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The Claudin 18.2 (CLDN18.2)-targeted IgG1 monoclonal antibody zolbetuximab (Vyloy) in combination with frontline chemotherapy extended progression-free survival (PFS) and overall survival (OS) vs placebo plus chemotherapy in patients with HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose disease was positive for CLDN18.2, according to data from a combined analysis of the phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) trials. These data were published in the 

. Findings from the studies supported the October 2024 FDA approval of zolbetuximab plus fluoropyrimidine- and platinum- containing chemotherapy for the first-line treatment of adult patients with locally advanced unresectable or metastatic, HER2-negative gastric or GEJ adenocarcinoma whose tumors are CLDN18.2 positive, as determined by an FDA-approved test.

Across the 2 studies, patients who received zolbetuximab (n = 537) achieved a median PFS of 9.2 months (95% CI, 8.4-10.4) compared with 8.2 months (95% CI, 7.6-8.4) among patients in the placebo arm (n = 535; HR, 0.71; 95% CI, 0.61-0.83). The median OS was 16.4 months (95% CI, 15.0-17.9) vs 13.7 months (95% CI, 12.3-15.3), respectively (HR, 0.77; 95% CI, 0.67-0.89).

“There were some differences in patient characteristics and country distribution, as well as the chemotherapy backbone, [between SPOTLIGHT and GLOW], so we wanted to perform a pooled analysis,” Kohei Shitara, MD, director of the Department of Gastrointestinal Oncology at the National Cancer Center Hospital East in Japan and first author of the pooled analysis, said in an interview with 

. “[We observed] a 29% reduction in the risk of progression or death [with zolbetuximab vs placebo]. Looking at the survival curves, there’s a nice separation between the 2 arms. An updated analysis of survival may change the shape of the Kaplan- Meier curves, but this study showed a very nice separation between the 2 arms.”

The baseline characteristics in the pooled analysis were well balanced between the zolbetuximab/chemotherapy and placebo/chemotherapy arms; the median age was 61.0 years (range, 22.0-83.0) vs 60.0 years (range, 20.0- 86.0). Most patients in both arms were men (62.4% vs 61.9%), were not from Asia (54.4% vs 53.8%), had 0 to 2 organs with metastases (76.0% vs 76.1%), did not undergo a prior gastrectomy (70.4% vs 70.7%), had the stomach as their primary disease site (81.6% vs 78.3%), and had an ECOG performance status of at least 1 (56.2% vs 57.8%).

In the safety population of the zolbetuximab arm (n = 533), any-grade treatment-emergent adverse effects (TEAEs) occurred in 99.2% of patients, including events of at least grade 3 severity (80.7%) and serious TEAEs (48.0%). Treatment-related adverse effects (TRAEs) leading to dose interruption of any study drug (72.2%), dose interruption of zolbetuximab (53.7%), discontinuation of any study drug (30.8%), discontinuation of zolbetuximab (10.5%), and death (2.1%) were also reported.

The most common any-grade TEAEs in the zolbetuximab arm included nausea (76.0%), vomiting (66.8%), and decreased appetite (45.2%). Grade 3 or higher TEAEs included neutropenia (18.2%), decreased neutrophil count (17.8%), and vomiting (14.3%).

“There were no new safety concerns [with zolbetuximab] at this updated follow-up,” Shitara said. “Gastrointestinal toxicity, such as nausea and vomiting, is more frequently observed with zolbetuximab [compared with] placebo. But, as previously described, these events mostly happen at first infusion and clearly decrease over subsequent cycles.”

Comparatively, in the safety population of the placebo arm (n = 527), any-grade TEAEs, grade 3 or higher TEAEs, and serious TEAEs were reported at rates of 98.9%, 74.8%, and 48.4%, respectively. TRAEs leading to dose interruption of any study drug (45.2%), dose interruption of placebo (19.0%), discontinuation of any study drug (23.3%), discontinuation of placebo (3.4%), and death (2.3%) also occurred.

In the placebo arm, the most common any-grade TEAEs included nausea (56.2%), diarrhea (40.2%), and anemia (37.8%). Grade 3 or higher TEAEs included decreased neutrophil count (17.6%), neutropenia (13.7%), and anemia (10.2%).

Additional efficacy findings from the pooled analysis demonstrated that the objective response rate (ORR) in the zolbetuximab group was 45.4% (95% CI, 41.2%-49.8%) with a 6.0% complete response (CR) rate vs 43.6% (95% CI, 39.3%-47.9%) with a 3.2% CR rate in the placebo arm. The median duration of response (DOR) was 8.1 months (95% CI, 6.4-9.0) vs 6.5 months (95% CI, 6.2-7.7).

Data from a subgroup analysis showed that patients in every subgroup experienced a PFS benefit with zolbetuximab vs placebo except for those with GEJ cancer (HR, 1.12; 95% CI, 0.80-1.57; 

 Similarly, every subgroup experienced an OS benefit with zolbetuximab vs placebo except for patients with GEJ cancer (HR, 1.02; 95% CI, 0.76-1.39).

GLOW was a global, double-blind study that enrolled adult patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. Eligibility criteria included moderate to strong CLDN18 membranous staining on at least 75% of tumor cells per immunohistochemistry, an ECOG performance status of 1 or less, radiologically evaluable disease by RECIST 1.1, and adequate organ function. CLDN18.2 positivity was determined using the investigational VENTANA CLDN18 (43-14A) RxDx Assay.

