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Marginalized communities historically have had difficulty accessing services from cancer centers via the community-based setting. Awareness campaigns, outreach efforts, and other smaller initiatives have not had the results needed to close the gap in helping patients with cancer get to these lifesaving services.

Investigators at Dana-Farber Cancer Institute in Boston, Massachusetts, developed a clinical outreach program combining diagnostic and patient navigation services.

 By streamlining services in 1 location, clinicians sought to integrate all elements of the patient journey to enhance shared decision-making, keep referral pathways concise, and potentially offer clinical trial enrollment. Recent findings published in 

 showed that the implementation of a colocation program significantly reduced the median time to cancer diagnosis, which may enhance the delivery of cancer care services in underserved communities.

Developed in 2009, the strategic cancer care equity program was created in response to a needs assessment that found cancer incidence and mortality rates to be significantly higher in the greater Boston area among historically marginalized populations such as patients of color and those of a lower socioeconomic status. Findings from the assessment also identified barriers to cancer care, including cost, perceptions of cancer, and care quality perceived as below standard.

In the program, cancer diagnostic services and patient navigation are offered together at a federally qualified health center (FQHC). Patients are referred by primary care providers for cancer-related issues such as preventative services, diagnosis, or reestablishment with oncologists for patients with a history of cancer (

). Oncology nurse navigators are employed to conduct patient intake assessments, oversee scheduling, coordinate team communication, and assist with patient insurance and financial grievances.

“We were interested in how we can impact care [in these] neighborhoods, and from a cancer center perspective, we were trying to figure out how can we decrease the time it takes…to get the cancer [diagnosis] worked up,” Christopher Lathan, MD, MS, MPH, chief clinical access and equity officer, the Christopher and Constance Hadley Family Chair, and the associate medical director of the DFCI Network at Dana-Farber, said in an interview with 

. “The impetus was to get out, be involved, and be present in the community. The idea was, if we are present and we helped with a diagnostic clinic, would that actually make a difference in outcomes? [We wanted] to see if this intervention that we hoped would give more access would also have a direct impact and make a difference in the lives of patients with cancer seen at those health centers.”

This type of colocation model previously has been applied in several community-based interventions, but there are very few examples of a colocation model being implemented at community-based diagnostic clinics for cancer care. Colocation in this instance means services are present in the same physical location without necessarily being integrated with one another. It can mean the sharing of equipment and staff, as well as coordinated services provided by health service providers. It has been hypothesized that colocation approaches can optimize access to care because the proximity of providers leads to enhanced communication and additional input in diagnostic decisions.

The program was initiated in January 2012 at an FQHC and primary care center in Roxbury, Massachusetts. Approximately 90% of patients treated at this FQHC are in minority groups, with 91% at or below the national poverty level.

Eligible patients were adults who received cancer-related services at the Roxbury facility between January 2012 and July 2018. Patients provided informed consent in person either at the end of their visit or during a follow-up visit with their primary care provider. Importantly, patients were not required to enroll in the study to receive services through the program.

The overall cohort included in the study consisted of 366 patients, 82 of whom had a cancer diagnosis. Most were women (60.1%), spoke English (59.8%), and had Medicaid as their insurance provider (55.0%).

The primary goal of the initiative was to resolve the cancer-related clinical issue within 21 days.

 Secondary outcome measures consisted of clinical trial enrollment and financial distress as reported by study participants (

Findings from the study showed that the median time to diagnostic resolution for patients with a cancer diagnosis, whether it was new, existing, or prior, was 12 days (95% CI, 8-21). Comparatively, the median time to diagnostic resolution was 25 days (95% CI, 18-28) in the overall cohort and 28 days (95% CI, 21-35) for patients without a cancer diagnosis. Median time to diagnostic resolution was not significantly affected by patient race, ethnicity, sex, age, insurance, language, employment status, or education.

“Our goal was to get that median time under 21 days for [patients with] cancer,” Lathan said. “The fact that we got it down to 12 days was surprising for us; we were happy, but surprised. [Additionally], 10% of the cohort that we reported were in a cancer clinical trial, that’s higher than average for this population. Looking at a subset of patients with active cancer, that [rate of clinical trial enrollment] goes up to 24%, which is again much higher than what you’d see nationally for this group. We don’t have a great hypothesis [as to why that is,] but being exposed to our cohort study and our navigation [services] might have allowed people to build more trust.”

Additional results showed that most patients in the overall cohort presented with a comorbidity (88%). The most common comorbidities were hypertension (42.6%), psychologic disorder (37.7%), diabetes (31.4%), and gastrointestinal tract/liver disease (27.3%). In terms of insurance status, most patients (85%) had plans that were contracted with Dana-Farber. Ten percent of the overall cohort and 24% of patients with cancer were subsequently enrolled in a clinical trial taking place at Dana-Farber. All patients with a cancer diagnosis who were being actively treated for their disease (n = 9) were enrolled in a clinical trial. A majority of the patients who were enrolled in trials were Black (71%).

