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Although it has already distinguished itself by earning recognition as a National Cancer Institute (NCI)-designated center (a status it has held since 1996), the University of Hawaii Cancer Center hopes to further expand its impact and address unmet treatment needs for patients with cancer living in Hawaii and the surrounding areas, as well as those of Hawaiian descent living outside the islands, by providing access to phase 1 clinical trials with its planned Early Phase Clinical Research Center.

“We are able to conduct certain types of clinical trials, but these are dominantly NCI Community Oncology Research Program studies because we have health disparity issues and health care access issues,” Naoto T. Ueno, MD, PhD, FACP, director of the University of Hawaii Cancer Center and interim program coleader of the Cancer Biology Program, Translational and Clinical Research in Honolulu, said in an interview with 

. “There has not been much of a focus on phase 1 studies for several decades. Sometimes we do small phase 1 [studies], but not a lot.”

“The importance of a phase 1 center at the University of Hawaii Cancer Center is much greater than for any other cancer center in the United States. The cancer center relies on 5 different community centers to provide clinical trials support for patients [in] both industry- and NCI-supported trials. But all these community centers are independent of each other. How can you bring them together in a space where they will not be competitive? A Phase I center achieves this goal.

None of the community institutions have the capacity to have a true phase 1 center on their own,” David R. Gandara, MD, codirector of the Center for Experimental Therapeutics in Cancer at UC Davis Comprehensive Cancer Center in California, chief medical officer of the International Society of Liquid Biopsy, and adjunct clinical professor in the Translational and Clinical Research Program at the University of Hawaii Cancer Center, said in an interview with 

The plans for the Early Phase Clinical Research Center were first announced in September 2019, when the University of Hawai’i Cancer Center received a $6.5 million grant from the National Institutes of Health to “build a clinical research center that will significantly improve access to experimental treatments for patients [with cancer] in Hawaii.” This grant matched the $6.5 million approved by the Hawai’i state legislature for the project, bringing its total funding to $13 million.

The development of a program and recruitment of staff at the Early Phase Clinical Research Center will be a joint venture between the University of Hawaii Cancer Center and its partners in the Hawaii Cancer Consortium: Hawaii Pacific Health, Kuakini Medical Center, and the Queen’s Medical Center. The center is currently under construction in a shell space with a square footage of 36,000 at the University of Hawaii Cancer Center in the Kakaʻako district of Honolulu. The new facility will be named Hoʻōla, which means healing in Hawaiian.

Phase 1 trials examine cutting-edge therapeutics and offer an option for patients with hard-totreat diseases who have not experienced efficacy with standard therapies. The main goal of the Early Phase Clinical Research Center is to provide the access to these trials and treatments that Hawaiians have been lacking without the need to travel to the continental United States as they’ve had to do in the past, Ueno explained. This necessary travel often leads to hardship for patients and their families in terms of finances, separation from loved ones, and disconnects in care, Gandara added.

“I was diagnosed with lung cancer 2 years ago, I have been treated with osimertinib [Tagrisso], and it has worked properly,” Diane Chong, a patient with lung cancer receiving treatment in Honolulu, said in an interview with 

. “However, at some point, I probably am going to have to do a clinical trial, which would mean having to travel to the mainland at an additional expense and time commitment. To have [access to] clinical trials here in Hawaii would definitely help individuals that are on this journey of cancer and knowing that we can be near friends and relatives during treatment is extremely valuable. The bottom line is that traveling to the mainland is expensive and involves staying in a place that you’re not familiar with, which puts even more stress on the situation. Being at home with family and friends is a very valuable benefit.”

Recent research findings have underscored the improved efficacy and safety of modern agents being evaluated in phase 1 clinical trials compared with those of the past. In a retrospective study published in the 

, study authors analyzed patient-level data from NCI-sponsored, investigator-initiated phase 1 trials of patients with solid tumors from January 2000 to May 2019.

Results from the study showed that among response-evaluable patients (n = 9325), the overall response rate (ORR) for all trials during the study period was 12.2% (95% CI, 11.5%-12.8%), with a 2.7% (95% CI, 2.4%-3%) complete response (CR) rate. Notably, the ORR increased from 9.6% (95% CI, 8.7%-10.6%) in 2000 to 2005 to 18% (95% CI, 15.7%-20.5%) in 2013 to 2019 (

 < .0001); the CR rates increased from 2.5% (95% CI, 2.0%-3.0%) to 4.3% (95% CI, 3.2%-5.7%), respectively. Additionally, the improvement in efficacy came without a significant negative impact on tolerability; the risk of treatment-related death was found to not change over time from 2000 to 2019 (

Beyond its anticipated clinical impact, the University of Hawaii Cancer Center announced that the establishment of the Early Phase Clinical Research Center will provide a significant boost on the Hawaiian economy. According to an economic analysis, the project will have an economic impact of $38.5 million over the next 10 years, with an approximate ongoing annual contribution of $6 million subsequently. Additionally, its construction will generate more than 30 short-term construction jobs and more than 65 long-term jobs once the center is operational. The facility will also house an Organoid Generation Facility, which will generate tumor models that are more representative of the population in Hawaii.