Patients were randomly assigned 1:1 to receive intravenous (IV) zolbetuximab 800 mg/m

 on day 1 of cycle 1, followed by 600 mg/m

 on day 1 of subsequent cycles or placebo. Both arms also received oral capecitabine (Xeloda) 1000 mg/m

 twice daily on days 1 through 14 of each cycle and IV oxaliplatin 130 mg/m

 on day 1 of each cycle for eight 21-day cycles. Treatment in both arms, with the exception of oxaliplatin, continued until disease progression, unacceptable toxicity, start of another anticancer therapy, or occurrence of other discontinuation criteria.

The primary end point was PFS per RECIST 1.1 by independent review committee (IRC). OS and time to confirmed deterioration were the key secondary end points, with additional secondary end points including ORR, DOR, and safety.

SPOTLIGHT Evaluates Zolbetuximab/mFOLFOX6 Combination

SPOTLIGHT was global, placebo-controlled, double-blind trial that enrolled adult patients with CLDN18.2-positive, HER2-negative, treatment- naive locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. Key inclusion criteria included having radiologically evaluable disease per RECIST 1.1, an ECOG performance status of 1 or less, and adequate organ function.

Eligible patients were randomly assigned 1:1 to receive IV zolbetuximab 800 mg/m2 on day 1 of cycle 1, followed by 600 mg/m

 on day 22 of cycle 1 and days 1 and 22 of subsequent cycles or placebo. Patients in both arms also received IV folinic acid 400 mg/m

 or, optionally in Japan, levofolinate 200 mg/m

 in a 46-hour to 48-hour infusion, and oxaliplatin 85 mg/m

 on days 1, 15, and 29. Treatment in both arms occurred over four 42-day cycles, and patients who did not experience disease progression continued treatment with zolbetuximab or placebo plus chemotherapy at the investigator’s discretion. Therapy continued until disease progression, unacceptable toxicity, start of another anticancer treatment, or occurrence of other discontinuation criteria.

The primary end point was PFS per IRC. OS and time to confirmed deterioration were the key secondary end points. Other secondary end points included ORR, DOR, and safety.

Zolbetuximab Wins Approval in Japan and Europe

In March 2024, zolbetuximab became the world’s first approved CLDN18.2-targeted therapy, earning an indication for patients with CLDN18.2-positive, unresectable, advanced or recurrent gastric cancer in Japan. Then, in September 2024, the European Commission approved the agent in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adult patients with locally advanced unresectable or metastatic CLDN18.2-positive, HER2-negative gastric or GEJ adenocarcinoma.

“We are waiting for approval in other regions outside of Japan [and Europe],” Shitara said. “This is a significant achievement in gastric cancer [because] we have very limited treatment options, but the magnitude of survival benefit was still modest and not enough. We need additional, better treatment [options. Next, we want] to combine [zolbetuximab] with the current available treatments, such as checkpoint inhibitors, and this is supported by clinical and preclinical studies.”

Shitara K, Shah MA, Lordick F, et al. Zolbetuximab in gastric or gastroesophageal junction adenocarcinoma. 

. 2024;391(12):1159-1162. doi:10.1056/NEJMc2409512

FDA approves zolbetuximab-clzb with chemotherapy for gastric or gastroesophageal junction adenocarcinoma. FDA. October 18, 2024. Accessed October 21, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zolbetuximab-clzb-chemotherapy-gastric-or-gastroesophageal-junction-adenocarcinoma

Shah MA, Shitara K, Ajani JA, et al. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. 

. 2023;29(8):2133-2141. doi:10.1038/s41591-023-02465-7

Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. 

. 2023;401(10389):1655-1668. doi:10.1016/S0140- 6736(23)00620-7

Astellas’ Vyloy (zolbetuximab) approved in Japan for treatment of gastric cancer. News release. Astellas Pharma Inc. March 26, 2024. Accessed October 7, 2024. https://www.astellas.com/en/news/29026

Astellas receives approval from the European Commission for Vyloy (zolbetuximab) in combination with chemotherapy for advanced gastric and gastroesophageal junction cancer. News release. Astellas Pharma Inc; September 20, 2024. Accessed October 7, 2024. https://www.astellas.com/en/news/29401

Articles

Zolbetuximab, a CLDN18.2-targeted monoclonal antibody, combined with chemotherapy, significantly improved progression-free and overall survival in patients with HER2-negative, CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma, as shown in the SPOTLIGHT and GLOW trials. The FDA approved this combination therapy in October 2024. The pooled analysis revealed a 29% reduction in progression or death risk with zolbetuximab. Safety profiles indicated common adverse effects like nausea and vomiting, with no new safety concerns. Zolbetuximab has also been approved in Japan and Europe for similar indications.

Clinical Perspectives 

Zolbetuximab plus chemotherapy extended PFS and OS in HER2–, locally advanced unresectable or metastatic, CLDN18.2+ gastric/GEJ adenocarcinoma.

Zolbetuximab Plus Chemotherapy Offers Survival Benefits in Treatment-Naive HER2– Gastric/GEJ Cancer

Cancer care institutions have responded to an interest from patients to be more involved in the research process than in years past by developing several patient-partnered research initiatives. However, investigators who champion patient-partnered research have experienced challenges to effective implementation of some of these ideas, such as the complicated patient consent process, the free sharing of health information, and interoperability issues between various electronic health record (EHR) systems.