Patients with a new or existing cancer diagnosis were all referred to Dana-Farber. Most of these patients received a treatment plan (66%), and 29% were given a surveillance plan. Those who were lost to follow-up after displaying a prior history of cancer were all reconnected with care; 59% and 41% of these patients were given a treatment and a surveillance plan, respectively.

Limitations of the study included the relatively small cohort size and the lack of information regarding cancer care and outcomes at the FQHC prior to the program. Lathan also noted that a lack of randomization has an impact on the generalizability, sustainability, and reproducibility of the findings. Additionally, economic considerations were not included as part of the study.

To address their study’s limitations, investigators created a system to gather longitudinal data. These findings will be used to follow project-level outcomes and eventually perform a prospective case-control analysis with another FQHC that has not yet implemented the study intervention. Notably, the intervention is currently being applied at 2 other FQHCs in the Boston area.

“The first thing of any of these studies is proof of concept and I feel like we’ve done a good job of that,” Lathan said. “The next step is to expand to other areas and see if the same thing happens. We’ve already expanded to a couple of other FQHC partners. The second thing is to look at if this is cost-effective in our current system. I also want to start to look at some other aspects, [such as] survivorship and look at some quality metrics for the patients, providers, and others in the system. We want to get into more detail with this cohort and figure out other interactions as well as social factors and how they might impact things.”

Stockman LS, Gundersen DA, Gikandi A, et al. The colocation model in community cancer care: a description of patient clinical and demographic attributes and referral pathways. 

 Published online March 20, 2023. doi:10.1200/OP.22.00487

Waldman LT, Svoboda L, Young BF, et al. A novel community-based delivery model to combat cancer disparities. 

. 2013;1(3-4):123-129. doi:10.1016/j.hjdsi.2013.09.004

Cancer diagnostic services in a community health center speed diagnosis for underserved populations. News release. Dana-Farber Cancer Institute. March 20, 2023. Accessed April 12, 2023. https://www.dana-farber.org/newsroom/news-releases/2023/cancer-diagnostic-services-in-a-community-health-center-speed-diagnosis-for-underserved-populations/ 

Articles

Colocation Approach Leads to Decreased Time to Diagnosis, Stimulates Clinician Collaboration

Nearly half of all brain tumors are associated with an underlying cancer diagnosis, and lung cancer is one of the most common of these. As improved cancer therapies are helping patients live longer, the safe and effective management of lung cancer brain metastases is coming to the fore. The goals we always keep in mind in these cases are to extend survival, prevent neurological dysfunction and improve quality of life. This article briefly reviews the progress made toward these goals made in recent years.

Surgery can be essential for making a diagnosis, maximizing resection of a solitary metastasis, and improving survival. It offers many advantages over other management strategies: Not only is the cancer locally removed, but the associated rapid resolution of mass effect and edema many times improves neurological issues and allows for faster tapering of corticosteroids used to treat symptomatic lesions.

Surgical risk can be reduced and neurological deficits minimized by using the following tools and strategies: 

Image-guided computer-assisted navigation 

Microsurgery and minimal-access craniotomy 

Cortical mapping and awake surgery if near critical areas

In most cases, adding whole brain radiation therapy (WBRT) or stereotactic radiosurgery to surgery has been essential to increase survival and reduce tumor recurrences. Sometimes open surgery is not necessary; however, a biopsy may be required to confirm the tumor diagnosis and guide patient management.

For decades, whole brain radiation therapy (WBRT) was considered standard treatment for patients with brain metastases. Although 70% to 90% of patients experience improved symptoms in 1 to 3 weeks, toxicities including alopecia, fatigue, skin erythema, headache, otitis media, somnolence syndrome, and leukoencephalopathy are common.

Most importantly, WBRT is associated with neurocognitive decline, which becomes more evident as patients live longer than 1 year. This risk can be lowered by newer approaches such as medications (eg, memantine) or modified radiation delivery such as hippocampal sparing during WBRT; however, delayed impact on cognition continues to be a factor.

This concern regarding delayed toxicity has reduced the role of WBRT in recent years. WBRT is still considered necessary for leptomeningeal disease and for cases involving numerous metastatic lesions, although the threshold is not well defined and is rising as other therapies prove effective for multiple metastases. WBRT is also traditionally standard for small cell lung cancer (SCLC) brain metastases, but evidence now indicates that stereotactic radiosurgery alone may be sufficient, if not favored, for up to 10 lesions.

Stereotactic radiosurgery offers multiple advantages over many other therapies, including lower cost and, in most cases, avoidance of general anesthesia for surgery. It involves a minimally invasive or noninvasive outpatient procedure with no meaningful recovery time. Additionally, in contrast to some of the limitations encountered with open surgery, stereotactic radiosurgery can safely treat lesions that are small, deep, or near critical areas.

Already the standard for limited small brain metastases, stereotactic radiosurgery has increasingly been used over the past few years as primary treatment for patients with up to 15 tumors and for large lesions. It also can be used as salvage treatment for recurrence of metastases following WBRT. Comparable with WBRT in terms of overall survival and local and distant control, it allows for faster time to systemic therapy and causes fewer toxicities, including neurocognitive impairment.