As the only NCI-designated center within 2500 miles, the University of Hawaii Cancer Center is unique in that it serves a very large catchment area relative to other cancer centers, covering approximately 7 million square miles and approximately 2 million individuals. Outside of the Hawaiian Islands, the center serves individuals from United States–Affiliated Pacific Islands, such as American Samoa, Guam, Palau, and the Northern Mariana Islands.

Research has indicated that Native Hawaiian and Pacific Islander patients are severely underrepresented in early-phase clinical trials examining anticancer therapeutics. In a 2021 review published in 

, investigators set out to better define race and ethnic representation in phase 1 oncology trials. To do so, they performed a rapid evidence assessment of published literature between January and December 2019 that included demographic representation of individuals recruited for phase 1 clinical trials of oncology agents.

Findings from the study demonstrated that across all regions globally, Native Hawaiian and Pacific Islander participants represented just 0.1% of the total number of participants (n = 9972). Similarly, among patients (n = 3197) in United States–only trials, Native Hawaiian and Pacific Islander patients again comprised just 0.1% of the population. Study authors noted that “participation of Native Hawaiian/Pacific Islander and American Indian/Native Alaskan patients was extremely low.”

The increased representation of Native Hawaiian and Pacific Islander patients in phase 1 clinical trials that the Early Phase Cancer Center aims to achieve is crucial for not only giving care to the patients who need it in the immediate term but also for drug development, Ueno said.

“That’s why it’s important to create a phase 1 center in our area for [the] community [and why] the FDA considers it a very high priority area to develop a phase 1 center,” Ueno said. “Addressing diversity, equity, and inclusion is very important in drug development. Much of the development has been driven by studies of [White] patients, followed by Black and Hispanic [patients]. Native Hawaiian [and] Pacific Islander [patients] are not represented at all. We need to obtain data among this population; we are really the only area that could [do so] in a natural manner and enrich the population of Asian Americans, Native Hawaiians, and Pacific Islanders [in clinical trial data].”

According to Ueno, the goal is to have the Early Phase Clinical Research Center operational by the middle of 2025. Construction of the facilities is expected to be completed by the end of 2024, he said. “The ultimate goal is for our patients to stay [in Hawaii] and have a similar opportunity for quality care compared with the mainland,” he said. “[We also] want to address health disparity and drug interaction in our racially and ethnically diverse population, because there is a need for more personalized treatments. There are more Native Hawaiians living on the mainland than in Hawaii now; the impact could [also] be significant in the population on the mainland. It’s not only about Hawaii, but it will also help the entire population of the United States.”

University of Hawai’i Cancer Center. National Cancer Institute. Updated June 27, 2023. Accessed January 3, 2024. 

https://www.cancer.gov/research/infrastructure/cancer-centers/find/uhawaiicc

UH Cancer Center receives $6.5M for state’s first cutting edge research clinic. News release. University of Hawai’i. September 26, 2019. Accessed January 3, 2024. 

https://www.hawaii.edu/news/2019/09/26/cancer-center-cutting-edge-research-clinic/

Chihara D, Lin R, Flowers CR, et al. Early drug development in solid tumours: analysis of National Cancer Institute-sponsored phase 1 trials. 

. 2022;400(10351):512-521. doi:10.1016/S0140-6736(22)01390-3

University of Hawaiʻi Cancer Center project will diversify the Hawaiʻi economy. News release. University of Hawai’i Cancer Center. July 22, 2020. Accessed January 3, 2024. 

https://www.uhcancercenter.org/about-us/2020-news-articles/639-uh-cancer-center-project-will-diversify-the-hawaii-economy

Catchment area. University of Hawai’i Cancer Center. Accessed January 3, 2024. 

https://www.uhcancercenter.org/128-education-and-outreach-info/671-catchment-area

Camidge DR, Park H, Smoyer KE, et al. Race and ethnicity representation in clinical trials: findings from a literature review of phase I oncology trials. 

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Articles

The University of Hawaii Cancer Center hopes to address treatment needs through its planned Early Phase Clinical Research Center.

Early-Phase Clinical Research Center Poised to Provide New Benefits in Hawaii and Beyond

In the United States, lung and bronchus cancer is the third most common cancer and causes the most cancer-related deaths.

Despite advances in screening, early detection, and treatment, the national 5-year relative survival rate for patients with lung cancer remains only 25.4%.

However, in sharp contrast, the 5-year survival rate for patients with localized lung cancer is significantly higher at 62.8%. Additionally, 5-year relative survival rates are 34.8% for regional, 8.2% for distant, and 15.1% for unknown stages (

 Low-dose CT (LDCT) screening leads to detection of lung cancer at a much earlier stage, thereby improving survival.

 An example of this mortality benefit was seen in the 2011 National Lung Screening Trial results, in which LDCT lung cancer screening exhibited a 20% (95% CI, 6.8%-26.7%; 

 = .004) relative reduction in lung cancer mortality compared with single-view posteroanterior chest radiography.

 According to a meta-analysis that pooled results from 9 randomized controlled trials, LDCT improves detection of early-stage lung cancers and reduces lung cancer mortality when compared with usual care/no screening or chest radiography.

Following the terrorist attacks in New York, New York, on September 11, 2001, there was great concern that the tens of thousands of individuals who were in the World Trade Center (WTC) area would develop cancer as a result of their exposure to known and suspected carcinogens such as asbestos, silica, polycyclic aromatic hydrocarbons, polychlorinated biphenyls, and dioxins.