“Traditionally, we’ve done research in a passive framework, where patients sign consent, they participate, and then they go back to their lives, and there’s not always a direct engagement with them along the process from study conception to protocol development to understanding the results and returning those results back to them,” Vinayak Venkataraman, MD, said in an interview with OncologyLive. “In recent years, we’ve come to understand that patients want to have a more direct role in research, not just participating but also being partners in that research and better understanding how that research is being developed and how it’s being used after the completion of the study.” 

Venkataraman is the sarcoma pathways director for the Center for Sarcoma and Bone Oncology Sarcoma Center at Dana-Farber Cancer Institute and an instructor in medicine at Harvard Medical School, both in Boston, Massachusetts. One such patient-partnered research initiative is the Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network. First announced in 2019 as part of the Cancer Moonshot Initiative, the PE-CGS Network is made up of 5 National Cancer Institute–funded research centers.

The Ohio State University serves as the coordinating center of the PE-CGS Network. The PE-CGS Network member institutions collaborate to develop best practices and address common issues, with the goal of better engaging with patients and community members to develop networks of direct participant engagement in research. The PE-CGS Network placed a particular emphasis on filling research gaps in the study of rare, deadly cancers.

"All of the sites are focused on promoting effective participant engagement and research, and by doing so, accelerating discoveries, especially in rare and understudied cancers or in understudied or underserved populations,” Venkataraman explained. “Each center has different research initiatives, but they’re united to determine how to better promote direct-to-participant engagement. This includes leveraging technology, [such as] visual and digital platforms. [We also want to] more culturally appropriately communicate our consent processes, protocols, and results.” 

 PE-CGS Network stakeholders (n = 138)—consisting of scientists, clinicians, genetic counselors, and research funders (93%) as well as community and patient representatives (7%)—met in 2021 to identify priorities for participant engagement within the PE-CGS Network. They set the top priorities for participant engagement in cancer research as tailoring education and communication materials to participants, identifying measures of participant engagement, identifying optimal strategies for participant engagement, understanding cancer disparities in the context of genomics research, and personalizing the return of genomic data to participants.

To tailor materials to participants, the stakeholders recommended using culturally sensitive language, writing at recommended reading levels, translating materials into multiple languages, using images and figures, and using educational materials to support informed consent. For example, the PE-CGS Network member institution Optimizing Engagement in the Discovery of Molecular Evolution of Low-Grade Glioma is employing a novel digital platform, Hugo Health, to enable bidirectional patient-centric messaging and education. In terms of measuring patient engagement, PE-CGS Network stakeholders suggested that data on participant satisfaction, changes in knowledge, study enrollment and retention rates, changes in trust with researchers, and genomic and clinical discoveries be collected to determine the effects of participant engagement in cancer genomics research. PE-CGS Network member institution Count Me In PE-CGS Center is using an iterative feedback loop to collect community input on study design, including a patient intake survey. 

With regard to identifying optimal engagement strategies, the stakeholders discussed rapid-cycle research and the use of comparative effectiveness as methods to address suboptimal research strategies and to evaluate culturally tailored engagement efforts. The PE-CGS Network member institution Washington University PE-CGS is engaging individuals who decided not to participate in research efforts to better understand reasons for refusal and to modify practices accordingly For the fourth priority on understanding the role of care disparities in cancer genomics research, stakeholders recommended the collection of data on such factors as patient environment, socioeconomic status, and structural racism and the integration of these data with cancer genomics data. 

Regarding the fifth and final priority, personalizing the return of genomic findings, the stakeholders recommended collecting participants’ input on how to best deliver and aid in the understanding of genomic results, including who participants would prefer explain the results and providing additional informational materials to participants and their families. These strategies are being employed by the PE-CGS Network member institution Center for Optimization of Participant Engagement for Cancer Characterization. 

“At the end of the day, patients own their data,” Venkataraman said. “They want to contribute to research, but they’re being hindered in doing that, and a lot of researchers are hindered in being able to do that because of financial, legal, and technical barriers.” 

Addressing the Persistent Roadblocks to Patient-Partnered Research

Despite the frameworks for patient-partnered research established by the PE-CGS Network, effectively applying these concepts has met with some difficulties, so additional efforts are needed, according to Venkataraman. In an article published in the 

 Venkataraman and his coauthors cited the participant consent process as a hindrance to patient-partnered research that needs to be improved. They noted that the process remains time-consuming despite the PE-CGS Network’s efforts, often taking more than 30 minutes to complete and requiring potential participants to parse through clinical trial documents with a median word count exceeding 5000 words.

The investigators pointed to the National Institutes of Health All of US informed consent process, which uses animations and interactive quizzes to assess participants’ understanding of a study at enrollment, as a model to consider further utilizing. Research has shown that 95% of all enrollees who used the All of US consent process could accurately answer questions about the study process.

“The consent process itself has a lot of barriers,” Venkataraman said. “Many consent forms have a lot of verbose and legal jargon that is difficult for a lot of patients, or even providers, to understand. They’re [still often] not given in languages outside of English, which is unfortunate when you’re trying to engage a diverse population. They’re not tailored to different developmental ages; an area of interest of the PE-CGS Network is encouraging young adults and adolescents to participate in research.” 

Despite patient consent allowing investigators to access and review health data, quickly obtaining these records has presented another challenge to patient-partnered research. Although patients can quickly obtain their own health information, institutions are often unable to obtain it due to ownership of the EHR housing the information. Thus, investigators who are trying to practice patient-partnered cancer genomic research must often navigate these varying institutional rules, which can be time-consuming and costly.

