epigenetic mechanism and spliceosome inhibition mechanism.”

The first-in-human, open-label, multicenter study included 86 patients. In the recurrent, high-grade glioma cohort (n = 38), 16 patients had 

-negative tumors. In the advanced/metastatic uveal melanoma cohort (n = 23), 10 patients were splicing mutation (SPLC) positive and 13 were SPLC negative. The primary end point was determining the recommended phase 2 dose (RP2D) of PRT811.

The ORR in the glioma cohort was 5.3%, with the best overall response being a CR. Moreover, 2.6% of patients in the cohort had unconfirmed PRs, 28.9% achieved stable disease (SD), 52.6% had progressive disease (PD), and 22% were not evaluable.

Patients in the uveal melanoma group experienced an ORR of 4.4%. In this cohort, the best response was a PR; however all responses were unconfirmed. SD was seen in 34.8% of the patients with uveal melanoma, 43.5% had PD, and 13% of patients were not evaluable.

-positive glioma, 2 durable CRs were observed. One patient had a CR for 31.0 months that was ongoing at data cutoff, and the other who had a CR had a median DOR of 7.5 months followed by PD. In the uveal melanoma group, 1 patient with a PR had a median DOR of 10.0 months followed by PD.

-mutant glioma], there are not many good treatment options for those who have received several lines of treatment before; [this is similar] in uveal melanoma,” Monga noted. “PRT811 certainly offers those patients a treatment option by itself. The ORR was at most modest, but there is potential for studying combination treatments, like with CDK4 inhibitors and IDH1 inhibitors.”

In terms of safety, any-grade TEAEs occurred in 98.4% of the safety population (n = 61), and grade 3 or higher TEAEs were observed in 52.5%. Any-grade TEAEs leading to dose reduction or dose interruption occurred in 78.7% of patients, and grade 3 or higher TEAEs led to dose reduction or interruption in 19.7% of patients. Serious TEAEs were observed in 21.3%, and these serious TEAEs were grade 3 or higher in 16.4%. Grade 5 TEAEs occurred in 3.3% of patients.

The study authors concluded that PRT811 displayed an acceptable safety profile and clinical activity in patients with glioma and metastatic uveal melanoma. The RP2D was determined to be 600 mg administered orally on a once-daily basis.

In April 2023, during the American Association for Cancer Research Annual Meeting, investigators presented findings from a phase 1 trial (NCT03573310) of the novel PRMT5 inhibitor JNJ-64619178 for the treatment of patients with advanced solid tumors, NHL, and lower-risk MDS.

 JNJ-64619178 is a highly potent and selective oral PRMT5 inhibitor that has been shown in preclinical study to induce widespread RNA splicing changes, as well as broad antitumor activity in solid and hematologic models.

The first-in-human, dose-escalation study of JNJ-64619178 enrolled adult patients with relapsed/refractory B-cell NHL or solid tumors. Data from the study showed that among efficacy-evaluable patients (n = 90), the ORR was 5.6%. Notably, patients with ACC (n = 26) achieved an ORR of 11.5% with a median progression-free survival of 19.1 months. Thrombocytopenia was determined to be the only DLT.

Finally, during the 2022 ASCO Annual Meeting, investigators presented the design of a phase 1/1b/2 trial (NCT05094336) that is evaluating the novel PRMT5 inhibitor AMG 193. AMG 193 belongs to a new class of PRMT5 inhibitors known as methylthioadenosine phosphorylase (MTAP) cooperative.

Deletion of the MTAP gene and the neighboring tumor suppressor gene CDKN2 can be found in approximately 10% to 15% of cancers and results in buildup of methylthioadenosine in cells. This buildup leads to partial inhibition of PRMT5; thus it has been hypothesized by investigators that MTAP-null tumors could be vulnerable to additional inhibition of PRMT5.

MTAP cooperative agents such as AMG 193 target and selectively inhibit the MTA-bound state of PRMT5 that is enriched in tumors harboring an MTAP deletion. This approach has demonstrated the ability to preferentially inhibit cell viability as well as inhibit tumor growth in MTAP-null cancer cell lines and tumor xenograft models, respectively.

