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.

After the Tampa General Hospital (TGH) Cancer Institute in Florida commemorated its second anniversary in April 2023, Eduardo M. Sotomayor, MD, the institute’s newly minted vice president and executive director, noted that the amount of progress achieved by the institution was made possible by its continued commitment to finding creative solutions to address the needs of patients. Sotomayor was named to his current appointments on November 30, 2023.

“There is a need for [the] cancer institute to provide the best care to the growing population in the Tampa Bay area,” Sotomayor, said in an interview with OncologyLive. “We are in the process of working through the vision, mission, and our strategic plan, but we are a cancer institute that is highly translational. We are going to be focused on basic science, but basic science that is going to rapidly translate to the bedside. We are committed to the community that we serve [and] we’re going to have very strong community outreach, engagement, education, and training.”

In December 2022, the TGH Cancer Institute, which also serves as the primary teaching hospital for the University of South Florida (USF) Morsani College of Medicine, received a 3-year accreditation from the Commission on Cancer (CoC). The CoC is a quality program established by the American College of Surgeons; earning accreditation signifies that the TGH Cancer Institute met 34 quality care standards, utilized a multidisciplinary approach, and demonstrated a commitment to improving patient outcomes and quality of life. Institutions that are accredited by the CoC diagnose and/or treat over 70% of all patients with a new cancer diagnosis.

In June 2023, TGH was honored as a top cancer hospital in the United States, according to Newsweek and Statista. The institution received this distinction by ranking in the top 3% of cancer hospitals in the nation based on hospital quality metrics and survey results encompassing replies from both patients and oncology health care professionals across the nation.

2021, the TGH Cancer Institute has experienced remarkable growth, both in terms of attracting talent and expanding their physical footprint. Since 2021, the cancer institute has recruited 22 physicians across surgical, radiation and hematologic oncology, as well as over 20 advanced practice providers, including pharmacists, nurses, managers, and administrators.

Additionally, the institute has continued to add locations to serve more patients across the Tampa area; in July 2023, TGH announced the opening of a state-of-the-art infusion center in the Tampa suburb of Brandon that consists of 26 fully functional private chemotherapy areas. The institute also plans to open a radiation oncology center at this location in the future. TGH Cancer Institute also has locations in other areas surrounding Tampa, including Riverview, North Tampa, and St Petersburg, and is able to serve patients on Florida’s east coast via their partnership with the Cancer Center of South Florida.

“I would have never imagined even in my wildest dreams the growth that we have [experienced]. I would say that where we are right now, is something that I was expecting to happen by 2025 or 2026,” Sotomayor said. 

The TGH Cancer Institute sets itself apart, especially from other cancer centers in its area, by offering initiatives such as the TGH-USF Health Precision Medicine Biorepository. Announced in October 2022, the biorepository is a facility located on the USF Health Morsani College of Medicine campus in downtown Tampa that collects, catalogs, and stores biologic samples for future research. The biorepository allows the institute to conduct clinical and translational research and to further develop precision medicine approaches that will have an impact for patients in the Tampa area and beyond.

“In that biobanking of cancer samples, around 30% of samples are coming from minority patients with cancer, which is very unique,” Sotomayor noted. 

Another unique program that has led to improved care for patients with cancer is the institute’s integration of the CareComm command center. Opened at TGH in August 2019, CareComm, which was developed in partnership with GE HealthCare, consists of 20 artificial intelligence apps, video walls made up of 38 large screens, 32 workstations, and multiple computer systems, and is staffed by a multidisciplinary clinical team. The artificial intelligence apps or “tiles” apply advanced analytics to aid decision- making, help monitor patient flow, and track delays in care, allowing the clinical staff to make better informed decisions regarding patient care, and even predict the needs of patients before they arise.

In October 2020, TGH reported that the integration of the CareComm command center had led to a $40 million reduction of systemwide inefficiencies since its inception. TGH noted that CareComm decreased the average length of stay for patients by eliminating 20,000 excess days.

TGH has also invested significant resources into upgrading its radiation oncology program. In January 2023, the cancer institute announced the expansion of the program to include new technologies, such as the CyberKnife and TrueBeam systems, as well as high dose–rate brachytherapy. CyberKnife is a radiosurgery system that offers a noninvasive alternative to surgery. The TrueBeam linear accelerator allows for fast and precise delivery of image-guided radiation therapy.

In terms of clinical trials, Sotomayor noted that, in addition to the full range of studies the institution offers across phases and tumor types, TGH Cancer Institute is focused on providing options for patients with cancers that are common in its catchment area. Sotomayor mentioned the brain tumor and sarcoma programs in particular, saying that they are busy and are aimed at filling unmet needs in the area. He also highlighted the institution’s dedicated phase 1 unit that is housed in its main location. 

“We [have] started developing our Clinical Translational Research Program, which is going very well; we are opening innovative phase 1, 2, and 3 clinical trials,” Sotomayor said. “Next year, we are going to speed up that effort. Also in 2024, we will be building our basic science company recruitment of top-notch cancer researchers from the nation. Being post COVID[- 19 pandemic] will help us recruit talented people. Because of all this growth the board of TGH and the CEO have made a commitment for the next 5 years to support the cancer institute. Next year we are going to apply for Center of Excellence Accreditation, but our ultimate goal is to pursue National Cancer Institute designation within the decade.”

Articles

Tampa General Hospital Cancer Institute has experienced much growth since its establishment, in terms of attracting talent and expanding their footprint.

Tampa General Hospital Cancer Institute Celebrates 2 Years of Growth and Innovation

Genetic screening and testing have been a part of clinical practice for decades. However, it is only recently that genetics has become an integral part of cancer care.

 genes were discovered in 1994 and 1995, respectively, and many other cancer predisposition genes have been identified in more recent years. People with 

 mutations are considered to have the most common hereditary cancer syndrome, called 

hereditary breast and ovarian cancer syndrome 

 The National Comprehensive Cancer Network (NCCN) provides detailed recommendations regarding cancer surveillance and risk reduction for patients with HBOC. The impact on clinical care and management was initially unknown, but research and ongoing studies have provided guidance and NCCN guidelines are updated annually.