“Even though [patients] have a legal right to access to their health information, it’s often very challenging for them to share that information with relevant providers and researchers,” Venkataraman explained. “The actual process of getting that data from institution A to institution B can be very cumbersome and costly for the research teams. We need to create infrastructures and technologies that allow patients to directly access their data and share it with whomever they want on a platform that’s readable and interoperable.” 

Venkataraman added that the lack of interoperability between EHR systems also contributes to the inability to transfer patient data from one institution to another and requires investigators interested in patient-partnered research to navigate various coding, specifications, capabilities, and data transfer capabilities to access patient EHR data. However, ongoing initiatives from the Office of National Coordinator for Health Information Technology, such as the Trusted Exchange Framework and Common Agreement and the United States Core Data for Interoperability, are aiming to address this issue. 

“We’re in an era where patient engagement and empowerment are important to making advances in [the treatment of patients with] rare and aggressive diseases,” Venkataraman said. “Patients are motivated to advance research through their direct participation, and it’s important for them to have a relationship with and respect from the research team [as well as] transparency and fidelity of data transfer. Anything we can do from an individual, health system, and research level to empower patients to directly participate in research and to have a bidirectional relationship with research [is important]. Using both technology and more culturally appropriate research methods, we can make a lot of advances in the future.”

Venkataraman V, Martin-Giacalone BA, Drake BF, et al. Overcoming systemic barriers to make patient-partnered research a reality. J Clin Oncol. Published online August 2, 2024. doi:10.1200/JCO.24.00347

About us. PE-CGS. Accessed October 8, 2024. bit.ly/3Y1WtUK

Schuster AL, Crossnohere NL, Bachini M, et al; Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network. Priorities to promote participant engagement in the Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network. Cancer Epidemiol Biomarkers Prev. 2023;32(4):487-495. doi:10.1158/1055-9965.EPI-22-0356

Doerr M, Moore S, Barone V, et al. Assessment of the All of Us research program's informed consent process. AJOB Empir Bioeth. 2021;12(2):72-83. doi:10.1080/23294515.2020.1847214

Patient-partnered research initiatives in cancer care are gaining traction, with efforts to involve patients more directly in the research process. Challenges such as complex consent processes, data sharing, and EHR interoperability hinder progress. The PE-CGS Network, part of the Cancer Moonshot Initiative, aims to enhance participant engagement, particularly in rare cancers, by leveraging technology and culturally sensitive communication. Priorities include improving consent processes, understanding cancer disparities, and personalizing genomic data return. Overcoming systemic barriers is crucial for advancing patient-partnered research and empowering patients in the research process.

Investigators who champion patient-partnered cancer research have experienced challenges to their effective implementation.

Personalized Initiatives Empower Patients to Actively Participate in Cancer Research

Xerostomia, the subjective sensation of dry mouth, is one of the most consequential long-term adverse effects of head and neck radiation. Xerostomia results from hyposalivation (reduced volume of saliva production) and salivary dysfunction (a change in the composition of saliva). Patients with radiation-induced xerostomia (RIX) can develop dental caries, impaired swallowing, diminished taste, and difficulty speaking. These associated symptoms can have a significant negative impact on overall quality of life. Older, 3D conformal radiation therapy results in long-term xerostomia in up to 80% of patients. The use of more modern radiation techniques, such as intensity-modulated radiation, partially spares the salivary glands but still results in RIX in over 40% of patients.

Radiation damages the saliva-producing acinar cells of salivary glands and results in fibrosis and cellular dysfunction.

 Radiation also damages salivary gland adult stem cells, the ultimate source for replenishing salivary gland tissue. After radiation, patients are encouraged to increase water consumption, consume specially prepared food, utilize salivary substitutes, or attempt to stimulate salivary production through parasympathomimetic drugs, chewing gum, or sugar-free mints.

 These supportive interventions are minimally effective at best, illustrating a critical need for improved therapies for RIX.

Mesenchymal stromal cells (MSCs) are cellular products derived from bone marrow, adipose tissue, or minor salivary glands and propagated ex vivo using established methods.

 MSCs can promote tissue healing in a variety of injurious settings. This is likely due to the production of tissue-promoting morphogens through their secretome, which has broad immunomodulatory and trophic activity.

Autologous MSCs are a promising cell-based therapy that allows for rejuvenating adult stem cells, as demonstrated in the gut.

 Our laboratory and others have demonstrated that intraglandular infusion of MSCs results in a 30% to 50% increase in salivary flow rate in mouse models of radiation-induced salivary gland dysfunction (

 To further support the use of MSC for the treatment of RIX, autologous and allogeneic MSCs have shown encouraging effects in recovering salivary function in patients with radiation-induced xerostomia in a series of Danish studies.

 These data have informed a phase 1 pilot trial (NCT04489732) and phase 1 clinical trial (NCT05820711) at the University of Wisconsin examining the use of autologous bone marrow–derived MSCs for treatment of radiation- induced xerostomia in patients who are 2 or more years out from completing radiation.

Although the data are promising, this work has several clear limitations. First, the approach employed in the Danish clinical trials utilized MSCs maintained in culture from liposuction until implantation.