 Soon after September 11, David J. Prezant, MD, chief medical officer for the Office of Medical Affairs at the Fire Department of the City of New York (FDNY) and a professor in the Department of Medicine (Pulmonary Medicine) and Department of Epidemiology & Population Health at Montefiore Einstein in Bronx, New York, began LDCT lung cancer screening for FDNY rescue and recovery workers based on their daily occupational exposures and exposures to WTC dust and gases. Lung cancer screening was offered to all WTC-exposed FDNY members with any history of smoking and/or intense WTC exposure, regardless of age.

In an effort to provide the best targeted screening to the WTC-exposed responders, we were interested in evaluating the accuracy and efficiency in occupational cohorts of both risk factor–based guidelines and risk model–based strategies for LDCT lung cancer screening.

 We chose to evaluate the 2014 United States Preventive Services Task Force (USPSTF) guidelines (the current version at the time and the most accepted in the United States); the National Comprehensive Cancer Network group 2 (NCCN-2) guidelines (which include other risk factors such as occupational exposures); the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial model (PLCOm2012); and the Bach model.

 These model-based strategies were selected because they are well validated, and the Bach model includes occupational (asbestos) exposure.

Our study included 930 WTC-exposed FDNY rescue/ recovery workers who underwent a baseline CT scan and were eligible for 1 of 4 screening guidelines/ models.

 These findings, which were published in 

 in 2021, demonstrated that 63 WTC-exposed firefighters and emergency medical services providers were diagnosed with lung cancer. The median age at diagnosis was 65 years (IQR, 57-71). Among the lung cancer cases, 56 (89%) were non–small cell carcinoma, including adenocarcinomas (n = 43), squamous cell carcinomas (n = 11), and large cell carcinomas (n = 2); 3 (4.8%) were small cell carcinoma; and 4 (6.3%) were other histologies. Of the 63 patients diagnosed with lung cancer, 50 individuals had their disease detected via LDCT screening, with 13 patients diagnosed based on clinical reasons other than screening.

All the patients who underwent LDCT screening were identified by the NCCN-2 guidelines. The USPSTF guidelines identified 28 patients, the PLCOm2012 model identified 32 patients, and the Bach model identified 29 patients. As such, the sensitivity of the NCCN-2 guidelines (79%) was determined to be greater than the USPSTF guidelines (44%), the PLCOm2012 model (51%), and the Bach model (46%). When reviewing the stage of diagnosis of the 50 cancers detected by LDCT screening, we found that 52% of the cases identified by the NCCN-2 guidelines were localized disease (stage I/ II). In contrast, the USPSTF guidelines, PLCOm2012 model, and Bach model identified a slightly lower proportion of localized disease (43%, 41%, and 38%, respectively). False-positive findings (suspicious nodules requiring follow-up that were not diagnosed as lung cancer by end of study) ranged from 79.7% to 83.8% (259/309 cases with NCCN-2 guidelines, 110/138 cases with USPSTF guidelines, 129/161 cases with the PLCOm2012 model, and 115/144 cases with the Bach model). Only a few patients required invasive procedures that did not result in a lung cancer diagnosis, ranging from 5.9% to 7.4% (4/54 cases with NCCN-2 guidelines, 2/30 cases with USPSTF guidelines, 2/34 cases with the PLCOm2012 model, and 2/31 cases with the Bach model).

Based on these results, we concluded that compared with USPSTF guidelines, the PLCOm2012 model, and the Bach model, the NCCN-2 guidelines screened the largest number of people and demonstrated the highest sensitivity in detecting lung cancer but were also associated with the lowest specificity. Since the publication of our findings, the USPSTF updated its guidelines in 2020 by lowering the screening age from 55 years to 50 years and smoking history from at least 30 pack-years to at least 20 pack-years to match the NCCN-2 guidelines used in our study. When applied to this cohort exposed to occupational and environmental hazards, our findings are consistent with the 2020 USPSTF expanded screening guidelines.

Our study participants are unique in that their screening and subsequent treatments are covered at no cost under the US federal government’s WTC Health Program (WTCHP). Their free access to care along with screening at an earlier age prior to the 2020 USPSTF screening update likely contributed to improved survival.

In findings from a separate study published in the 

 in 2021, we observed a 26% reduction in the risk of death from lung cancer in WTC-exposed rescue/ recovery workers enrolled in the WTCHP compared with patients with cancer from the state of New York (relative rate, 0.74; 95% CI, 0.56-0.97).

 A similar benefit was not observed among WTC-exposed rescue/recovery workers who were not enrolled in the WTCHP and were thereby less likely to receive similar LDCT cancer screening.

Our study findings demonstrate that beginning lung cancer screening at the age of 50 years and in those with fewer pack-years likely contributes to improved survival after a lung cancer diagnosis.

Findings from this study also highlight the importance of obtaining a complete exposure history when caring for patients and the need to tailor cancer screening guidelines for individuals who have unique environmental factors and occupational exposures such as those experienced at the WTC site on September 11, 2001, and in the months that followed.

Rachel Zeig-Owens, DrPH, is research assistant professor in the Department of Epidemiology & Population Health at Albert Einstein College of Medicine in Bronx, New York; member of the Cancer Epidemiology, Prevention & Control Research Program at Montefiore Einstein Comprehensive Cancer Center in Bronx; and director of epidemiology for the World Trade Center Health Program at the Fire Department of the City of New York in New York.