For large brain metastases (≥ 2 cm), single-session radiosurgery does not consistently provide durable control. Instead, we recommend staged treatment (ie, 2 stereotactic radiosurgery treatments performed 1 month apart) effectively boosting the target and achieving approximately 90% 1-year local control. This strategy capitalizes on the tumor volume shrinkage that is often observed between sessions, reducing the irradiated volume, and possibly making the tumor more responsive to the next treatment. Systemic therapy is allowable between the 2 treatments. We have found this approach to be feasible, safe, and effective, obviating the need for surgical intervention even for large brain metastasis in select cases.

Radiation necrosis or radionecrosis (a delayed impact of radiation treatment seen in 5% to 10% of patients) remains a concern following both WBRT and stereotactic radiosurgery, especially as it can be clinically and radiologically difficult to distinguish from recurrent tumors. We closely monitor all patients with MRI after radiation therapy to detect suspicious lesions early, as well as radionecrosis when it is more likely to be limited and even reversible if treated promptly.

In recent years, we have changed how we treat non–small cell lung cancer (NSCLC) tumors driven by 

 rearrangements. This has had significant impact on control of lung cancer-related brain metastases.

Prior to 2015, the tyrosine kinase inhibitors (TKIs) used for targeted therapy of NSCLC offered very good systemic control but very little control of brain metastases. Since 2015, TKIs with central nervous system (CNS) activity have become available and have quickly moved from second-line to frontline therapy. We now even have data supporting adjuvant use of one TKI, osimertinib (Tagrisso), for 

-positive tumors. These developments have given us the welcome option of withholding WBRT in TKI-naïve patients.

-driven tumors with brain metastases, virtually all patients who are TKI-naïve receive TKI therapy plus stereotactic radiosurgery. The first-line TKI is osimertinib for those with 

-positive tumors and alectinib (Alecensa) for those with 

-positive tumors we will continue osimertinib if there are 2 or fewer lesions and extracranial control is being achieved. If there are multiple lesions and extracranial control is being lost, we continue with stereotactic radiosurgery alone and decide whether and when to add chemotherapy. For disease progression in patients with 

-positive tumors, alectinib may be followed by the second-line TKI lorlatinib (Lorbrena) before considering switching to chemotherapy.

For patients with tumors with no driver mutations, immunotherapy with a checkpoint inhibitor with or without chemotherapy is used in addition to stereotactic radiosurgery.

Whether and when we can use systemic therapy alone is a key research question currently under study. Given the known benefits from local therapy, many oncologists are understandably reluctant to use systemic therapy alone, even though the appeal of systemic therapy is compelling, given its potential impact on controlling the disease throughout the body. However, there continue to be multiple unknowns regarding the timing and sequence of systemic therapy in relation to stereotactic radiosurgery or WBRT, as well as regarding the advisability of trying another TKI if CNS progression occurs.

Even as the field grapples with these questions, the progress made in the past few years—particularly the advent of systemic therapies and improvements in the use of stereotactic radiosurgery—deserves recognition. These advances underscore the importance of multidisciplinary expertise in the management of lung cancer brain metastases. And with so much still unknown despite these advances, the need for a multidisciplinary team approach to optimize individual treatment strategies may be the greatest imperative of all.

Lilyana Angelov, MD, is director of the Gamma Knife Center in the Brain Tumor and Neuro-Oncology Center at Cleveland Clinic in Ohio.

Samuel Chao, MD, is a professor at Cleveland Clinic Lerner College of Medicine, and an oncologist at the Brain Tumor and Neuro-Oncology Center and the Department of Radiation Oncology at Cleveland Clinic in Ohio.

Marc Shapiro, MD, is an associate staff member in the Department of Solid Tumor Oncology at Cleveland Clinic in Ohio.

As improved cancer therapies are helping patients live longer, the safe and effective management of lung cancer brain metastases is coming to the fore. 

Clinical Updates for the Management of Lung Cancer Brain Metastases

(claudin-18.2; CLDN18.2) has become a promising target for the treatment of patients with digestive malignancies, such as gastric cancer (GC), gastroesophageal junction (GEJ) cancer, esophageal cancer, and pancreatic cancer, because of its limited expression in healthy tissues and abnormal overexpression in a range of malignancies.

 Multiple clinical trials of CLDN18.2-targeted therapies, including monoclonal antibodies, bispecific antibodies, antibody-drug conjugates (ADCs), and chimeric antigen receptor (CAR) T-cell therapies, are ongoing, with some showing promising early results.

 If these findings hold up in larger trials, standardizing methods of CLDN18.2 detection and positivity thresholds, optimizing novel therapies’ efficacy and safety profiles, and finding rational therapeutic combinations with existing agents will be help to integrate CLDN18.2-targeted therapies into clinical practice.

The claudin family has 27 known members, and their expression pattern in cancer cells depends on the tumor cells’ origin.

 In healthy cells, CLDN18.2 expression is limited to the tight junctions of differentiated gastric mucosal membrane epithelial cells, where this protein’s primary functions are to preserve the barrier function of gastric mucosa, control cell lineage differentiation, and prevent leakage of sodium and hydrogen ions in gastric acid.