 To expand this approach to a multi-institutional setting, it is important to cryopreserve MSCs to be transported from a central cell therapy laboratory to a delivery site. We have previously demonstrated that cryopreservation and large-scale culture expansion—key features of deliverable, practical cellular therapy— lead to MSC senescence, which can impair MSC function.

 Additionally, although not tested in this or prior studies, it is possible that repeated injections of MSCs will be required to optimize salivary function. This will require patients to either undergo an MSC harvesting procedure before each injection or the ability to cryopreserve a patient’s MSCs for serial injection. Repeated allogeneic injections can lead to allogeneic reactivity and limit cell engraftment.

Our proposed approach of autologous interferon gamma, tumor necrosis factor-α (TNF-α) preactivation of cryopreserved MSCs overcomes both limitations. Bone marrow aspirates and liposuction as sources for bone marrow–derived and adipose-derived MSCs, respectively, are associated with undesirable procedure-related consequences.

 In contrast, the minor salivary gland biopsy is well tolerated, performed in office, and requires only local lidocaine before an incision of less than 1 cm in the inner lower lip. Minor salivary gland–derived MSCs, or MSC(SG), represent an attractive tissue source for patients who have not received radiation therapy due to the ease of harvesting procedure.

All prior studies have focused on treating chronic RIX rather than preventing it before fibrosis and other late radiation effects. Thus, we have designed a clinical trial to investigate whether transplantation of autologous minor salivary gland–derived, interferon gamma, TNF-α prelicensed, cryopreserved, and culture-rescued MSCs into salivary glands after radiation will provide an innovative remedy to prevent chronic xerostomia in patients with head and neck cancer.

The proposed clinical trial will enroll patients with newly diagnosed head and neck cancer recommended to undergo radiation as part of their curative treatment (

). Consenting patients will undergo minor salivary gland biopsy to obtain MSC(SG) and then proceed to standard-of-care radiation. The MSC(SG) will be expanded, prelicensed with interferon gamma and TNF-α, and cryopreserved. Three months after the completion of radiation, they will undergo history, physical examination, and posttreatment imaging. If they are found to have no evidence of residual cancer, then they will undergo injection of cryopreserved MSC(SG) into the major salivary glands. They will be followed for safety/tolerability, salivary production, and quality of life. Our study will be the first-in-human trial of interferon gamma, TNF-α prelicensed MSC(SG) for the prevention of chronic radiation-induced xerostomia.

Grace Blitzer, MD, is an assistant professor in the Department of Human Oncology at the University of Wisconsin Carbone Cancer Center.

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Platt MS, Kohler LJ, Ruiz R, Cohle SD, Ravichandran P. Deaths associated with liposuction: case reports and review of the literature. 

Mentz JA, Mentz HA, Nemir S. Pneumothorax as a complication of liposuction. 

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Partner Perspective

A phase 1 trial is examining the use of mesenchymal stromal cells for treatment of radiation-induced xerostomia in patients who have completed radiation.

Partner Perspectives: Mesenchymal Stromal Cells Could Serve as Preventive Therapy for Chronic Radiation-Induced Dry Mouth

With the groundbreaking FDA approval in August 2024 of afamitresgene autoleucel (afami-cel; Tecelra) for unresectable or metastatic synovial sarcoma, marking the first US approval of an engineered cell therapy for a solid tumor, investigators are turning their attention to a new therapeutic target of interest: melanoma-associated antigen 4 (MAGEA4), the antigen that afami-cel targets.

“MAGEA4 is a protein that gets reexpressed on certain cancer cells as part of the transcriptional reprogramming that happens when a cancer revolves from a normal cell state into a cancer cell state,” Brian A. Van Tine, MD, PhD, the sarcoma program director and a professor of medicine in the Division of Medical Oncology and a professor of pediatrics at Washington University in St Louis, Missouri, explained in an interview with 

. “[It belongs to] a series of testicular antigens that are developmental pathway proteins that [usually] aren’t expressed in normal cells, which makes them ideal targets for cancer therapies. The 2 cancers that have a high expression of MAGEA4 are synovial sarcoma and myxoid/round cell [liposarcoma]. However, between 1% and 3% of all solid tumors also express MAGEA4 on the cell surface, making it an avenue for the development of T-cell therapies and bispecific T-cell engagers.”

Solid tumors with MAGEA4 expression include non–small cell lung cancer (NSCLC), head and neck squamous cell carcinoma, ovarian cancer, urothelial cancer, melanoma, and gastroesophageal cancers. Expression of MAGEA4 in normal tissue is limited to immune-privileged sites. The antigen is processed intracellularly, leading to peptide fragments being presented with human leukocyte antigens (HLAs) on the cell surface, which form epitopes that are weakly recognized by natural T-cell receptors (TCRs).

Afami-Cel Sets the Precedent for Cell Therapy in Solid Tumors

Afami-cel is an autologous T-cell therapy that is designed to express a TCR targeted against a MAGEA4 peptide. Findings from a preclinical study showed that afami-cel displayed potent cytotoxic effects and effector-cytokine release against HLA-A*02/MAGEA4-expressing cancer cells.

The FDA granted accelerated approval to afami-cel for the treatment of adult patients with unresectable or metastatic synovial sarcoma who have received prior chemotherapy; are positive for HLA-A*02:01P, HLA-A*02:02P, HLA-A*02:03P, or HLA-A*02:06P; and have tumors expressing MAGEA4 as determined by FDA-approved or -cleared companion diagnostic devices. The regulatory decision was supported by findings from cohort 1 of the phase 2 SPEARHEAD 1 trial (NCT04044768).