Krystal L. Cleven, MD, MS, is assistant professor of medicine in the Division of Pulmonary Medicine at Montefiore Health System and Albert Einstein College of Medicine and codirector of Montefiore Asthma Center, all in Bronx, New York.

Cancer stat facts: common cancer sites. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Accessed January 10, 2024. https://seer.cancer.gov/statfacts/html/common.html 

Cancer stat facts: lung and bronchus cancer. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Accessed January 10, 2024. https://seer.cancer.gov/statfacts/html/lungb.html

Ettinger DS, Wood DE, Akerley W, et al. NCCN Guidelines insights: non-small cell lung cancer, version 4.2016. 

. 2016;14(3):255-264. doi:10.6004/jnccn.2016.0031

Aberle DR, Adams AM, Berg CD, et al; National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. 

. 2011;365(5):395-409. doi:10.1056/NEJMoa1102873

Huang KL, Wang SY, Lu WC, Chang YH, Su J, Lu YT. Effects of low-dose computed tomography on lung cancer screening: a systematic review, meta-analysis, and trial sequential analysis. 

 2019;19(1):126. doi:10.1186/s12890-019-0883-x

Lioy PJ, Weisel CP, Millette JR, et al. Characterization of the dust/smoke aerosol that settled east of the World Trade Center (WTC) in lower Manhattan after the collapse of the WTC 11 September 2001. 

. 2002;110(7):703-714. doi:10.1289/ehp.02110703

Landrigan PJ, Lioy PJ, Thurston G, et al; NIEHS World Trade Center Working Group. Health and environmental consequences of the world trade center disaster. 

. 2004;112(6):731-739. doi:10.1289/ehp.6702

Cleven KL, Vaeth B, Zeig-Owens R, et al. Performance of risk factor-based guidelines and model-based chest CT lung cancer screening in World Trade Center-exposed fire department rescue/recovery workers. 

. 2021;159(5):2060-2071. doi:10.1016/j.chest.2020.11.028

Gray EP, Teare MD, Stevens J, Archer R. Risk prediction models for lung cancer: a systematic review. 

. 2016;17(2):95-106. doi:10.1016/j.cllc.2015.11.007

Moyer VA; U.S. Preventive Services Task Force. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. 

. 2014;160(5):330-338. doi:10.7326/M13-2771

Wood DE, Kazerooni EA, Baum SL, et al. Lung cancer screening, version 3.2018, NCCN Clinical Practice Guidelines in Oncology. 

. 2018;16(4):412-441. doi:10.6004/jnccn.2018.0020

Tammemägi MC, Katki HA, Hocking WG, et al. Selection criteria for lung-cancer screening. 

 2013;368(8):728-736. doi:10.1056/NEJMoa1211776

Bach PB, Kattan MW, Thornquist MD, et al. Variations in lung cancer risk among smokers. 

. 2003;95(6):470-478. doi:10.1093/jnci/95.6.470

Goldfarb DG, Zeig-Owens R, Kristjansson D, et al. Cancer survival among World Trade Center rescue and recovery workers: a collaborative cohort study. 

. 2021;64(10):815-826. doi:10.1002/ajim.23278

Investigators evaluated risk factor–based guidelines and risk model–based strategies for lung cancer screening in World Trade Center–exposed responders. 

The Importance of Lung Cancer Screening in Individuals Exposed to the World Trade Center Disaster

Data revealing encouraging efficacy and a well-tolerated safety profile of the first-in-class inhibitor enasidenib (Idhifa) plus venetoclax (Venclexta) have generated excitement among investigators in targeting 

 mutations for patients with relapsed or refractory acute myeloid leukemia (AML).

“The treatment of patients with relapsed/refractory AML remains challenging. The combination of enasidenib and venetoclax represents a potential option for the group of patients with AML [and] 

 mutations,” Steven Chan, MD, PhD, senior scientist at Princess Margaret Cancer Centre in Toronto, Ontario, said in a statement to 

. “For those who are eligible for an allogeneic stem cell transplant, this treatment may be an effective and lower-intensity option to achieve a remission and bridge to transplant.”

Findings from the phase 1b/2 ENAVEN-AML study (NCT04092179) revealed that the overall response rate (ORR) was 70% for patients with 

-mutant AML treated with enasidenib and venetoclax (n = 23), which included a 57% complete response (CR) rate (

 The median duration of response was 16.6 months (95% CI, 5.0-not reached [NR]) and 6 patients remain on the study. Three patients proceeded to hematopoietic stem cell transplantation following CR.

 mutations are prevalent in approximately 8% to 12% of patients with AML and are more frequent in those with natural-killer AML, occurring at a rate of 19%.

 Research has not clearly shown what the impact of 

 mutations on outcomes is, although some findings have indicated there may be a favorable prognosis with 

 mutations in the setting of standard intensive chemotherapy.3

Enasidenib has held an FDA indication since August 2017 as monotherapy for the treatment of 

-mutant relapsed or refractory AML.4 National Comprehensive Cancer Network guidelines, which cite enasidenib as a treatment for patients with relapsed/refractory AML and an 

 mutation, note that venetoclax may also be used with hypomethylating agents (HMAs) or low-dose cytarabine; low-intensity therapy with HMAs is also recommended.