The first-in-human, multicenter trial of AMG 193 is enrolling approximately 30 adult patients with MTAP-null advanced/metastatic solid tumors not amenable to curative surgery and/or radiation. The dose exploration phase 1a/b portion will examine the agent at 5 dose levels until PD or withdrawal.

The coprimary end points in phase 1a/b are DLTs, TEAEs, serious adverse effects, as well as changes in vital signs and clinical laboratory tests.

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Chen Y, Shao X, Zhao X, et al. Targeting protein arginine methyltransferase 5 in cancers: roles, inhibitors and mechanisms. 

. 2021;144:112252. doi:10.1016/j.biopha.2021.112252

Kim H, Ronai ZA. PRMT5 function and targeting in cancer. 

. 2020;4(8):199-215. doi:10.15698/cst2020.08.228

Prabhu L, Martin M, Chen L, et al. Inhibition of PRMT5 by market drugs as a novel cancer therapeutic avenue. 

. 2022;10(1):267-283. doi:10.1016/j.gendis.2022.04.001

Feustel K, Falchook GS. Protein arginine methyltransferase 5 (PRMT5) inhibitors in oncology clinical trials: a review. 

. 2022;5(3):58-67. doi:10.36401/JIPO-22-1

Ahnert JR, Perez CA, Wong KM, et al. PF-06939999, a potent and selective PRMT5 inhibitor, in patients with advanced or metastatic solid tumors: a phase 1 dose escalation study.

. 2021;39(suppl 15):3019. doi:10.1200/JCO.2021.39.15_suppl.3019

A dose escalation study of PF-06939999 In participants with advanced or metastatic solid tumors. ClinicalTrials.gov. Updated November 22, 2022. Accessed September 21, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT03854227

Watts JM, Bradley TJ, Thomassen A, et al. A phase I/II study to investigate the safety and clinical activity of the protein arginine methyltransferase 5 inhibitor GSK3326595 in subjects with myelodysplastic syndrome and acute myeloid leukemia. 

. 2019;134(suppl 1):2656. doi:10.1182/blood-2019-130337

Taylor NP. GSK kills one of Barron’s early darlings, axing 2 synthetic lethal programs and Epizyme pact. Fierce Biotech. February 9, 2022. Accessed September 22, 2023. https://www.fiercebiotech.com/biotech/gsk-kills-one-barron-s-early-darlings-axing-two-synthetic-lethal-programs-and-epizyme-pact#:~:text=Shortly%20after%20becoming%20GlaxoSmithKline’s%20chief,molecule%20GSK3368715%20from%20its%20pipeline

Postel-Vinay S, Italiano A, Romano PM, et al. METEOR-1: a phase I study of the safety and efficacy of the protein arginine methyltransferase 5 (PRMT5) inhibitor GSK3326595 in advanced solid tumors. 

. 2022;33(suppl 7):S746-S747. doi:10.1016/j.annonc.2022.07.585

An open-label, dose escalation study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK3326595 in participants with solid tumors and non-Hodgkin’s lymphoma (Meteor 1). ClinicalTrials.gov. Updated June 28, 2022. Accessed September 22, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT02783300

Monga V, Johanns TM, Stupp R, et al. A phase 1 study of the protein arginine methyltransferase 5 (PRMT5) brain-penetrant inhibitor PRT811 in patients (pts) with recurrent high-grade glioma or uveal melanoma (UM). 

. 2023;41(suppl 16):3008. doi:10.1200/JCO.2023.41.16_suppl.3008

Vieito M, Moreno V, Spreafico A, et al. Phase 1 study of JNJ-64619178, a protein arginine methyltransferase 5 inhibitor, in advanced solid tumors. 

. 2023;29(18):3592-3602. doi:10.1158/1078-0432.CCR-23-0092

Villar MV, Spreafico A, Moreno V, et al. First-in-human study of JNJ-64619178, a protein arginine methyltransferase 5 (PRMT5) inhibitor, in patients with advanced cancers. 