Elevated expression of CLDN18.2 often accompanies cancer, particularly malignancies of the digestive system.1 By performing immunohistochemistry (IHC) on whole tissue sections, CLDN18.2 protein expression was identified in 42.2% of a cohort of 481 patients in Germany who had undergone total or partial gastrectomy for GC or GEJ. The intensity of positive expression was distributed among histoscores of up to 1+ (weak; 14.8% of the positive samples), 2+ (intermediate; 13.3%), or 3+ (strong, 14.1%). Samples were classified as having high expression if 40% or more of tumor cells showed 2+ or greater staining intensity whereas malignancies with 10% or more of tumor cells showing any expression were classified as having low expression levels.

In contrast, IHC analysis of formalin-fixed, paraffin-embedded tissue sections identified CLDN18.2 expression in approximately 74.4% of 367 Korean patients with GC, with 108 (29.4%) samples classified as CLDN18.2 positive based on IHC scores of 2+ or higher with staining on 40% or more of tumor cells.

 In a study of tissue samples from 263 Japanese patients, CLDN18.2 expression was observed in 87% and 80% of primary gastric tumors and lymph node metastases, respectively, with 52% and 45%, respectively, classified as having moderate to strong expression of 2+ or greater on IHC testing.

These variations suggest that ethnic differences, among other factors, should be further investigated in assessing the impact of CLDN18.2 expression in GC.

 However, not all studies of tumor CLDN18.2 expression have been conducted in gastric tumors. In one study of 202 patients with primary pancreatic tumors, CLDN18.2 expression in at least 1% of tumor cells was found in 59.2% of primary pancreatic adenocarcinomas, 69.4% of lymph node metastases, and 65.7% of liver metastases.

Malignant transformation of gastric epithelial tissue leads to disruption of cell polarity and then to exposure of CLDN18.2 epitopes on the cell surface.

 Although targeted monoclonal antibodies are largely unable to access CLDN18.2 located in tight-junction supramolecular complexes in normal tissue, the perturbations in cell polarity that expose CLDN18.2 epitopes may theoretically enable CLDN18.2targeted antibodies to bind to CLDN18.2 in malignant tissues with minimal off-target effects, making CLDN18.2 an attractive target for therapy.

Zolbetuximab is a novel chimeric immunoglobulin G1 (IgG1) monoclonal antibody that binds to CLDN18.2 on the surface of cancer cells and triggers cell death by activating antibody-dependent cellular cytotoxicity (ADCC) and complement- dependent cytotoxicity (CDC) pathways.

Adding zolbetuximab to chemotherapy showed a survival advantage over a first-line standard chemotherapy regimen in the SPOTLIGHT trial (NCT03504397), marking the first phase 3 results to show the benefits of targeting CLDN18.2 in any tumor type, investigations said in reporting the findings in 

 The study enrolled 565 patients from 20 countries with previously untreated CLDN18.2-positive, HER2-negative locally advanced unresectable or metastatic GC or GEJ. CLDN18.2 positivity was defined as 75% or more of tumor cells showing moderate to strong CLDN18.2 membranous staining on IHC testing.

Participants were randomly assigned to receive zolbetuximab (n = 283) or placebo (n = 282) plus mFOLFOX6 (modified folinic acid, fluorouracil, and oxaliplatin).

After a median follow-up of approximately 13 months, the median progression-free survival (PFS) was 10.61 months (95%CI, 8.9012.48) in patients who received zolbetuximab plus mFOLFOX6; it was 8.67 months (95% CI, 8.21-10.28) for those who received placebo plus mFOLFOX6 (HR, 0.75; 95% CI, 0.60-0.94; P = .0066).

 Median overall survival (OS) was 18.23 months in the zolbetuximab group and 15.54 months in the placebo group (HR, 0.75; 95% CI, 0.60-0.94; P = .0053).

 The overall incidence of all-grade and grade 3 or higher treatment-emergent adverse events (TEAEs) was similar between the groups, at greater than 99% for all-grade TEAEs, and 87% and 78% for the zolbetuximab and placebo groups, respectively, for grade 3 or higher TEAEs. The most common events in the zolbetuximab and placebo groups, respectively, were nausea (82% and 61%), vomiting (67% and 36%), and decreased appetite (47% and 33%).

Kohei Shitara, MD, and colleagues concluded that zolbetuximab plus mFOLFOX6 led to one of the longest median OS reported in phase 3 trials of patients with locally advanced unresectable or metastatic GC or GEJ adenocarcinoma, according to a presentation at the 2023 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium in January. Shitara is chief of the Department of Gastrointestinal Oncology at National Cancer Center Hospital East in Kashiwa, Japan. The survival benefits were observed across most subgroups and could represent a new standard-ofcare regimen for patients with CLDN18.2-positive, HER2-negative disease, investigators said.