SPEARHEAD 1 was an open-label, nonrandomized study that included 3 cohorts. Cohort 1 consisted of patients aged 16 to 75 years with HLA-A*02–positive, MAGEA4-expressing metastatic or unresectable synovial sarcoma or myxoid round cell liposarcoma who had received at least 1 prior line of chemotherapy. Patients underwent lymphodepletion and received afami-cel at a dose range of 1.0×10

 T cells via a single intravenous infusion. The primary end point was overall response rate (ORR) in cohort 1 per RECIST 1.1, assessed by an independent review committee; secondary end points included progression-free survival (PFS), overall survival (OS), and safety.

At a median follow-up of 32.6 months (IQR, 29.4-36.1), patients with synovial sarcoma (n = 44) achieved an ORR of 39% (95% CI, 24%-55%) and those with myxoid round cell liposarcoma (n = 8) experienced an ORR of 25% (95% CI, 3%-65%). Notably, the median OS among patients with synovial sarcoma was not reached (NR; 95% CI, 15.4-not estimable) and the median PFS was 3.8 months (95% CI, 2.8-6.4). The estimated 12- and 24-month OS rates in patients with synovial sarcoma and a RECIST response were 90% (95% CI, 65%-99%) and 70% (95% CI, 43%-87%), respectively.

The median duration of response was 11.6 months (95% CI, 4.4-18.0) in patients with synovial sarcoma and 4.2 months (95% CI, 2.9-5.5) in patients with myxoid round cell liposarcoma. Among patients with synovial sarcoma, the overall probability of being alive and not on additional systemic treatment at 24 months was 30% (95% CI, 13%-39%).

“There is a group of patients who do not respond and come off treatment rather early, but [there is another group who have] deep, durable responses on [afami-cel] for years, as long as you have a major response,” Van Tine noted. “I have patients who have been on this trial who are still on the trial from the beginning. If you can get a deep response, [it] can be incredibly durable, and this [is accompanied by a] high quality of life because there’s no more chemotherapy, no oral medications—there’s nothing other than getting surveillance scans. There’s a lot of effort to [examine] that group who don’t have a deep and durable response, understand why they don’t, and try to make it so that they can. We’re not quite sure what to add yet, but this is the work that’s ongoing.”

Safety findings from SPEARHEAD 1 showed that 100% of patients in cohort 1 who received afami-cel experienced any-grade treatment-emergent adverse effects (TEAEs). The most common any-grade TEAEs included cytokine release syndrome (CRS; 71%), decreased white blood cell count or leukopenia (27%), pyrexia (23%), and decreased neutrophil count or neutropenia (23%). Grade 3 or worse cytopenia occurred in 19% of cohort 1 and included neutropenia (10%), anemia (8%), and thrombocytopenia (6%).

“With cellular therapies, we always worry about CRS,” David S. Hong, MD, deputy chair of the Department of Investigational Cancer Therapeutics in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, said in an interview with 

“The vast majority of these patients had grade 1 or 2 [CRS], which is somewhat different than [the CRS from]chimeric antigen receptor T-cell therapies being developed in lymphoma. We’ll see what happens as more and more of these [products] get approved and enter the clinic. But overall, my experience [is that] cellular therapies in solid tumors tend to be less toxic than in lymphomas and other [hematologic malignancies].”

Notably, cohort 1 had no treatment-related deaths and no deaths within the first 30 days following afami-cel infusion. There were 28 deaths overall, all of which resulted from disease progression, according to investigators.

The phase 1 study (NCT03132922) that preceded SPEARHEAD 1 examined afami-cel in patients withesophageal (n = 2), gastric (n = 1), head and neck (n = 3), ovarian (n = 9), and urothelial (n = 2) cancers as well as melanoma (n = 1), NSCLC (n = 2), synovial sarcoma (n = 16), and myxoid round cell liposarcoma (n = 2). In the modified intention-to-treat population (n = 38), the ORR was 24% (95% CI, 11.4%-40.2%), which included 7 patients with synovial sarcoma and 1 patient each with NSCLC and head and neck cancer who had a partial response. The median PFS and OS were 12.3 weeks (95% CI, 10.9-19.1) and 42.9 weeks (95% CI, 20.7-NR), respectively.

Afami-cel is also set to be examined in the phase 1/2 pediatric basket study SPEARHEAD-3 (NCT05642455), which is enrolling patients aged 2 to 21 years with HLA-A*02–positive, MAGEA4-expressing advanced synovial sarcoma, malignant peripheral nerve sheath tumors, neuroblastoma, or osteosarcoma. Eligible patients must have received prior chemotherapy and have an ECOG performance status of 1 or less or a Lansky score of 80 or more.

The primary end point is the incidence of TEAEs. Secondary end points include ORR, PFS, OS, and pharmacokinetics. The study is currently recruiting patients, and the primary completion date is estimated for October 2026.

“The hope is that we can scale [afami-cel] into more common tumor types,” Hong said. “In order for this to happen, we’ll need the vein-to-vein time of the drug to be much shorter. It currently takes approximately 6 weeks, if not longer, [to produce].”