 However, ivosidenib (Tibsovo) is only recommended as an option for patients with 

 mutations, are present in most low-grade diffuse gliomas.

 The mutations result in overproduction of R-2-hydroxyglutarate, epigenetic dysregulation, impaired cellular differentiation, and an immunosuppressive tumor microenvironment.

In the open-label ENAVEN-AML study, response rates varied for patients with 

 R172 mutations (n = 12) compared with those with 

 R140 mutations (n = 11).1 Patients with 

 R172 mutations achieved an ORR of 83% comprised of a 67% CR rate, and those with 

 R140 mutations experienced an ORR of 55%, which included a 45% CR rate. Additional data revealed that the median overall survival (OS) was 9.4 months (95% CI, 8.2-NR) and the 18-month OS rate was 42% (95% CI, 27%-66%) among all patients with 

“In the ENAVEN trial, we found that the all-oral combination of enasidenib and venetoclax was associated with a high response rate in patients with relapsed/refractory 

-mutated AML, especially in those with a mutation at 

 R172,” Chan said. “The combination treatment was also well tolerated. Further studies comparing this combination regimen with other treatments in the frontline and relapsed/refractory settings are warranted.”

Following the phase 1b portion of the trial, the recommended phase 2 dose was determined to be 100 mg daily of enasidenib and 400 mg daily of venetoclax, each given on days 1 to 28 of every cycle.

“The drugs in this combination are administered orally and once a day,” Chan noted. “The ease of administration of this regimen is advantageous over other combinations that require subcutaneous or intravenous injections.”

In the safety population (n = 27), hematological treatment-emergent adverse effects (TEAEs) that occurred at grades 1 to 2 and grades 3 to 5 included thrombocytopenia (4% and 26%, respectively), anemia (4% and 19%), neutropenia (0% and 15%), and leukocytosis (0% and 8%). Grade 1 to 2 nonhematologic TEAEs included nausea (41%), diarrhea (37%), hyperbilirubinemia (33%), constipation (30%), liver function test abnormalities (26%), electrolyte or metabolic abnormalities (22%), pneumonia (19%), and intracranial bleeding (4%). Grade 3 to 5 TEAEs included neutropenic fever (41%), pneumonia (22%), hyperbilirubinemia (15%), electrolyte or metabolic abnormalities (11%), liver function test abnormalities (7%), and diarrhea (4%) (

Severe AEs occurred in 30% of patients and included infections or neutropenic fever (26%) and small bowel obstruction (4%). Dose interruptions (56%); dose modifications (15%); and treatment discontinuation (78%) due to allogeneic stem cell transplant (15%) and progressive disease, relapse, or death (63%) were also recorded. Investigators noted that there was no significant myelosuppression observed and the infection rate was as expected for relapsed or refractory AML.

“Overall, the safety profile of the combination regimen was similar to the ones associated with each drug alone. We did not observe any unexpected toxicities. Treatment with IDH inhibitors including enasidenib has been shown to cause differentiation syndrome. In our study cohort, differentiation syndrome was not observed. The addition of venetoclax to enasidenib may decrease the risk of developing this condition. However, a larger study is required to confirm this hypothesis,” Chan explained.

The oral inhibitor vorasidenib (AG-881), which was designed for brain penetrance, significantly improved PFS at a preplanned interim analysis of the global phase 3 INDIGO trial (NCT04164901) in patients with 

-mutated residual or recurrent grade 2 glioma, meeting the trial’s primary end point.

Patients who received the agent (n = 168) achieved a median PFS of 27.7 months (95% CI, 17.0-not estimable [NE]) vs 11.1 months (95% CI, 11.0-13.7) for patients who received placebo (n = 163; HR, 0.39; 95% CI, 0.27-0.56; 1-sided 

 = .000000067). All subgroups examined also experienced a benefit with vorasidenib.

Time to next intervention (TTNI) was also significantly improved with vorasidenib; the median TTNI was NR in the investigative arm vs 17.8 months (95% CI, 15.0-NE) in the placebo arm (HR, 0.26; 95% CI, 0.15-0.43; 1-sided 

 = .000000019); 24-month rates were 83.4% compared with 27.0%, respectively.

The agent received fast track designation from the FDA in March 2023.

 Safety data presented with the preplanned interim efficacy analysis at the 2023 American Society of Clinical Oncology Annual Meeting revealed low discontinuation rates due to TEAEs at rates of 3.6% for vorasidenib vs 1.2% for placebo; grade 3 or higher AEs occurred at rates of 22.8% vs 13.5%, respectively.

 Treatment interruption (29.9% vs 22.7%) and dose reduction (10.8% vs 3.1%) due to AEs occurred in the vorasidenib and placebo arms, respectively, as well; no fatal TEAEs were observed.

Investigations Underway in Relapsed/Refractory Disease

A phase 2 study (NCT03683433) at The University of Texas MD Anderson Cancer Center in Houston is enrolling patients with recurrent or refractory 

-mutated AML to receive enasidenib in combination with azacitidine (Vidaza).

 Additionally, another phase 2 clinical trial (NCT04203316) is enrolling patients at least 24 months old but younger than 21 years old with relapsed or refractory 

-mutated AML to receive enasidenib monotherapy.