Zolbetuximab also was studied in combination with capecitabine plus oxaliplatin (CAPOX) in the phase 3 GLOW trial (NCT03653507), which reported significantly longer PFS and OS compared with placebo plus CAPOX in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic GC or GEJ cancer. CLDN18.2 positivity was defined as 75% or more of tumor cells with strong to moderate membranous CLDN18.2 staining via IHC testing.

The median PFS by independent review among participants in the zolbetuximab arm (n = 254) was 8.21 months (95% CI, 7.46-8.84) vs 6.80 months (95% CI, 6.14-8.08) in the placebo arm (HR, 0.687; 95% CI, 0.544-0.866; P = .0007). The median OS was 14.39 months (95% CI, 12.29-16.49) in the zolbetuximab group vs 12.16 (95% CI, 10.28-13.67) in the placebo group (HR, 0.771; 95% CI, 0.615-0.965; P = .0118).

Similarly, the phase 2 FAST trial (NCT01630083) found that PFS and OS were significantly better with the addition of zolbetuximab to epirubicin, oxaliplatin, and capecitabine in patients with previously untreated locally advanced, inoperable, or metastatic GC, GEJ, or esophageal adenocarcinoma with moderate to strong CLDN18.2 expression in 40% or more of tumor cells. Findings showed that adding zolbetuximab resulted in significantly lower risk for a PFS event of 55% compared with 74% with chemotherapy alone (HR, 0.44; 95% CI, 0.29-0.67; P < .0005). Median OS was 13.0 months with zolbetuximab vs 8.3 months with chemotherapy alone (HR, 0.55; 95% CI, 0.39-0.77; P < .0005).

The benefits of zolbetuximab appeared to be particularly prominent in the subgroup of patients with at least 70% of tumor cells staining positive for CLDN18.2 protein expression via IHC (median PFS, 9.0 months vs 5.7 months with chemotherapy alone; HR, 0.38; 95% CI, 0.23-0.62; P < .0005; median OS, 16.5 months vs 8.9 months with chemotherapy alone; HR, 0.50; 95% CI, 0.33-0.74; P < .0005).

 The most commonly reported TEAEs were nausea (81.8% and 76.2%), vomiting (67.5% and 54.8%), anemia (45.5% and 35.7%), and neutropenia (44.2% and 34.5%) in the zolbetuximab and placebo groups, respectively.

Astellas Pharma Inc, the company developing zolbetuximab, plans to use findings from the SPOTLIGHT and GLOW trials to establish a foundation for regulatory submissions to the FDA and agencies around the world.

In pancreatic cancer, antitumor activity of zolbetuximab with or without gemcitabine in preclinical models of CLDN18.2-positive pancreatic tumors prompted the initiation of a phase 2 open-label, randomized study (NCT03816163) that is assessing the efficacy and safety of zolbetuximab plus gemcitabine and nab-paclitaxel (arm 1) compared with the chemotherapy agents alone (arm 2) in patients with metastatic disease with moderate to strong CLDN18.2 expression in 75% or more of tumor cells in IHC testing.

 The trial began with a safety lead-in phase to confirm the recommended phase 2 dose, followed by randomly assigning 2:1 approximately 357 patients to the zolbetuximab-containing or the chemotherapy-alone regimen.

The primary end points include dose-limiting toxicities (DLTs) in the safety lead-in phase, OS in the randomization phase, and safety and tolerability in both trial phases.

ASKB589 is a humanized IgG1 monoclonal antibody that binds to CLDN18.2 with high affinity and has enhanced ADCC activity.

 Preliminary safety and efficacy data from an ongoing phase 1/2 dose-escalation and dose-expansion study (NCT04632108) showed no DLTs among 51 patients with advanced solid tumors who received ASKB589.13 In part B of the trial, the addition of ASKB589 to capecitabine plus oxaliplatin resulted in partial responses in 9 of 12 evaluable patients and stable disease in the remaining 3 patients for an overall response rate (ORR) of 75% and a disease control rate (DCR) of 100%.

 The most common treatment-related adverse events (TRAEs) with ASKB589 plus chemotherapy included nausea (76%), vomiting (66%), hypoalbuminemia (52%), granulocytopenia (38%), and hypoleukemia (33%).

Osemitamab (TST001), the second most advanced CLDN18.2-targeting antibody in terms of clinical development, is a humanized IgG1 antibody that binds to the extracellular domains of the CLDN18.2 protein and exerts anticancer effects via ADCC and CDC processes.

 Based on preclinical findings that osemitamab has strong antitumor activity as a single agent and synergizes with immune checkpoint inhibitors in CLDN18.2-positive tumors, the phase 1/2a TranStar102 trial (NCT04495296) was initiated. For this study, CLDN18.2 positivity is defined as membranous staining of 1+ or greater intensity in 10% or more of tumor cells by IHC testing. 

The study includes dose-escalation and dose-expansion phases evaluating osemitamab in combination with nivolumab (Opdivo), a PD-1 inhibitor, plus CAPOX (cohort G) or with nivolumab (cohort H) in patients with GC or GEJ adenocarcinoma.