MAGEA4-Directed Agents Beyond Afami-Cel Progress Through the Development Pipeline

MAGEA4 is being explored as a potential target for multiple novel T-cell therapies in several tumor types. IMA401 is a next-generation, half-life–extended TCR-based bispecific T-cell engager that targets both MAGEA4 and MAGEA8. The agent is being evaluated in an ongoing phase 1 study (NCT05359445) in patients with recurrent or refractory solid tumors with HLA-A*02:01–positive, MAGEA4/8-expressing disease who had received or were not eligible for all available indicated standard-of-care therapies.

Initial data from this study presented during the 2024 European Society for Medical Oncology Congress showed that efficacy-evaluable patients (n = 29)—who were heavily pretreated with a median of 3 (range, 2-8) prior lines of therapy—achieved an ORR of 21%. Additionally, those with high MAGEA4/8 expression (n = 17) achieved an ORR of 29% and a disease control rate of 53%. The toxicity profile of the agent was manageable, with the most common treatment-related AEs being low-grade CRS, transient lymphopenia, and neutropenia; dose escalation in the study is ongoing.

Another early-phase study, the phase 1 APOLLO trial (NCT05798897), is investigating the novel multitumor-associated antigen-specific T-cell agent MT-601 for the treatment of patients with relapsed/refractory lymphoma who did not respond to or are ineligible for anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. MT-601 uses a non–genetically modified approach to target 6 tumor antigens upregulated in lymphoma cells: survivin, PRAME, WT1, NY-ESO-1, SSX2, and MAGEA4.

In April 2024, the principal investigator of the APOLLO study presented findings at the Global Summit on Hematologic Malignancies on a study participant with follicular non-Hodgkin lymphoma who had experienced 12 prior treatment failures, including with axicabtagene ciloleucel (Yescarta), after transformation to diffuse large B-cell lymphoma (DLBCL) but achieved a complete response (CR) with MT-601 and remained in CR 3 months after treatment. Another patient with DLBCL who was ineligible for CAR T-cell therapy achieved a partial response with MT-601 at 8 weeks post treatment. Updated data from a third patient with DLBCL who had experienced 4 prior failed lines of therapy, including with an anti-CD19 CAR T-cell agent, indicated that the patient remained in CR 9 months after receiving MT-601.

“The most important thing to realize is that right now, we have a [MAGEA4–directed] product that is FDA approved for synovial sarcoma,” Van Tine said. “There’s going to be this new academic-private practice partnership for managing these therapies, which is new for the solid tumor doctors. There are going to be a lot of constructive conversations happening between private practices [regarding] getting access to these [therapies], testing locally, and getting treated at the center. This is going to change how oncology is practiced, but for the patients in whom it works, it’s the most transformative thing I’ve seen in my career.”

Adaptimmune receives U.S. FDA accelerated approval of Tecelra (afamitresgene autoleucel), the first approved engineered cell therapy for a solid tumor. News release. Adaptimmune Therapeutics plc. August 1, 2024. Accessed October 3, 2024. bit.ly/3BAIq1e

Hong DS, Van Tine BA, Biswas S, et al. Autologous T cell therapy for MAGE-A4+ solid cancers in HLA-A*02+ patients: a phase 1 trial. 

29(1):104–114. doi:10.1038/s41591-022-02128-z

FDA grants accelerated approval to afamitresgene autoleucel for unresectable or metastatic synovial sarcoma. FDA. Updated August 2, 2024. Accessed October 3, 2024. bit.ly/3Y96jFP

D’Angelo SP, Araujo DM, Abdul Razak AR, et al. Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma (SPEARHEAD-1): an international, open-label, phase 2 trial. 

. 2024;403(10435):1460-1471. doi:10.1016/S0140-6736(24)00319-2

SPEARHEAD-3 pediatric study. ClinicalTrials.gov. Updated April 24, 2024. Accessed October 3, 2024. https://clinicaltrials.gov/study/NCT05642455

Wermke M, Ochsenreither S, ChatterjeeM, et al. Initial safety, pharmacokinetics, and anti-tumor activity data of TCER IMA401, a MAGEA4/8-directed half-life extended TCR bispecific, in phase I dose escalation. 

. 2024;35(suppl 2):S681-S682. doi:10.1016/j.annonc.2024.08.1060

Principal investigator from City of Hope National Medical Center invited to present clinical data from Marker Therapeutics APOLLO study at 11th Global Summit on Hematologic Malignancies. News release. Marker Therapeutics Inc. April 8, 2024. Accessed October 4, 2024. bit.ly/3XNlLWK

Afamitresgene autoleucel (afami-cel; Tecelra) has received FDA approval for treating unresectable or metastatic synovial sarcoma, marking a significant milestone as the first engineered cell therapy for a solid tumor. This therapy targets the melanoma-associated antigen 4 (MAGEA4), which is expressed in various solid tumors. The phase 2 SPEARHEAD 1 trial demonstrated promising efficacy and safety results, with notable overall response rates and survival outcomes. Ongoing research aims to expand the application of MAGEA4-directed therapies to other tumor types, potentially transforming oncology practice.

Pathways

Brian A. Van Tine, MD, PhD, and David S. Hong, MD, discuss the MAGEA4 pathway and the FDA approval of afami-cel in synovial sarcoma.

MAGEA4 Opens the Door for Engineered Cellular Therapies in Solid Tumors

As of October 4, 2024, 10 FDA approvals have entered the non–small cell lung cancer (NSCLC) arena in the calendar year, and within the past 2 weeks of the aforementioned date, approvals for those with resectable and nonresectable disease have further added to the paradigm.