Richard-Carpentier G, Gupta G, Cameron C, et al. Final results of the phase Ib/II study evaluating enasidenib in combination with venetoclax in patients with 

-mutated relapsed/refractory myeloid malignancies. 

. 2023;142(suppl 1):159. doi:10.1182/blood-2023-188341

NCCN. Clinical Practice Guidelines in Oncology. Acute myeloid leukemia, version 6.2023. Accessed January 15, 2024. bit.ly/47E6Zo9

Issa GC, DiNardo CD. Acute myeloid leukemia with 

. 2021;11(6):107. doi:10.1038/s41408-021-00497-1

FDA granted regular approval to enasidenib for the treatment of relapsed or refractory AML. FDA. August 1, 2017. Accessed January 15, 2024. bit.ly/3O3G2mM

Mellinghoff IK, Van Den Bent MJ, Blumenthal DT, et al. INDIGO: a global, randomized, double-blinded, phase 3 study of vorasidenib versus placebo in patients with residual or recurrent grade 2 glioma with an IDH1/2 mutation. 

. 2023;41(suppl 17):LBA1. doi:10.1200/JCO.2023.41.17_suppl.LBA1

Servier’s pivotal phase 3 INDIGO trial investigating vorasidenib in IDH-mutant low-grade glioma meets primary endpoint of progression-free survival (PFS) and key secondary endpoint of time to next intervention (TTNI). News release. Servier. March 14, 2023. Accessed January 15, 2024. https://prn.to/3U1mx25

Enasidenib and azacitidine in treating patients with recurrent or refractory acute myeloid leukemia and 

 gene mutation. ClinicalTrials.gov. Updated August 18, 2023. Accessed January 15, 2024. bit.ly/3SjdXKQ

Enasidenib for the treatment of relapsed or refractory acute myeloid leukemia patients with an IDH2 mutation. ClinicalTrials.gov. Updated December 11, 2023. Accessed January 15, 2024. bit.ly/3tXdmoL

The combination of the first-in-class inhibitor enasidenib plus venetoclax has generated excitement targeting IDH2 mutations in relapsed/refractory AML.

Enasidenib Plus Venetoclax Yields High Response Rates Targeting IDH2 Mutations in R/R AML 

As chimeric antigen receptor (CAR) T-cell therapies and off-the-shelf options with T-cell engagers continue to revolutionize the treatment paradigm in multiple myeloma, several recent regulatory approvals of T-cell engagers are providing more options for improved personalization. With targets such as BCL2 and FcRH5 having a role in determining therapeutic agents, Sagar Lonial, MD, FACP, detailed recent data on targeted agents, CAR T-cell therapies, and off-the shelf agents that may also shed light on how best to incorporate these agents into a potential new sequencing algorithm.

“Treating a patient [who experiences] late relapse is more complicated now than it was 3 years ago [because] we have more options targeting BCMA, options targeting GPRC5D, and [we are] getting comfortable with either referring patients for CAR T-cell [therapy] earlier or referring for T-cell engager therapy earlier,” Lonial said in an interview with 

. “[These] are things that need to be top of mind unless your practice can sustain giving patients T-cell engagers from the get-go or sustain CAR T cells on their own, depending upon the kind of practice setting you’re in. Those are key parts of improving outcomes for patients with myeloma.”

Ciltacabtagene autoleucel (cilta-cel; Carvykti) and idecabtagene vicleucel (ide-cel; Abecma), the CAR T-cell products holding indications in multiple myeloma,

 have continued to demonstrate encouraging results, but new approvals of off-the-shelf agents and the development of targeted therapies such as sonrotoclax (BGB-11417) are generating excitement, according to Lonial (

). Lonial is chair of the Department of Hematology and Medical Oncology and the Anne and Bernard Gray Family Chair in Cancer at Emory University School of Medicine and is the chief medical officer at the Winship Cancer Institute.

“There were a number of trials that came out in the past 12 to 18 months that are driving current treatment practice. The phase 3 trials comparing CAR T cells with standard therapies in earlier lines of therapy—CARTITUDE-4 [NCT04181827] and KarMMa-3 [NCT03651128]—are important studies that are setting the stage for bringing CAR T-cell therapy earlier in the treatment paradigm,” Lonial said.

The final progression-free survival (PFS) analysis of KarMMa-3, which was conducted with a median follow-up of 30.9 months, revealed that patients with triple-class–exposed relapsed or refractory multiple myeloma experienced deep and durable responses with ide-cel vs standard-of-care (SOC) regimens. Patients achieved an overall response rate (ORR) of 71% (95% CI, 66%-77%) in the ide-cel arm (n = 254) comprised of a 44% (95% CI, 38%-50%) complete response (CR) rate vs a 42% (95% CI, 34%-51%) ORR in the standard regimen arm (n = 132) comprised of a 5% (95% CI, 2%-9%) CR rate. The median duration of response (DOR) was 16.6 months (95% CI, 12.1-19.6) in the ide-cel arm vs 9.7 months (95% CI, 5.5-16.1) in the SOC arm. A significant benefit was observed with the CAR T-cell therapy regarding PFS: The median PFS was 13.8 months in the ide-cel arm vs 4.4 months in the SOC arm (HR, 0.49; 95% CI, 0.38-0.63).