Up to 10% of cancers arise in those who carry an inherited gene mutation.

 This is particularly important for Black patients, as research at our Montefiore Einstein Comprehensive Cancer Center found that not only are Black patients more likely than White patients to have a specific type of colorectal cancer that has worse outcomes, but they are also more likely to have tumors with more genetic mutations that preclude them from receiving certain therapies.

In the 1970s, Montefiore Einstein was one of the first academic medical centers to offer population carrier screening for Tay-Sachs disease, an autosomal recessive neurologic genetic disorder that results in death in early childhood.

 In the late 1990s, we participated in the first 

 genetic testing of more than 1000 Ashkenazi Jewish women in the New York area, which led to a pivotal paper by Mary-Claire King, PhD, published in Science in 2003.

Lifetime risk of breast cancer among female mutation carriers was 82%, and lifetime risk of ovarian cancer was 54% for 

 mutation carriers. Additionally, risk appeared to increase with time: Breast cancer risk by age 50 was 24% among mutation carriers born before 1940 and was 67% among women born after 1940. This was one of the first studies to show physical exercise and lack of obesity in adolescence was associated with delayed breast cancer onset.

As the inheritance of most cancer predisposition genes is autosomal dominant, population screening is challenging and guidelines have evolved. Additionally, there are ethical, legal, and social implications of genetic testing, especially in diverse populations.

In 1987, during my gynecologic oncology rotation as a fourth-year medical student, I participated in the care of a 65-year-old woman with ovarian cancer. Fast forward 12 years, I am a practicing obstetrician- gynecologist and I see a patient who tells me her mother was diagnosed in 1987 with ovarian cancer and had surgery at the same hospital, and during the same month that I did my acting internship. We were able to ascertain that I took care of her mother in 1987!

 testing, which was not available to her mother at the time. Today, it is standard of care to test for hereditary cancer syndromes for any patient with a first- or second-degree relative with ovarian cancer. My patient, in fact, did have a mutation or pathogenic variant in 

Over the past 20-plus years, my patient has had a bilateral mastectomy with reconstruction, a bilateral salpingo-oophorectomy, and has been involved in research looking for predisposition to pancreatic cancer. She has had annual dermatologic and ophthalmologic examinations and has never had cancer. She is considered a previvor, a patient with a pathogenic variant who has never had cancer. We have reviewed and discussed the research and the clinical management of 

 over the past 2 decades together. We have also discussed the options of in vitro fertilization and preimplantation genetic testing of embryos for her children, which would avoid hereditary cancer caused by the familial variant in future generations. This patient has also been instrumental as a resource for other previvors in their decision-making regarding proactive medical and surgical options. She has told her story at community events and is willing to talk to community members who are struggling.

At Montefiore Einstein, genetic testing started in the Department of Obstetrics and Gynecology and Women’s Health, where women with ovarian cancer were treated and those with breast cancer received their gynecologic care. We used grants and appealed to companies to cover testing for our patients.

Today, screening and testing occur within the Division of Reproductive and Medical Genetics. We see adults at risk for hereditary cancer syndromes as well as those with cancer and those without, such as their family members. Each patient meets with a genetic counselor and a medical geneticist to discuss their options. Pre- and posttest counseling are critical.

There is also a discussion about insurance and out-of-pocket costs, which today are considered minimal. Additionally, I review the Genetic Information Nondiscrimination Act of 2008 with patients, which does not protect their genetic information if they apply for life and long-term disability insurance. It is critical that this specialty is experienced as comprehensive clinical care. As such, our genetics program is also embedded in our new breast cancer center, which we designed to be a singular location for breast health, advancing our ability to deliver the most personalized care to our patients.

A Star Shapes the Genetic Testing Landscape

At Montefiore Einstein and across the country, 2013 was a pivotal year for genetic testing in cancer care. Angelina Jolie wrote an editorial in 

 status and revealed that she voluntarily had a prophylactic mastectomy. Genetic testing often has a stigma, and Jolie helped others realize that genetic testing was crucial, offering many benefits.

Jolie’s family history was significant, and a pathogenic variant was found. However, a pathogenic variant was not found for many families that had significant breast and ovarian cancer, signaling there may be other genetic mutations not yet accounted for. In 2015, panel testing for hereditary cancer syndromes expanded to involve many genes, such as 

, and others involved in Lynch syndrome; but again, these new tests were not always covered by insurance. Over the past 8 years, we have seen that many of these genes can be actionable clinically and because of this change in management and the possibility of improved health care outcomes, insurance coverage is almost always available.

The Importance of Diversity in Genetic Testing

Genetic testing is now an integral part of cancer care, partly due to the Precision Medicine Initiative launched by former President Barack Obama and the National Institutes of Health, which aims to understand how a person’s genetics, environment, and lifestyle can help determine the best approach to prevent or treat disease. Despite these great strides, at the national level, we continue to see a significant number of individuals who should be offered genetic testing but never get it. Lack of knowledge about genetic testing among professionals and patients alike contribute to this trend. At Montefiore Einstein, members of our division are participating in seminars, grand rounds, and lectures to educate patient and physicians in hopes of overcoming the misconceptions and fears associated with genetic testing in our communities.

In 2017, we conducted a study at Montefiore Einstein that asked patients about their perceived cancer risk. We found that more than 30% of patients had a mother with breast cancer did not think that they were high risk. Moreover, more than 30% of patients deemed high risk were never offered genetic screening or testing from a health care professional. This is an issue I have witnessed in my practice.