 Patients with HER2-negative or unknown locally advanced or metastatic disease who have not received prior first-line therapy will be assigned to cohort G; participants with disease recurrence after at least 2 prior systemic therapies will be eligible for cohort H.

Investigators are scheduled to present an update on PFS and duration of response from TranStar102 at the 2023 ASCO Annual Meeting in June. A poster on the phase 1/2 TranStar101 study (NCT04396821) evaluating osemitamab plus nivolumab with or without mFOLFOX6 in patients with GC or GEJ adenocarcinoma or with gemcitabine plus nab-paclitaxel in participants with pancreatic adenocarcinoma also is on the agenda.

PT886 is a bispecific antibody that targets CLDN18.2 and CD47, a member of the immunoglobulin superfamily that is overexpressed in multiple tumor types and decreases phagocyte activity by binding to SIRPα on phagocytic cells.16 PT886 uses IgG1 to exert ADCC via natural killer cells and antibody-dependent cellular phagocytosis via macrophages while targeting CD47 removes the inhibition of macrophage-mediated phagocytosis.

 An open-label, dose-escalation and dose-expansion phase 1 study (NCT05482893) has been initiated at The University of Texas MD Anderson Cancer Center in Houston to study the safety, tolerability, pharmacokinetics, and preliminary efficacy of PT886 in patients with unresectable or metastatic GC, GEJ adenocarcinoma, or pancreatic ductal adenocarcinoma for which no standard therapies are available.

TJ-CD4B is being evaluated in a phase 1 dose-escalation and dose-expansion study (NCT04900818) in patients with advanced solid tumors, namely GC, GEJ carcinoma, esophageal adenocarcinoma, and pancreatic ductal carcinoma, in which it was found to be safe and well tolerated at a weekly dose up to 3 mg/kg.

The clinical trial investigators are planning to study the drug in biomarker-selected populations.

CMG901 is an ADC that is composed of an antiCLDN18.2 monoclonal antibody joined to a cytotoxic payload (monomethyl auristatin E ) by a cleavable linker. It has demonstrated anticancer activity via bystander killing, ADCC, and CDC.

 The FDA granted CMG901 a fast track designation in April 2022 as a monotherapy for treatment of patients with unresectable or metastatic GC and GEJ cancer that is relapsed and/or refractory to approved therapies.

Interim results of a phase 1a trial (NCT04805307), which is being conducted in China, involved 13 patients with advanced GC or GEJ cancer and 14 patients with pancreatic cancer.

 Findings showed that CMG901 was well tolerated (the rate of grade 3 or higher TRAEs was 11.1%, and no grade 4 or 5 TRAEs were reported) and led to an ORR and DCR of 75% and 100%, respectively, in the 8 patients with CLDN18.2-positive GC or GEJ cancer.19 The phase 1b dose-expansion phase of the trial is enrolling patients with GC/GEJ adenocarcinoma, pancreatic cancer, and other solid tumors, and multiple phase 2 and 3 trials are in the planning stages.

CT041 is composed of autologous T cells genetically engineered to express a CLDN18.2-targeted CAR, which includes a humanized scFv specific to CLDN18.2, a CD8α hinge region, a CD28 costimulatory domain, and a CD3ζ signaling domain.

 In an interim analysis of a phase 1 trial (NCT03874897) that included patients with CLDN18.2-positive cancers (expression intensity of 2+ or greater and positive tumor cell rate 40% or higher) of the digestive system, all patients experienced a grade 3 or higher hematologic toxicity related to the preconditioning regimen, and 94.6% of patients had grade 1 or 2 cytokine release syndrome (CRS), although no cases of grade 3 or higher CRS were observed.

 The ORR and DCR were 48.6% (95% CI, 31.9%-65.6%) and 73.0% (95% CI, 55.9%-86.2%), respectively, among all patients and 57.1% (95% CI, 37.2%-75.5%) and 75% (95% CI, 55.1%-89.3%), respectively, among patients with GC.

 A single-arm, open-label phase 1b trial (NCT04404595) that enrolled a US-based population with CLDN18.2-positive, advanced GC or pancreatic adenocarcinoma found that all CRS events were grade 1 or 2; no DLTs, treatment-related deaths, immune effector cell–associated neurologic syndrome, or severe gastrointestinal-related adverse events were reported. The only grade 4 events were hematologic toxicities associated with the conditioning regimen.

 Among 8 evaluable patients, 3 patients (all of whom had GC) had a clinical response.

Challenges of Targeting CLAUDINS and Next Steps 

Although multiple CLDN18.2-targeted therapies appear promising for treatment of patients with CLDN18.2-positive cancers, several challenges need to be addressed in the ongoing development of safe and effective therapies.1 Identifying the optimal drug format for targeting for CLDN18.2 remains an ongoing effort.

 Although bispecific monoclonal antibodies and ADCs are novel approaches that may improve efficacy of CLDN18.2-targeted therapies, the clinical development and application of these molecules overall are less mature than with traditional monoclonal antibodies, which have extensive development experience, well-developed regulatory systems, and a longer history of clinical use.