 The practice-changing indications as well as notable data have sparked conversations in not only the early-stage setting but also the neo(adjuvant) and metastatic settings.

Nivolumab (Opdivo) plus platinum-doublet chemotherapy joined durvalumab (Imfinzi) when it received another indication on October 3, 2024, as neoadjuvant treatment followed by single-agent adjuvant nivolumab for adults with resectable (tumors ≥ 4 cm and/or node positive) NSCLC and no known 

 Just a few months earlier, on August 15, 2024, a durvalumabplus platinum-containing chemotherapy regimen received the same indication for this patient population.

“The most important advances of this year thus far are in early-stage NSCLC with the advent of neoadjuvant immunotherapy plus chemotherapy,” Julie R. Brahmer, MD, MSc, FASCO, said in an interview with 

. “We know that patients with stage II and stage IIIA disease benefit from neoadjuvant therapy, and there are multiple perioperative paradigms that are now approved for giving neoadjuvant chemotherapy and immunotherapy followed by immunotherapy in the adjuvant setting, as well.”

Durvalumab’s addition to the perioperative treatment paradigm was based on data from the phase 3 AEGEAN trial (NCT03800134), in which the durvalumab regimen reduced the risk of an event-free survival (EFS) event by 32% vs the placebo regimen (HR, 0.68; 95% CI, 0.53-0.88; 

 This marked the second approval in the perioperative space; the first was the October 16, 2023, FDA approval of pembrolizumab (Keytruda) plus platinum-containing chemotherapy as neoadjuvant treatment followed by adjuvant pembrolizumab for patients with resectable NSCLC. New data from the phase 3 KEYNOTE-671 study (NCT03425643), which supported the approval, showed a significant overall survival (OS) benefit with perioperative immunotherapy vs neoadjuvant chemotherapy alone.

Findings from the second interim analysis revealed that the 36-month estimated OS rates were 71% (95% CI, 66%-76%) in the pembrolizumab arm (n = 397) vs 64% (95% CI, 58%-69%) in the placebo arm (n = 400; HR, 0.72; 95% CI, 0.56-0.93; 1-sided 

 = .0052). Moreover, with a median follow-up of 36.6 months (IQR, 27.6-47.8), the HR for EFS continued to favor the pembrolizumab regimen (HR, 0.59; 95% CI, 0.48-0.72). At the first interim analysis, significantly improved pathologic complete response (pCR) rates occurred among patients treated with pembrolizumab (18%) vs placebo (4%; 1-sided 

“The data that have continued to come out on these regimens show that if patients achieve a pCR with neoadjuvant chemotherapy and immunotherapy, they do extremely well for quite some time,” Brahmer said. “[In] most of the studies, we have not seen long-term OS [data], but in the KEYNOTE-671 study [with the pembrolizumab regimen], there was an advantage from the survival standpoint, in addition to having decreased risk of cancer recurrence.”

Early-Stage Setting: Neoadjuvant Chemoimmunotherapy Represents a Key Step Forward

“In the early-stage setting, it is exciting [having] neoadjuvant therapy and trying to move the bar [to figure out] how these types of therapies work for patients, knowing that patients who achieve a pCR do well after treatment. But for practice, the devil is in the details,” Brahmer noted. “Knowing patients’ fusions and driver mutations can help you decide whether neoadjuvant therapy is needed since patients with 

 mutations don’t do well with single-agent immunotherapy plus chemotherapy. Every practice needs to figure out how to operationalize getting these answers quickly to start the therapy for these patients or take them directly to surgery, depending on those results.”

Brahmer added that with time and more mature data, it will become clearer which combination therapy should be used for select patients. The phase 2 NeoCOAST-2 trial (NCT05061550), which examined 3 different durvalumab-based combinations, was the first global, phase 2 trial to show efficacy and a manageable safety profile of an antibody-drug conjugate in the neoadjuvant setting for patients with resectable NSCLC.

In 2024, significant advancements in non-small cell lung cancer (NSCLC) treatment have emerged, with 10 FDA approvals, including neoadjuvant and adjuvant therapies. Notable approvals include nivolumab and durvalumab combined with chemotherapy for resectable NSCLC, showing improved event-free survival. Pembrolizumab also demonstrated significant overall survival benefits in early-stage settings. The introduction of adjuvant alectinib for ALK-positive NSCLC and ivonescimab for advanced NSCLC highlights the evolving treatment landscape. These developments will be discussed at the 22nd Annual Winter Lung Cancer Conference in early 2025.

Julie R. Brahmer, MD, MSc, FASCO, details practice-changing indications and notable data in the early-stage, neo(adjuvant), and metastatic NSCLC settings.



Vol. 25/No. 14 | Oncology Live®

Zolbetuximab Plus Chemotherapy Offers Survival Benefits in Treatment-Naive HER2– Gastric/GEJ Cancer

Personalized Initiatives Empower Patients to Actively Participate in Cancer Research

Partner Perspectives: Mesenchymal Stromal Cells Could Serve as Preventive Therapy for Chronic Radiation-Induced Dry Mouth

MAGEA4 Opens the Door for Engineered Cellular Therapies in Solid Tumors

Brahmer's Take: Advancements in 3 Cornerstone Settings of NSCLC

Gynecologic Cancer Paradigm Sees Huge Gains With FDA-Approved Regimens

A Call to Action: Determining Optimal Dose, Schedule, and Appropriate Modifications for Antineoplastic Pharmaceutical Agents