Additional data from KarMMa-3 presented at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition revealed that health-related quality-of-life (QOL) improvements occurred sooner with CAR T-cell therapy vs SOC; investigators noted that patients who received the onetime infusion of ide-cel (n = 249) experienced health-related QOL improvements approximately 2 to 3 months following the infusion that were sustained for greater than 2 years.

The CARTITUDE-4 trial also showed that QOL improvements were seen with CAR T-cell therapy compared with standard of care for patients with relapsed or refractory multiple myeloma.

 At month 12, 40% of patients receiving cilta-cel (n = 126) achieved a clinical meaningful improvement in global health status score compared with 24% in the SOC arm (n = 125). At a median follow-up of 15.9 months (range, 0.1-27.3), the risk of disease progression or death was significantly lower for those treated with cilta-cel (n = 208) vs SOC (n = 211).

 The median PFS was not reached (NR) in the cilta-cel arm vs 11.8 months in the SOC arm (HR, 0.26; 95% CI, 0.18-0.38; 

 < .001) and 12-month PFS rates were 75.9% (95% CI, 69.4%-81.1%) vs 48.6% (95% CI, 41.5%-55.3%), respectively.

Lonial stressed the importance of timing when administering CAR T-cell therapy, noting that patients are sometimes referred to him following treatment with several lines of therapy, at which point blood counts and renal function are poor, leaving the patient with limited or no treatment options.

“Referral even at the time of first relapse so that you get on the agenda of the CAR T-cell center and receive guidance on what to do next and when to see the patient back [is needed]. Early visits with a CAR T center are going to remain critically important,” Lonial said.

Off-The-Shelf Approaches With T-Cell Engagers

Treatment options for patients with relapsed or refractory multiple myeloma who have received at least 4 prior lines of therapy—including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody—include the following agents that hold recent accelerated approvals: elranatamab-bcmm (Elrexfio; August 14, 2023),

 teclistamab-cqyv (Tecvayli; October 25, 2022),

and the most recent, talquetamab-tgvs (Talvey; August 9, 2023).

“Seeing the updated data on the T-cell engagers elranatamab and teclistamab was important in the past year [regarding] how to use these agents in an effective way. The other new targeted [agent] we got in the past year was talquetamab,” Lonial said.

In the phase 2 MagnetisMM-3 trial (NCT04649359), patients treated with elranatamab who had received 4 prior lines of therapy but had not received prior BCMA-directed therapy (n = 97) achieved an objective response rate of 57.7% (95% CI, 47.3%-67.7%) comprised of a 25.8% CR or better rate; the median DOR was NR (95% CI, 12.0-not estimable).

With teclistamab, patients who were also BCMA naive (n = 110) achieved an ORR of 61.8% (95% CI, 52.1%-70.9%) in the MajesTEC-1 trial (NCT03145181; NCT04557098).

Further, meaningful ORRs were observed in patients treated with talquetamab who had received at least 4 prior lines of therapy and were not exposed to prior T-cell redirection therapy (n = 187).

In the phase 2 MonumenTAL-1 trial (NCT04634552), those given the agent at 0.4 mg/kg weekly (n = 100) achieved an ORR of 73% (95% CI, 63.2%-81.4%) with a CR rate of 9%. Patients given talquetamab 0.8 mg/kg biweekly (n = 87) achieved an ORR of 73.6% (95% CI, 63.0%-82.4%) with a CR rate of 13%.

“These treatments allow an off-the-shelf approach for management of relapsed and refractory myeloma. CAR T-cell therapies are great, but of the people that you want to give a CAR T-cell therapy to, maybe half of them [receive one], whereas talquetamab, elranatamab, and even teclistamab are off the shelf. There are some challenges with logistics to giving them if you’re in a community practice, but in general, they can be done within a week, which from a patient perspective is a whole lot easier than waiting 6 or 8 weeks and figuring out what to do from a CAR T perspective,” Lonial noted.

“We’re excited about the next-generation BCL2 inhibitors,” Lonial said. “We saw data at the ASH meeting from compounds [such as] sonrotoclax, [which] appears to be more potent than venetoclax [Venclexta] with a better adverse effect profile. That is a drug and target we’re very interested and excited about.”

The BCL2 inhibitor sonrotoclax is a BH3 mimetic with a short half-life of 4 hours. The agent has demonstrated high selectivity and has greater than 10-fold potency than venetoclax.

Preliminary results from the phase 1b/2 BGB-11417-105 trial (NCT04973605) revealed that sonrotoclax given daily at 80 mg, 160 mg, 320 mg, and 640 mg in 21-day cycles was well tolerated in combination with dexamethasone in patients with relapsed or refractory multiple myeloma with translocation 11;14 who previously received at least 3 prior lines of therapy.

 At a median follow-up of 5.5 months (range, 2.4-21.1), patients treated with the 640-mg dose (n = 10), which was selected as the recommended phase 2 dose, achieved an ORR of 70%; responses were partial (30%), very good partial (20%), complete (10%), and stringent complete (10%). The most common any grade treatment-emergent adverse effects at the 640 mg dose level included insomnia (40%) and nausea (40%). Additionally, no dose-limiting toxicities or significant hematologic toxicities occurred at any dose level.