I recently saw a 36-year-old patient with colon cancer. The father of my patient had kidney cancer and the grandmother had uterine cancer, both at young ages. No one had discussed the possibility of a hereditary cancer syndrome with this patient.

Montefiore Einstein genetic counselors and genetic physicians help our patients understand the advantages of genetic testing and the clinical actionability. We have found that this team approach works very well. We also encourage patients to inform their family members for their own well-being and future generations; however, we sometimes find they are not available or willing.

We conduct germline genetic testing as well as somatic testing. The outcomes of both tests affect clinical management and recruitment for clinical trials. Research is ongoing to analyze the correlation of somatic testing with germline genetic testing.

We have a long way to go to educate our community, including patients and health care professionals, on the value of genetic consultation and testing when there is any family history of cancer.

The research we conduct where we practice in the Bronx and Westchester, New York, is critical for advancing literature and clinical practice because our population is incredibly diverse. Many people in our population are hesitant to undergo genetic testing as there is an underlying distrust likely stemming from historical events, which is why it is important for members of the medical community to advocate on behalf of their patients. Ongoing research regarding quality improvement initiatives for screening and prevention as well as adherence to guideline’s recommended preventive care will help address these issues.

When Einstein clinicians went door-to-door testing for Tay-Sachs disease in the 1970s, they used the adage “knowledge is power.” We use that same adage today and hope that our cancer genetic testing helps save lives.

Susan D. Klugman, MD, FACOG, FACMG, is program director of Medical Genetics and Genomics, director of Reproductive and Medical Genetics, and professor of obstetrics and gynecology, women's health, and pediatrics at Montefiore Health System & Albert Einstein College of Medicine in Bronx, New York. She is also president of the American College of Medical Genetics and Genomics. 

Somasundaram K. BRCA1 and BRCA1 genes and inherited breast and/or ovarian cancer: benefits of genetic testing. 

. 2010;1(3):245-249. doi:10.1007/s13193-011-0049-7

NCCN. Clinical Practice Guidelines in Oncology. Genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 2.2024. Accessed November 9, 2023. https://www.nccn.org/ professionals/physician_gls/pdf/genetics_bop.pdf

Anand P, Kunnumakkara AB, Sundaram C, et al. Cancer is a preventable disease that requires major lifestyle changes. 

. 2008;25(9):2097-2116. doi:10.1007/s11095-008-9661-9

Goel S, Negassa A, Khot A, et al. Comparative effectiveness research: the impact of biologic agents in ethnic minorities with metastatic colorectal cancer. 

. 2017;16(4):286-292. doi:10.1016/j.clcc.2017.03.004

Schneider A, Nakagawa S, Keep R, et al. Population-based Tay-Sachs screening among Ashkenazi Jewish young adults in the 21st century: hexosaminidase A enzyme assay is essential for accurate testing. 

. 2009;149A(11):2444-2447. doi:10.1002/ajmg.a.33085

King MC, Marks JH, Mandell JB; New York Breast Cancer Study Group. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. 

. 2003;302(5645):643-646. doi:10.1126/science.1088759

. May 14, 2013. Accessed November 9, 2023. https://www.nytimes.com/2013/05/14/opinion/my-medical-choice.html 

Wiesman C, Rose E, Grant A, Zimilover A, Klugman S, Schreiber-Agus N. Experiences from a pilot program bringing BRCA1/2 genetic screening to the US Ashkenazi Jewish population. 

. 2017;19(5):529-536. doi:10.1038/gim.2016.154

Genetic screening and testing have only recently become an integral part of cancer care.

The Role of Genetics in Cancer Care Continues to Expand

As novel drugs targeting the Aurora A kinase (AURKA) pathway continue to advance through the development pipeline, the AURKA inhibitor alisertib (MLN8237) has emerged as an agent of particular note, demonstrating early signals of efficacy with a manageable safety profile for the treatment of patients with locally advanced or metastatic breast cancer whose disease is resistant to endocrine therapies.

“Patients with estrogen receptor [ER]-positive metastatic breast cancer will inevitably develop resistance to first-line endocrine therapies, and AURKA upregulation is one of the mechanisms of acquired resistance to CDK4/6 inhibitors,” Karthik V. Giridhar, MD, an oncologist specializing in breast cancer at Mayo Clinic in Rochester, Minnesota, said in an interview with 

®. “We truly need drugs to help target this pathway in the clinic.”

“[The] AURKA pathway is a novel pathway that has been understudied in breast cancer,” Tufia C. Haddad, MD, said in an interview with 

. “[Alisertib has] shown very significant clinical activity in a clinical setting for which we have no standard-of-care [SOC] therapies at the present time, which is after progression on a CDK4/6 inhibitor and endocrine therapy.”

Haddad, an associate professor of oncology at Mayo Clinic College of Medicine and Science, chair of practice innovation and platform at Mayo Clinic Comprehensive Cancer Center, and medical director of Care at Home in the Center for Digital Health, explained that alisertib was initially developed as an antimitotic agent to inhibit the cell cycle. Therefore, the agent has chemotherapy-like properties and inhibits the cell cycle through a targeted approach for a specific mitotic kinase.

The Aurora kinases—A, B, and C— are isoform serine/threonine kinases that regulate mitosis and meiosis.

 AURKA is located within the region of chromosome 20q13.2, and Aurora B kinase is in the region of chromosome 17p13.3 Additionally, AURKA is highly expressed in small cell lung cancer (SCLC).

Activation of AURKA is associated with downregulation of ERα expression, endocrine resistance, and it is implicated in CDK4/6 inhibitor resistance. Preclinical metastatic breast cancer models have shown that alisertib upregulates ERα and restores endocrine sensitivity.