 CAR T-cell therapies targeting CLDN18.2 share the same obstacles that these agents face in solid tumors overall in terms of the risk of immunosuppressive effects, highly variable response rates, and a complicated and expensive production process.

Future efforts for developing CLDN18.2-targeted therapies should aim to maximize binding affinity for the target, minimize immunogenicity, and optimize the half-life to exert antitumor activity with minimal adverse effects, investigators said.

Identifying the optimal patient population via biomarker studies also is important for maximizing the potential benefit of CLDN18.2-targeted therapies.

 The variability in CLDN18.2 positivity rates among studies may be caused by discrepancies in detection methods, thresholds for positivity, and patient populations among studies.

 Development of specific reagents that can differentiate CLDN18.2 from other CLDN18 splice variants and standardization of the cutoff for CLDN18.2 positivity are needed to better identify which patients are most likely to benefit from CLDN18.2targeted treatment, investigators said.

1. Cao W, Xing H, Li Y, et al. Claudin18.2 is a novel molecular biomarker for tumor-targeted immunotherapy. Biomark Res. 2022;10(1):38. doi:10.1186/s40364-022-00385-1

2. Kyuno D, Takasawa A, Takasawa K, et al. Claudin-18.2 as a therapeutic target in cancers: cumulative findings from basic research and clinical trials. Tissue Barriers. 2022;10(1):1967080. doi:10.1080/21688370.2021.1967080

3. Dottermusch M, Krüger S, Behrens HM, Halske C, Röcken C. Expression of the potential therapeutic target claudin-18.2 is frequently decreased in gastric cancer: results from a large Caucasian cohort study. Virchows Arch. 2019;475(5):563-571. doi:10.1007/s00428-019-02624-7

4. Baek JH, Park DJ, Kim GY, et al. Clinical implications of claudin18.2 expression in patients with gastric cancer. Anticancer Res. 2019;39(12):6973-6979. doi:10.21873/anticanres.13919

5. Rohde C, Yamaguchi R, Mukhina S, Sahin U, Itoh K, Türeci Ö. Comparison of claudin 18.2 expression in primary tumors and lymph node metastases in Japanese patients with gastric adenocarcinoma. Jpn J Clin Oncol. 2019;49(9):870-876. doi:10.1093/jjco/hyz068

6. Wöll S, Schlitter AM, Dhaene K, et al. Claudin 18.2 is a target for IMAB362 antibody in pancreatic neoplasms. Int J Cancer. 2014;134(3):731-739. doi:10.1002/ijc.28400

7. Astellas announces zolbetuximabmeets primary endpoint in phase 3SPOTLIGHT trial as first-line treatment inclaudin 18.2 positive, HER2-negativelocally advanced unresectable ormetastatic gastric andgastroesophageal junction (GEJ)cancers. News release. Astellas Pharma Inc. November 17, 2022. Accessed March 7, 2023. 

8. 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, randomized, double-blind, phase 3 trial. Lancet. Published online April 14, 2023. doi:10.1016/S0140-6736(23)00620-7

9. Shitara KL, Lordick F, Bang YJ, et al. Zolbetuximab + mFOLFOX6 as 1L treatment for patients with claudin-18.2+ (CLDN18.2+)/HER2– locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: primary results from phase 3 SPOTLIGHT study. J Clin Oncol. 2023;41(suppl 4):LBA292. doi:10.1200/JCO.2023.41.4_suppl.LBA292

10. Xu RH, Shitara K, Ajani JA, et al. Zolbetuximab + CAPOX in 1L claudin-18.2+ (CLDN18.2+)/HER2− locally advanced (LA) or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: primary phase 3 results from GLOW.J Clin Oncol.2023;41(suppl 36):405736. doi:10.1200/JCO.2023.41.36_suppl.405736

11. Sahin U, Türeci Ö, Manikhas G, et al. FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma. Ann Oncol. 2021;32(5):609-619. doi:10.1016/j.annonc.2021.02.005

12. Park W, O’Reilly EM, Furuse J, et al. Zolbetuximab plus gemcitabine and nab-paclitaxel (GN) in first-line treatment of claudin 18.2–positive metastatic pancreatic cancer (mPC): phase 2, open-label, randomized study.J Clin Oncol. 2023;41(suppl 4):TPS782. doi:10.1200/JCO.2023.41.4_suppl.TPS782

13. Zhang M, Gong J, Wang J, et al. A phase I/II study of ASKB589 (anti-claudin 18.2 [CLDN18.2] monoclonal antibody) in patients with solid tumors.J Clin Oncol.2023;41(suppl 4):397.doi:10.1200/JCO.2023.41.4_suppl.397

14. Guo W, Germa C, Qi C, et al. TST001 (a high affinity humanized anti-claudin18.2 monoclonal antibody) in combination with nivolumab plus capecitabine and oxaliplatin as first-line or with nivolumab as late-line treatment in locally advanced and metastatic gastric/gastroesophageal junction (G/GEJ) cancer: design of cohorts from a phase I/IIa study (TST001-1002).J Clin Oncol. 2023;41(suppl 4):TPS476. doi:10.1200/JCO.2023.41.4_suppl.TPS476