. 2020;31(suppl 4):S470. doi:10.1016/j.annonc.2020.08.651

Villalona-Calero MA, Patnaik A, Maki RG, et al. Design and rationale of a phase 1 dose-escalation study of AMG 193, a methylthioadenosine (MTA)-cooperative PRMT5 inhibitor, in patients with advanced methylthioadenosine phosphorylase (MTAP)-null solid tumors. 

. 2022;40(suppl 16):TPS3167. doi:10.1200/JCO.2022.40.16_suppl.TPS3167

Despite the discovery of protein arginine methyltransferase 5 more than 20 years ago, interest in the potential oncogene as a treatment target for patients with hematologic and solid malignancies has increased in recent years with the advancement of multiple novel agents through preclinical and early-phase studies.

Early Trials of PRMT5 Inhibitors Leave Much to Be Desired, But Optimism Remains

Small cell lung cancer (SCLC) has continued to evolve in recent years, in part from immunotherapy (IO)/chemotherapy combinations in the frontline setting with atezolizumab and durvalumab, respectively.

 For the secondline setting, the addition of lurbinectedin (Zepzelca) has shown intriguing data while also raising questions about the agent’s optimal role in this population. These newer strategies and therapeutics in were discussed in detail during an OncLive Peer Exchange

, which was moderated by Taofeek Owonikoko, MD, PhD, professor of medicine in the Division of Hematology-Oncology of the University of Pittsburgh and chief of hematology and oncology at the University of Pittsburgh Medical Center Hillman Cancer Center.

Nearly 240,000 new patients will be diagnosed with lung cancer in 2023 in the United States; SCLC accounts for 14% of lung cancers and is a usually more aggressive subtype.

 When diagnosed with SCLC, which commonly peaks between aged 75 and 79 years in men and women, 94% of patients have disease that has spread beyond the lungs. The incidence of all lung cancers, including SCLC, peaks about 5 years earlier in African American men compared with White men. Regarding outcomes, the 2-year survival rate in SCLC has increased to 19% and 16% in 2017 to 2018 among women and men from 10% and 8% in 1975 to 1976, respectively.

While progress in outcomes has been greater in non–small cell lung cancer, recent advances, including molecularly targeted therapies against 

, checkpoint inhibitors that boost immune response, improved staging, and video-assisted surgery have all contributed to progress in treatment of all types of lung cancer, including in SCLC.

 Owonikoko added, however, that outcomes for SCLC remain dismal, as most patients are diagnosed with incurable, extensive-stage disease.

Challenges Surround Early Diagnosis in SCLC

Konstantinos Leventakos, MD, an assistant professor of medicine and oncology at Mayo Clinic in Rochester, Minnesota, added that the biggest challenge in SCLC is that it is fast growing in nature and that more efficient screening methodologies would be useful in identifying the disease earlier. “Have we seen patients being diagnosed with SCLC through screening? Yes, but whether we have seen a meaningful reduction in the mortality because we were able to recognize many patients in early stages are data that we don’t yet have. So while oncologists are pro-screening because it saves lives, more personalized and more SCLC specific strategies are needed.”

Patients should also be treated sooner for pneumonia for an extended time, particularly smokers, and an earlier biopsy could aid in earlier diagnoses. “Once there is a histologic confirmation of SCLC, immediate referral to oncology is required, and the health care system should be ready to accommodate fast referrals for patients with SCLC,” Leventakos said.

Jacob Sands, MD, a thoracic medical oncologist at Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School, agreed that lung screening is the best way to improve SCLC outcomes as it allows earlier-stage intervention.

Defining the Role of Biomarkers in SCLC Diagnosis and Treatment

Anne Chiang, MD, PhD, an associate professor and associate cancer center director of clinical initiatives at Yale School of Medicine, explained that PD-L1 expression must be assessed prior to determining treatment for an individual patient with SCLC.