“Alisertib targeting this novel AURKA pathway is a potential unmet need that could be fulfilled,” Haddad said. “One step beyond that [is] because alisertib is targeting these cells that have stem cell–like properties, by eradicating the stem cells there could potentially be better therapeutic activity with alisertib relative to drugs that target other pathways of endocrine resistance. Some of that head-to-head evaluation certainly needs to occur both preclinically and clinically before we can draw any conclusions on that, but we’re excited about that potential.”

Haddad and Giridhar detailed findings from Mayo Clinic Comprehensive Cancer Center colleague Antonio D’Assoro, MD, PhD, who is an assistant professor of biochemistry and molecular biology and an associate professor of pharmacology.

“My preclinical collaborator in the laboratory, Dr Antonio D’Assoro discovered a novel nonmitotic action and role for AURKA,” Haddad said. “He showed in the laboratory that when AURKA is activated it stimulates the epithelial-mesenchymal transition [EMT] in breast cancer cells. Specifically, when you take luminal ER-positive breast cancer cells that are sensitive to endocrine therapy when AURKA is activated in this setting, these cells undergo EMT reprogramming, and the clonal propagation of these cells that have stem cell–like features—so they’re more basal, lose their ER expression, become resistant to endocrine therapy, and have enhanced metastatic potential. Alisertib aims to block AURKA potentially in both its mitotic properties as well as these nonmitotic properties with that activation of EMT reprogramming.”

Giridhar added, “Dr D’Assoro helped identify that treatment with the AURKA inhibitor alisertib helped to restore that epithelial phenotype and potentially resensitize the endocrine therapy. That background helped set the stage for the phase 2 TBCRC041 study [NCT02860000] study.”

Alisertib Demonstrates Efficacy in Advanced Breast Cancer

The TBCRC041 trial evaluated alisertib as monotherapy and in combination with fulvestrant (Faslodex) in patients with locally advanced or metastatic breast cancer resistant to endocrine therapies. Findings from the trial revealed that the AURKA inhibitor had a manageable safety profile and displayed promising clinical activity as monotherapy. However, treatment with the doublet did not increase objective response rates (ORRs) or progression-free survival (PFS) compared with alisertib alone. Haddad noted that the rationale for combining the agents was to restore sensitivity; alisertibwould restore the sensitivity to endocrine therapy, and then fulvestrant could be added to treatment.

“All patients who participated in this clinical trial had advanced metastatic breast cancer that, even though it was ER-positive, had become resistant to endocrine therapy; all received prior fulvestrant and their tumors had become resistant to fulvestrant; and all received CDK4/6 inhibitors because that had become the SOC during this the course of this clinical trial,” Haddad, who was also the study’s lead author, explained. “Additionally, 58.2% of patients had received prior chemotherapy as well. These were patients who had seen a lot of prior therapies.”

The ORR for patients in the monotherapy arm (n = 46) was 19.6% (90% CI, 10.6%-31.7%), comprised of all partial responses (PRs), compared with 20.0% (90% CI, 10.9%- 32.3%) for patients treated with alisertib plus fulvestrant (n = 45), which included 1 complete response and 8 PRs.

The median duration of response (DOR) was 15.1 months in the monotherapy arm, and the 24-week clinical benefit rate (CBR) was 41.3% (90% CI, 29.0%-54.5%). The estimated median PFS was 5.6 months (95% CI, 3.9-10.0), and the 1-year overall survival (OS) rate was 75.1% (95% CI, 63.4%-89.0%). Patients in the combination arm experienced a median DOR of 8.5 months, a 24-week CBR of 28.9% (90% CI, 18.0%-42.0%), an estimated median PFS of 5.4 months (95% CI, 3.9-7.8), and a 1-year OS rate of 62.7% (95% CI, 49.7%-79.0%).

“It is very encouraging that there was a sizeable proportion of patients who were durable responders,” Giridhar said.

Regarding safety, a single grade 5 respiratory failure event occurred in a patient receiving the doublet. The most common grade 2 treatment-related adverse effects (AEs) that occurred in the monotherapy and combination therapy arms were alopecia (41% and 40%, respectively), decreased white blood cell count (28% and 18%), fatigue (24% and 29%), anemia (22% and 22%), and decreased neutrophil count (15% and 13%). Decreased neutrophil count was the most common grade 3 (24% and 20%) and grade 4 event (17% and 22%), respectively. Additional grade 4 events in the monotherapy and combination therapy arms included decreased white blood cell count (4% and 9%) and decreased platelet count (2% and 2%); in the monotherapy arm anemia, febrile neutropenia, acute coronary syndrome, and thrombotic microangiopathic hemolysis occurred in 1 patient each.

Giridhar noted that “with the pulse dosing [in this study] we saw fewer issues with mucositis and some of the hematologic toxicities than we [have] seen with the continuous dosing schedules. The pulse dosing schedule was very well tolerated. Alisertib was given on days 1 to 3, 8 to 10, and 15 to 17 on a 28-day cycle. Otherwise, there is a continuous weekly schedule [that has been used in other studies with alisertib] with 1 week on, 2 weeks off—you have to give a couple of weeks off due to the hematologic AEs.”

“The drug was well tolerated,” Haddad added. “Approximately one-third of patients required a dose reduction, and [approximately] 10% of patients [in the monotherapy arm] stopped participation in the trial due to toxicities as opposed to progression of their cancer. We saw a favorable safety profile.”

Findings from a phase 1/2 study (NCT01045421) that examined alisertib monotherapy showed that among evaluable patients with breast cancer (n = 49), SCLC (n = 48), non­–small cell lung cancer (n = 23), head and neck squamous cell carcinoma (n = 45), and gastroesophageal adenocarcinoma (n = 47), ORRs were 18% (95% CI, 9%-32%), 21% (95% CI, 10%-35%), 4% (95% CI, 0%-22%), 9% (95% CI, 2%-21%), and 9% (95% CI, 2%-20%), respectively. Alisertib 50 mg was given twice daily for 7 days in 21-day cycles. The most common any-grade AEs in the overall population (n = 249) were fatigue (42%), alopecia (39%), diarrhea (35%), nausea (31%), and anemia (27%). The most prevalent grade 3/4 events were neutropenia (44%), leukopenia (22%), and anemia (16%).