Enrollment is currently ongoing for the sonrotoclax plus dexamethasone expansion cohort as well as the dose-finding sonrotoclax plus dexamethasone and carfilzomib (Kyprolis) arms.

“Another T-cell engager, cevostamab, which targets FcRH5, is a drug that we’re excited about,” Lonial said. Cevostamab is being evaluated in an ongoing phase 1 study (NCT03275103) as monotherapy in patients with relapsed or refractory multiple myeloma.

 The phase 1/2, multicohort CAMMA 2 study (NCT05535244) is also ongoing and enrolling patients with relapsed or refractory multiple myeloma who previously received BCMA-targeted therapy.

Lonial also added that “the new CELMoDs iberdomide [CC-220] and mezigdomide are drugs we’re very excited about. They’re more potentthan lenalidomide [Revlimid] and pomalidomide [Pomalyst] and seem to have a better safety profile as well.”

Additionally, the novel, potent, oral CRBN E3 ligase modulator iberdomide in combination with bortezomib (Velcade) and dexamethasone had more tumoricidal activity and immune-modulatory effects than immunomodulatory agents such as lenalidomide, according to investigators who presented the data at the 

 International Myeloma Society Meeting. Of patients with transplant-ineligible, newly diagnosed multiple myeloma who received iberdomide plus bortezomib and dexamethasone in the phase 1/2 CC-220-MM-001 trial (NCT02773030), the regimen elicited an ORR of 100% in the efficacy-evaluable population (n = 16). Median follow-up was 12.63 months.

When considering approaches and developing a treatment plan for patients with multiple myeloma, Lonial explained that “we’ve gotten good at giving continuous therapy in myeloma, but we need to get away from the continuous therapy model and get to defined duration of therapy guided by depth of response—things like MRD might be helpful. The question I get from patients is: Can we replace transplants with CAR T cells? I don’t know that we can right now and so transplants need to remain an important part of their treatment approaches. But is there a way to put our best drugs and best targets together so that [we] can combine them and ultimately cure [patients with] the disease and stop treatment?”

When considering therapies and weighing the pros and the cons, the 28th Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas, and Myeloma (Winter Hematology) serves as a platform for practitioners to connect and dive into treatment scenarios as well as clinical situations. Advances in CAR T-cell therapy and T-cell engagers will be spotlighted along with bispecific agents and antibody-drug conjugates at the conference, which is taking place February 29, 2024, to March 3, 2024, in Miami Beach, Florida.

“As a community oncologist, you’re [balancing a lot] with every disease, every treatment, and new FDA approvals. The winter hematology conference lets you hear about that from the hematology perspective [and] have access to faculty outside of their lectures to make connections/contacts [that can be] used as a resource for your patients in the coming year,” Lonial, who is cochairing the conference, said.

FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. FDA. February 28, 2022. Updated March 7, 2022. Accessed January 10, 2024. bit.ly/3Heb7jT

FDA approves idecabtagene vicleucel for multiple myeloma. FDA. March 26, 2021. Updated March 29, 2021. Accessed January 10, 2024. bit.ly/3Hcyevc

Otero PR, Ailawadhi S, Arnulf B, et al. Idecabtagene vicleucel (ide-cel) versus standard (std) regimens in patients (pts) with triple-class–exposed (tce) relapsed and refractory multiple myeloma (RRMM): updated analysis from KarMMa-3. 

. 2023;142(suppl 1):1028. doi:10.1182/blood-2023-178933

Delforge M, Patel KK, Eliason L, et al. Effects of idecabtagene vicleucel (ide-cel) versus standard regimens on health-related quality of life (HRQOL) in patients with relapsed/refractory multiple myeloma (RRMM) who had received 2-4 prior regimens: updated results from the phase 3 KarMMa-3 trial.

. 2023;142(suppl 1):96. doi:10.1182/blood-2023-179152

Mina R, Mylin AK, Yokoyama H, et al. Patient-reported outcomes in the phase 3 CARTITUDE-4 study of ciltacabtagene autoleucel vs standard of care in patients with lenalidomide-refractory multiple myeloma after 1-3 lines of therapy. 

. 2023;142(suppl 1):1063. doi:10.1182/blood-2023-178798

San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. 

. 2023;389(4):335-347. doi:10.1056/NEJMoa2303379

FDA grants accelerated approval to elranatamab-bcmm for multiple myeloma. FDA. August 14, 2023. Accessed January 10, 2024. bit.ly/3tsmz7L

FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. FDA. October 25, 2022. Accessed January 10, 2024. bit.ly/47LPpih

Sagar Lonial, MD, FACP, details how CAR T-cell therapies and off-the-shelf treatments are improving outcomes for patients with multiple myeloma.  

Vol 25/No. 3 | Oncology Live®

Early-Phase Clinical Research Center Poised to Provide New Benefits in Hawaii and Beyond

The Importance of Lung Cancer Screening in Individuals Exposed to the World Trade Center Disaster

Enasidenib Plus Venetoclax Yields High Response Rates Targeting IDH2 Mutations in R/R AML

Lonial Spotlights CAR T-Cell and Off-the-Shelf Treatments in Multiple Myeloma

SABCS 2023 Findings Build on Positive Momentum in HER2+ Breast Cancer

Actionable Molecular Findings: Increasingly Clinically Relevant but Also Increasingly Complex