The panel reflected on a patient case of a 68-year-old male with SCLC who was also identified to have pleural hepatic and brain metastases. Despite the heavy disease burden, the patient had an ECOG performance status of 0 and started treatment with nivolumab (Opdivo), carboplatin, etoposide. After 2 cycles, as well as following completion of 4 cycles, there was progressive improvement in the pleural pericardial effusions, reduction in the overall metastatic burden, and significant shrinkage in the hepatic metastases. Overall, the patient experienced minimal toxicity with the regimen and a clear improvement in terms of the associated symptoms.

Having a response to treatment after 2 cycles, followed by a deeper response after cycle 4 was uncommon, making Sands optimistic about this particular patient case. However, Chiang said this scenario was typical in her practice.

While Chiang said most patients with SCLC are metastatic, similar to this individual patient, they can have responses to treatment. “We have a responsibility to these patients to prepare them for what may come next. In most cases, there is recurrence. There’s a window to talk to our patients and make sure that they understand and can prepare without giving up hope, for what may come next.”

Frontline standard-of-care (SOC) options for SCLC treatment include the combination of atezolizumab, carboplatin, and etoposide; the second option is platinum plus etoposide and durvalumab (Imfinzi). Both options are FDA approved and widely used, the panel noted. “These are both PD-L1 inhibitors and patients like hearing that these are not toxins,” Sands said.

The indication for atezolizumab was based off findings from the phase 3 IMpower133 trial (NCT02763579), in which the PD-L1 inhibitor plus chemotherapy improved median overall survival to 12.3 months compared with 10.3 months in the chemotherapy plus placebo arm (HR, 0.70; 95% CI, 0.54-0.91; P = .007).

Having cisplatin available, as well as patients who have hemocytopenia because of bone marrow involvement, would put the durvalumab plus platinum/etoposide regimen as his preference in the frontline setting.

In the limited-stage disease setting, Leventakos said data are limited for incorporating immunotherapy. Moreover, in the absence of a clinical trial, standard treatment for those with limited-stage disease is concurrent chemoradiation, which usually comprises cisplatin with etoposide. Leventakos cited frequent situations of starting with 1 cycle of chemotherapy and catch up with radiation in the following cycle or as soon as possible. Also, in the case of a resected SCLC nodule, adjuvant cisplatin, preferably with etoposide, would be his approach.

The phase 3 CASPIAN trial (NCT03043872) explored the efficacy and safety of durvalumab alone or combined with tremelimumab (Imjudo) and platinum-based chemotherapy followed by durvalumab maintenance therapy vs chemotherapy alone as a first-line treatment for patients with ES-SCLC.

 Preliminary findings did demonstrate an overall survival (OS) improvement with the immunotherapy regimen, but it was not found to be statistically significant. However, updated data showed that the durvalumab combination continued to show an improved overall survival (OS) vs chemotherapy alone.

 Specifically, in longer study follow-up, which was a median follow-up of 39.4 months, the median OS at 3 years was 12.9 months vs 10.5 months, respectively (HR, 0.71; 95% CI, 0.60-0.86; 

 = .0003), and the 3-year OS rate was 17.6% vs 5.8%, respectively.

In the other arm of the CASPIAN trial, durvalumab/tremelimumab plus etoposide/cisplatin chemotherapy (EP) also continued to improve OS vs chemotherapy alone. Median OS was 10.4 months (HR, 0.81; 95% CI, 0.67-0.97; 

 = .0200), and the 36-month OS rate was 15.3%. At 3 years, three times more patients with SCLC were estimated to be alive when given durvalumab plus chemotherapy versus chemotherapy alone, with most patients still receiving durvalumab at the data cutoff. These data established durvalumab plus chemotherapy as the first-line SOC for patients with extensive-stage (ES)–SCLC.

“I love showing my patients the tail of the curve for the CASPIAN trial. I show it to them because it’s important that they know that they could be living in 3 years, even if they have disease that has spread to the brain,” Chiang said. “The CASPIAN trial showed us that you can triple the survival from 6% to 18%. We’re working on clinical trials to try to improve that even more.”

First-line durvalumab plus chemotherapy benefited the OS and progression-free survival (PFS) irrespective of the presence of brain metastases in patients with SCLC, supporting its SOC use.