“This pathway is also being evaluated in triple-negative breast cancer,” Haddad said. “We’re just scratching the surface for how alisertib can have activity not just in endocrine-resistant breast cancer, but also across other molecular subtypes.”

Further, data presented at the 2023 American Society of Clinical Oncology Annual Meeting regarding the selective, reversible, small molecule AURKA inhibitor VIC-1911 revealed that the agent demonstrated preclinical activity as monotherapy and as combination therapy with the 

 Investigators concluded that the preclinical findings supported further evaluation of the agent plus sotorasib in treatment-naive 

 G12C-mutated NSCLC; however, a phase 1a/1b study (NCT05374538) evaluating the combination therapy in patients with locally advanced or metastatic 

 G12C-mutated NSCLC was terminated, cited as sponsor decision.

“Some of the additional work that is ongoing is looking at other approaches with different endocrine agents,” Haddad noted. “Also, now that we have the emergence of the oral selective estrogen receptor degraders, [we are] looking at other endocrine therapy backbones for alisertib combinations to see if we can improve upon some of the initial results we’ve seen thus far.”

Further combinations are under consideration as a study published in 

 revealed that the combination of alisertib and the kinase inhibitor sorafenib (Nexavar) may be a promising treatment for patients with aggressive thyroid carcinoma. A synergistic effect between alisertib and sorafenib in anaplastic thyroid carcinoma and differentiated thyroid cancer was confirmed in xenograft models and in vitro.

In September 2023, alisertib was granted orphan drug designation by the FDA for the treatment of patients with extensive-stage SCLC based on data from the phase 1/2 alisertib monotherapy study of patients with advanced solid tumors.

Additionally, the phase 2 PUMA-ALI-4201 trial (NCT06095505) is planning to evaluate alisertib monotherapy at the 50-mg dose in patients with extensive-stage SCLC. The study will enroll patients who experienced disease progression following first-line platinum-based chemotherapy and immunotherapy.

“Some of the immediate next steps will be focusing on optimization of the dose and schedule of the drug so that we can optimize its efficacy and minimize the toxicities. [We are] focusing initially on optimization of dose and schedule, in anticipation of moving the drug forward for additional efficacy [evaluation], clinical trials, and [evaluation] against some of our current SOC therapies,” Haddad said.

Additionally, Giridhar highlighted that correlative analyses will take place following the TBCRC041 study. “On TBCRC041 there are some robust correlatives. Patient blood samples and patient tissue metastatic biopsies were collected at multiple time points. Right now, we’re delving into these correlatives, and we are keen on better understanding the biology that is associated with those prolonged responders. We have multiple patient-derived xenograft models that were generated from patients [who] were both sensitive to alisertib and who had intrinsic resistance and acquired resistance to alisertib. There’s going to be a lot of science that comes out of this phase 2 study to help better understand and characterize both the molecular biology and the treatment patterns associated with alisertib response,” Giridhar said.

Haddad TC, Suman VJ, D’Assoro AB, et al. Evaluation of alisertib alone or combined with fulvestrant in patients with endocrine-resistant advanced breast cancer: the phase 2 TBCRC041 randomized clinical trial. 

. 2023;9(6):815-824. doi:10.1001/jamaoncol.2022.7949

Kovacs AH, Zhao D, Hou J. Aurora B inhibitors as cancer therapeutics. 

. 2023;28(8):3385. doi:10.3390/molecules28083385

Bisht P, Jaswal S, Gupta GD, Verma SK. A comprehension on synthetic strategies of Aurora kinase A and B inhibitors. 

. 2023;1278:134935. doi:10.1016/j.molstruc.2023.134935

Canova S, Trevisan B, Abbate MI, et al. Novel therapeutic options for small cell lung cancer. 

. 2023;25(11):1277-1294. doi:10.1007/s11912-023-01465-7

Khalafi S, Lockhart AC, Livingstone AS, El-Rifai W. Targeted molecular therapies in the treatment of esophageal adenocarcinoma, are we there yet? 

. 2020;12(11):3077. doi:10.3390/cancers12113077

Melichar B, Adenis A, Lockhart AC, et al. Safety and activity of alisertib, an investigational aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gastro-oesophageal adenocarcinoma: a five-arm phase 2 study. 

. 2015;16(4):395-405. doi:10.1016/S1470-2045(15)70051-3

Goldberg SB, Punekar SR, Velcheti V, et al. A phase 1a/1b study of aurora kinase A inhibitor VIC-1911 as monotherapy and in combination with sotorasib for the treatment of 

 G12C-mutant non–small-cell lung cancer. 

. 2023;41(suppl 16):TPS9140. doi:10.1200/JCO.2023.41.16_suppl.TPS9140

VIC-1911 monotherapy in combination with sotorasib for the treatment of KRAS G12C-mutant non-small cell lung cancer. ClinicalTrials.gov. Updated September 28, 2023. Accessed December 7, 2023. bit.ly/46XTsYm

Jingtai Z, Linfei H, Yuyang Q, et al. Targeting Aurora-A inhibits tumor progression and sensitizes thyroid carcinoma to sorafenib by decreasing PFKFB3-mediated glycolysis. 

. 2023;14(3):224. doi:10.1038/s41419-023-05709-z

Puma Biotechnology receives FDA orphan drug designation for alisertib for the treatment of small cell lung cancer. News release. Puma Biotechnology. September 21, 2023. Accessed December 7, 2023. bit.ly/3R8SZfX

A study of alisertib in patients with extensive stage small cell lung cancer. ClinicalTrials.gov. Updated October 23, 2023. Accessed December 7, 2023. bit.ly/3Tfs3xI

As novel drugs targeting the AURKA pathway continue to advance through the development pipeline, alisertib has emerged as an agent of particular note.

AURKA Pathway Gains Ground as Targetable Option in Metastatic Breast Cancer

As targeted therapies in colorectal, gastroesophageal, biliary tract, and other gastrointestinal (GI) cancers continue to gain traction, and as additional therapeutic targets for novel agents emerge, consistently testing for biomarkers will be key to identifying more targetable alterations for novel therapeutics and determining which patients will benefit most from these therapies, according to E. Gabriela Chiorean, MD.

With the November 16, 2023, FDA approval of pembrolizumab (Keytruda) plus fluoropyrimidine- and platinum-based chemotherapy for the first-line treatment of adult patients with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma,

 another immunotherapy option has joined nivolumab (Opdivo) in the treatment paradigm.

When considering how to best incorporate recently approved agents into care, Chiorean explained that pembrolizumab plus fluoropyrimidine- and platinum-based chemotherapy adds to the immune checkpoint inhibitor data that investigators already have with nivolumab. The 2021 approval of nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy for patients with advanced or metastatic gastric cancer, GEJ cancer, and esophageal adenocarcinoma was supported by findings from the phase 3 CheckMate 649 study (NCT02872116). Patients with a combined positive score (CPS) of at least 5 who received the combination experienced a statistically significant improvement vs chemotherapy alone in progression-free survival (HR, 0.68; 95% CI, 0.58-0.79; 

 < .0001) and overall survival (OS; HR 0.71; 95% CI, 0.61-0.83; 

 < .0001). Irrespective of CPS score, all patients receiving the combination achieved a statistically significant improvement vs chemotherapy alone in OS (HR, 0.80; 95% CI, 0.71-0.90; 

“Nivolumab has been approved [by the FDA] for patients with HER2-negative gastroesophageal cancer [and it’s] mostly used for patients with [a] CPS of more than 5,” Chiorean said in an interview with 

. Chiorean is a full professor of medicine at the University of Washington, clinical director of the GI Medical Oncology Program at Fred Hutchinson Cancer Center, and director of the Clinical Research GI Oncology Program at the University of Washington/Fred Hutchinson Cancer Center in Seattle.

“Pembrolizumab has been approved irrespective of CPS, but we are very aware that the benefit is mostly for patients with a CPS higher than 1 or even higher than 10,” she explained. “Immunotherapies for advanced gastroesophageal cancers do apply for those with positive PD-L1 expression, whether it’s a CPS score more than 1, more than 5, or more than 10, depending on what immune checkpoint inhibitors we use.”

Looking Beyond DNA Testing To Find Alterations

As gene alterations become more prevalent therapeutic targets, DNA and RNA testing is of the upmost importance. Findings from a diagnostic study published in 

 examining paired DNA and RNA sequencing of 43,524 individuals who underwent germline testing for hereditary cancer revealed that RNA evidence was necessary for the classification of 17.1% of pathogenic or likely pathogenic splicing variants. Additionally, 71.1% of existing splicing variants of uncertain significance were resolved by evidence from RNA tests. Investigators concluded that concurrent RNA and DNA sequencing improves detection of novel variants and classification of existing ones.

“It’s exciting to apply these new therapeutics based on the targeted alterations that we find—we just have to test everybody,” Chiorean said. “We also have to be very careful to include both DNA testing as well as RNA testing because we may miss certain genetic alterations if we exclusively use DNA tests. There are RNA-based tests that can be more effective in finding genetic fusions, such as 

 fusions. These fusions are important because now we have agents targeting them.”

Pralsetinib (Gavreto) and selpercatinib (Retevmo) are both targeted agents included in the National Comprehensive Cancer Network guidelines for the treatment of patients with unresectable and metastatic biliary tract cancers with 

 Additionally, selpercatinib holds an indication for patients with locally advanced or metastatic solid tumors with 

 fusions who have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.

“We need to make sure we test [for] everything—microsatellite instability [MSI] status, tumor mutational burden, DNA, and RNA—in order to discover all the possible targetable alterations of our patients, because there are more and more treatments available, both in clinical trials and with FDA approvals.... Every tumor needs to be sequenced and when it’s not available we need to test [for] these molecular abnormalities with liquid biopsies [and] with circulating tumor [ct]DNA,” Chiorean said.

Approximately 50% of patients with colorectal cancer (CRC) will develop colorectal liver metastases––clinically heterogeneous lesions associated with poor prognosis.

In a retrospective study conducted in China that examined the genomic alterations of CRC liver metastases in 144 patients using next-generation sequencing, investigators found that the most prevalent alterations were 

“We know that certain cancers are more likely to shed ctDNA in the blood—pancreatic cancer tends to be a cancer [that is] less positive [for] ctDNA, but in CRCs, especially in those with liver metastases, liquid biopsies are very useful,” Chiorean said.

“Moreover, we are trying to conduct more tests regarding how we can declare whether the patient is immune competent vs not. How do we determine the immune microenvironment that could be more amenable to be targeted with immunotherapies or not?” Chiorean asked. “These are very new biomarkers, which are not genetic based; they are more [representative of] a profile having to do with a tumor microenvironment and the host that the patient represents. We are doing a lot of research in this arena in terms of finding new markers for immune therapeutics [and] for stroma-targeted therapies.”

In addition to the GI biomarkers of HER2 overexpression, MSI-high status, and PD-L1 expression, emerging biomarkers include CLDN18.2, which is present in approximately 30% of gastric/GEJ cancers, and FGFR2, which is rarer and reported in approximately less than 10% of gastric cancers.

In July 2023, the FDA granted priority review to the biologics license application seeking the approval of the first-in-class monoclonal antibody zolbetuximab for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma and CLDN18.2-positive tumors.