In the durvalumab plus chemotherapy arm of the trial, adverse events (AEs) were reported by few patients before starting treatment in both arms. Baseline AE rates were maintained in both arms up to 24 weeks after starting treatment, except for itchy skin, which increased from 13% at baseline to 34% at cycle 6 in the durvalumab/chemotherapy arm and 12% at baseline to 42% at cycle 8 in the chemotherapy-alone arm. Dizziness increased from 16% to 40% at cycle 5 in the durvalumab/chemotherapy arm.

In a second case scenario, the panel highlighted a 78-year-old female patient who was initially admitted for weight loss and dysphasia. A PET scan showed a significant fluorodeoxyglucose avidity in the mass and a 4R node, and the biopsy led to a SCLC diagnosis. The patient was initially treated for limited-stage disease with concurrent carboplatin and etoposide with radiation, but a recurrence occurred after 7 months. The patient then completed 4 cycles of chemotherapy and atezolizumab before starting maintenance treatment with the PD-L1 inhibitor. Her disease progressed again about 5 months after starting treatment. Lurbinectedin was then started, but following further disease progression, lurbinectedin therapy was discontinued.

Lurbinectedin received FDA approval in June 2020 for the treatment of adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy. The decision was based off findings in the multicenter, open-label, multicohort PM1183-B-005-14 trial (Study B-005; NCT02454972), which comprised 105 patients with metastatic SCLC.

Results showed that lurbinectedin led to an overall response rate of 35.2% and a disease control rate of 68.6%.

Second-line options, beyond lurbinectedin, can include a standard chemotherapy doublet, Leventakos said, but treatment in the second-line setting is not being offered as much as it should. “The old classic second-line treatment in the [United States] is an inhibitor with topotecan, while other countries might use irinotecan. In the US, topotecan was the main second-line treatment. Lurbinectedin has changed the second-line setting.”

“Lurbinectedin is a great tool for us. Patients tolerate it well and we’ve had good responses. It’s the second-line tool for most patients. It would be great if we could combine lurbinectedin with immunotherapy,” Chiang said.

Cell viability testing in SCLC models confirm high 

–expressing cell lines are 4 times more sensitive to lurbinectedin compared with low 

–expressing cell lines, suggesting a potential biomarker for lurbinectedin.

However, in the relapsed setting, the combination of lurbinectedin plus doxorubicin did not improve OS vs control in patients with relapsed SCLC, though it did demonstrate a favorable hematologic safety profile.

Overall, activity with lurbinectedin has led to the ongoing, randomized phase 3 LAGOON study (NCT05153239) which is evaluating lurbinectedin alone or lurbinectedin/irinotecan vs investigators choice or irinotecan in patients with relapsed SCLC.

“This is an exciting time for SCLC. We’re developing this idea that we can have precision medicine, that there’s not just 1 uniform SCLC, that there are subtypes that we can leverage and hope to be able to understand why some of the trials in the past were negative. Perhaps we didn’t capture the right population,” Chiang concluded. Overall, we are starting to develop some real inroads into helping our patients with SCLC.”

Mathieu L, Shah S, Pai-Scherf L, et al. FDA approval summary: atezolizumab and durvalumab in combination with platinum-based chemotherapy in extensive stage small cell lung cancer. 

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https://clinicaltrials.gov/study/NCT03043872

While progress in outcomes has been greater in non–small cell lung cancer, recent advances, including molecularly targeted therapies against EGFR and ALK, checkpoint inhibitors that boost immune response, improved staging, and video-assisted surgery have all contributed to progress in treatment of all types of lung cancer, including in SCLC.

Vol. 24/No. 17 | Oncology Live®

AON Goes Public, Aims to Leverage Increased Resources Into Improved Patient Care

Providing Timely Cancer Care Access Is Crucial Amid Growing Patient Volume

Early Trials of PRMT5 Inhibitors Leave Much to Be Desired, But Optimism Remains

Novel Frontline Combinations Influence Later-Line Treatment Strategies in SCLC

Artificial Technology and the Future of Cancer Care: The Good, Bad and Potentially Very Ugly