Additionally, in April 2021, the novel FGFR2 inhibitor bemarituzumab plus modified fluoropyrimidine, leucovorin, and oxaliplatin (mFOLFOX6) received breakthrough therapy designation from the FDA for the frontline treatment of patients with 

-overexpressing, HER2-negative metastatic and locally advanced gastric and GEJ adenocarcinoma following positive results from the phase 2 FIGHT study (NCT03694522).

 Bemarituzumab is currently under investigation with mFOLFOX6 in the phase 3 FORTITUDE-101 trial (NCT05052801) and with mFOLFOX6 and nivolumab in the phase 3 FORTITUDE-102 trial (NCT05111626).

“In addition, because [we can make] adoptive immunotherapies more active and reactive against the patient’s cancer using the patient’s human leukocyte antigen [HLA] testing, HLA testing is becoming more important. Knowing the proteins that present an antigen to the immune system such that patients may become able to participate in adoptive immunotherapy trials [is important]. Biomarkers are being extended beyond next-generation sequencing,” Chiorean noted.

Chiorean noted that upcoming presentations at the 

 School of Gastrointestinal Oncology® (SOGO®), which is scheduled to take place on February 24, 2024, in Los Angeles, California, will address these novel treatment options in addition to “various aspects of multidisciplinary care, ranging from the nonoperative or operative management of stage IV CRC to using targeted [therapy] and/or immunotherapy in early-stage gastroesophageal as well as hepatobiliary cancers. [The treatment of patients with] hepatobiliary cancers is typically very multidisciplinary because it involves surgery, interventional radiology, radiation oncology, and medical oncology.”

The American Cancer Society listed 11 regimens used to treat stage IV colon cancer in August 2023, noting that these were only “some of the most commonly used regimens.” Radiation and surgery were also cited as options in certain cases.

“A lot of debate exists in terms of managing stage IV CRC that has been resected, oligometastatic disease that has been resected, [and] the role of ctDNA. These sessions will be of huge interest [at SOGO 2024] in order to understand the players that have to be engaged in making treatment decisions for our patients,” Chiorean said.

At SOGO 2024, sessions will include “The Role of ctDNA in Colon Tumor Management” presented by Sidharth R. Anand, MD, MBA, who is a medical oncologist and hematologist at UCLA Health in Los Angeles, California, and “Management of Stage IV no evidence of disease [NED] CRC” presented by Marwan G. Fakih, MD, who is a medical oncologist, professor in the Department of Medical Oncology & Therapeutics Research, associate director for Clinical Sciences, medical director of the Briskin Center for Clinical Research, division chief of GI Medical Oncology, and co-director of the Gastrointestinal Cancer Program, all at City of Hope in Duarte, California.

“[We] are looking at the RAS inhibitors, pan-RAS inhibitors, [and] KRAS G12C inhibitors, both as monotherapy as well as in combination therapies,” Chiorean noted. “Certainly, we’re also looking at cancer vaccines [and] at oncolytic viruses. These are very exciting agents that may [become a part of] combination therapeutics with immune checkpoint inhibitors or even chemotherapies. Indeed, there are several classes of agents, both targeted as well as immune-based therapies, that are very exciting and I look forward to 2024 [to see] more, hopefully positive results.”

FDA approves pembrolizumab with chemotherapy for HER2-negative gastric or gastroesophageal junction adenocarcinoma. FDA. November 16, 2023. Accessed November 30, 2023. bit.ly/46FhSpl

FDA approves nivolumab in combination with chemotherapy for metastatic gastric cancer and esophageal adenocarcinoma. FDA. April 16, 2021. Accessed November 30, 2023. bit.ly/482TDSQ

Horton C, Hoang L, Zimmermann H, et al. Diagnostic outcomes of concurrent DNA and RNA sequencing in individuals undergoing hereditary cancer testing. 

. Published online November 4, 2023. doi:10.1001/jamaoncol.2023.5586

NCCN. Clinical Practice Guidelines in Oncology. Biliary tract cancers, version 3.2023. Accessed November 30, 2019. bit.ly/3RjK2Sa

NCCN. Clinical Practice Guidelines in Oncology. Colon cancer, version 4.2023. Accessed November 30, 2019. bit.ly/3N5l4Ud

Tsilimigras DI, Ntanasis-Stathopoulos I, Pawlik TM. Liquid biopsies in colorectal liver metastases: towards the era of precision oncologic surgery. 

. 2022;14(17):4237. doi:10.3390/cancers14174237

Bao X, Wang K, Liu M, et al. Characterization of genomic alterations in colorectal liver metastasis and their prognostic value. 

. 2022;9:760618. doi:10.3389/fcell.2021.760618

Sato Y, Okamoto K, Kawano Y, et al. Novel biomarkers of gastric cancer: current research and future perspectives. 

. 2023;12(14):4646. doi:10.3390/jcm12144646

Astellas announces US FDA grants priority review for zolbetuximab biologics license application. News release. Astellas Pharma Inc. July 6, 2023. Accessed November 30, 2023. bit.ly/3Rmo7d2

Amgen’s investigational targeted treatment bemarituzumab granted breakthrough therapy designation. News release. Amgen. April 19, 2021. Accessed December 6, 2023. bit.ly/3nbaEnW

Treatment of colon cancer, by stage. American Cancer Society. Updated August 8, 2023. Accessed November 30, 2023. bit.ly/48f6yl5

The article discusses the importance of biomarker testing in the treatment of gastrointestinal (GI) cancers, particularly with the advent of targeted therapies. It highlights the recent FDA approval of pembrolizumab and nivolumab for the treatment of certain GI cancers, and the need for DNA and RNA testing to identify genetic alterations for targeted therapeutics. The article also discusses the potential of new biomarkers and the importance of comprehensive testing to identify all possible targetable alterations.

E. Gabriela Chiorean, MD, highlights the importance of consistently testing for biomarkers with RNA-based tests in addition to DNA-based tests.

Discovering Fusions Requires More Than DNA Testing in GI Cancers 

Few would disagree with the statement that we live in complex times. Although there is no intent here to further discuss the continuing effect of the COVID-19 pandemic, the scientifically undeniable current and future effects of climate change, or the ever-expanding misinformation regularly reaching all members of our society through interactions with social media platforms, it would be an error of great consequence to ignore these factors in the future. Finally, although it is difficult to assign any one cause to disturbing results of population-based public health outcomes, the trends must be considered worrisome.

Consider, for example, a 2023 report from the National Vital Statistics System that in 2021 maternal mortality in the United States (32.9 deaths per 100,000 births) was at its highest level in more than 50 years. The US topped the list for risk of such deaths, higher than any other “high-income country.”

 In addition, recent CDC data revealed a 3% increase in infant mortality from 2021 to 2022, the first such increase in decades.

Also, consider the recent report from the CDC that noted that “exemptions” from the requirement to receive essential childhood vaccinations increased in 40 states for the 2022-2023 school year compared with the previous reporting period. In addition, 10 states permit an exemption for at least 1 vaccine in more than 5% of kindergarten students.

 Although the overall national rate of vaccination in this critical age group (nearly 93%) remains high, it is the trend that is concerning.

With this in mind, this commentary focuses on the role the scientific and public health communities must play in this evolving societal environment, specifically in the cancer arena.

It is difficult to overstate the relevance of the degree of trust the public has for national and local public health representatives in ensuring critical health-related messages will be heard, understood, and appropriately acted upon. Unfortunately, our society is at a critical juncture where this expertise and leadership are both regularly and often vigorously challenged.

Of course, factors outside the direct control of the scientific and public health communities have contributed to the current state of affairs, including the effect of pandemic-related continually evolving events as well as national/local decisions with major economic and societal consequences (school and business closures, mask mandates). In addition, the rapid expansion and ease of use of a variety of artificial intelligence programs have made it much easier for a limited number of individuals or groups who desire to spread health-related misinformation to succeed.

However, it must also be acknowledged that the current source of tension between a substantial segment of society (including many local and national elected officials) and the scientific and public health communities is the result of specific actions that have only served to heighten the disagreements. For example, meaningful questions have been raised regarding the effectiveness of continued mandates for COVID-19 vaccination on public or even individual health.

 Equally relevant issues are events that simply challenge and raise questions within the public’s mind for the basic integrity of the scientific process, including claims of objectivity for the often vigorously lauded peer-reviewed process. The newsworthy retractions of high-profile publications, as well as reports highlighting the increasing overall number of withdrawn papers, can only increase the public’s concern for the validity of scientific claims.

Further, it is relevant to note the historically opaque scientific literature and the rather rigid approach to defining the quality of evidence. As a result of greater public access to this literature, less-than-optimal or poorly considered scientific communication and commentary can lead to the rapid spread on a variety of social media platforms of misleading interpretations of what has been stated in even high-impact peer-reviewed publications.

Consider a report published recently in the highly regarded 

 that examined evidence supporting the clinical utility of mask mandates.

 When reaching their conclusions regarding the overall impact, the authors found very limited randomized trial data that documented the benefit of this public health strategy, and they chose to ignore other evidence that solidly supported this strategy.

As noted by Naomi Oreskes, PhD, the Henry Charles Lea Professor of the History of Science at Harvard University in Boston, Massachusetts, in her blistering commentary on the topic, “Cochrane ignored this epidemiological evidence because it didn’t meet its rigid standard. I have called this approach ‘methodological fetishism,” when scientists fixate on a preferred methodology and dismiss studies that don’t follow it. Sadly, it’s not unique to Cochrane. By dogmatically insisting on a particular definition of rigor, scientists in the past have landed on wrong answers more than once.”

Tremendous success has been documented in our efforts to improve cancer outcomes, notably a recently reported 33% reduction in cancer related death rates in the United States since 1991, which translates into an estimated 3.8 million deaths averted.

 Despite this widely acknowledged impressive past success, the issue being raised in this commentary is for the future of cancer care, early detection, and critically important prevention.

 editorial related to the future of artificial intelligence in health care noted the “total administrative spending in the US is estimated to be up to 1 trillion dollars a year, more than the spending for the entire health care systems in Germany, France, and Italy combined.”

 Add to this profound dysfunction and enormous financial strain on the US, the rapidly rising costs of new antineoplastic agents, as well as the impact of an aging population with an anticipated higher cancer incidence, and it is not difficult to conclude our society must somehow discover alternative approaches to influence malignancy-associated outcomes.

Effective communication to the public regarding the known benefits of well-established screening strategies and other approaches to prevent or reduce the risk of cancer or its recurrence, such as smoking cessation, human papillomavirus vaccination, or even regular exercise, may offer the realistic potential to produce a highly cost-effective impact on both cancer incidence and outcomes.

But in the face of the tsunami of misinformation as well as the current state of trust of the scientific and public health communities, is the public going to listen to what they have to say?

And what might be done to favorably change the situation?

Declercq E, Thoma M. Measuring US maternal mortality. 

Maurie Markman, MD, details how public trust is critical in the future of cancer care, diving into what leads to mistrust and misinformation today. 

Vol. 25/No. 1 | Oncology Live®

Tampa General Hospital Cancer Institute Celebrates 2 Years of Growth and Innovation

The Role of Genetics in Cancer Care Continues to Expand

AURKA Pathway Gains Ground as Targetable Option in Metastatic Breast Cancer

Discovering Fusions Requires More Than DNA Testing in GI Cancers

Public Trust in Science and the Future of Cancer Care Is Crucial