15. Transcenta to present two clinical trial progress at ASCO. News release. Transcenta Holding Limited; May 8, 2023. Accessed May 11, 2023. bit.ly/41vHzpM

. 16. Overman MJ, Melhem R, Blum-Murphy MA, et al. A phase I, first-in-human, open-label, dose escalation and expansion study of PT886 in adult patients with advanced gastric, gastroesophageal junction, and pancreatic adenocarcinomas. J Clin Oncol.2023;41(suppl 4):TPS765. doi:10.1200/JCO.2023.41.4_suppl.TPS765

17. I-Mab receives FDA orphan drug designation for its novel claudin 18.2 × 4-1BB bispecific antibody TJ-CD4B for the treatment of gastric cancer. News release. I-Mab Biopharma. March 3, 2022. Accessed March 7, 2023.https://bit.ly/3IYRlJI

18. FDA granted CMG901 fast track designation for unresectable or metastatic gastric and gastroesophagealjunction cancer which have relapsed and/or are refractory to approved therapies.News release.Keymed Biosciences. April 19, 2022. Accessed March 7, 2023.https://prn.to/3ZWVNzl

19. Xu R, Wei X, Zhang D, et al. A phase 1a dose-escalation, multicenter trial of anti-claudin 18.2 antibody drug conjugate CMG901 in patients with resistant/refractory solid tumors. J Clin Oncol.2023;41(suppl 4):352.doi:10.1200/JCO.2023.41.4_suppl.352

20. QiC, GongJ, Li J,et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results. Nat Med.2022;28(6):1189-1198. doi:10.1038/s41591-022-01800-8

21. Botta GP, Becerra CR, Jin Z, et al. Multicenter phase Ib trial in the U.S. of salvage CT041 CLDN18.2-specific chimeric antigen receptor T-cell therapy for patients with advanced gastric and pancreatic adenocarcinoma.J Clin Oncol.2022;40(suppl 16):2538.doi:10.1200/JCO.2022.40.16_suppl.2538

Oncology Live®

CLDN18.2 has become a promising target for the treatment of patients with digestive malignancies, such as gastric cancer, gastroesophageal junction cancer, esophageal cancer, and pancreatic cancer, because of its limited expression in healthy tissues and abnormal overexpression in a range of malignancies.

Claudin-18.2 Emerges as a Novel Therapeutic Target in GI Malignancies

As longer-term data read out for established regimens in urothelial cancer and up-and-coming therapeutics inch toward approval, optimizing treatment approaches relies on buy-in from multidisciplinary teams and patients.

“It’s great to see how the field is rapidly evolving and how we can provide more options for our patients,” Petros Grivas, MD, PhD, said in a recent 

. “In the past 6 years, we have all these new agents— checkpoint inhibitors, 2 antibody-drug conjugates, targeted therapy— all recently approved and many more to come.”

As more options expand the use of systemic therapies in practice to either avoid or reduce the invasiveness of surgical approaches, discussions across teams as well as with patients are vital. “It’s a balanced discussion about the risks and benefits of trimodal therapy vs surgery,” Mamta Parikh, MD, MS, said. “We often have patients who see radiation oncologists and surgeons….It is important for them to get both perspectives. It comes down to the individual patient—what they’re willing to undergo—and I think clinical trials are so important in this area because I do feel that we may be on the cusp of getting to real bladder preservation for all of our patients with muscle-invasive disease.”

Parikh and Grivas joined a panel of genitourinary cancer experts to unpack how the latest data presented at the 2023 American Society of Clinical Oncology Genitourinary Cancers (ASCO GU) Symposium will influence practice for patients with urothelial carcinomas.

Most patients with high-risk, non–muscle-invasive bladder cancer (NMIBC) with cancer that does not respond or recurs within 12 months have a poor prognosis and will require a radical cystectomy.

The single-arm, multicohort phase 2 KEYNOTE-057 trial (NCT02625961) evaluated the safety and efficacy of the PD-1 inhibitor pembrolizumab (Keytruda) monotherapy in patients with BCG-unresponsive high-risk NMIBC who were ineligible or declined to undergo radical cystectomy. Results from cohort A supported the FDA approval of pembrolizumab monotherapy for this patient population in January 2020.

Cohort B of KEYNOTE-057 included patients with papillary tumors without carcinoma in situ (CIS) and the primary end points were 12-month disease-free survival (DFS) rate of high-risk NMIBC and complete response (CR) rate. After approximately 45 months of follow-up, pembrolizumab showed notable antitumor activity in patients with non-CIS papillary high-risk NMIBC unresponsive to BCG. There were no new safety concerns, and the toxicity was manageable and consistent with cohort A. Results indicate that pembrolizumab monotherapy may be beneficial for patients with non-CIS papillary high-risk NMIBC that is refractory to BCG and who also declined or were ineligible for radical cystectomy.

Among patients in this cohort (n = 132), the 12-month DFS rate for high-risk NMIBC rate was 43.5% (95% CI, 34.9%-51.9%). The 24- and 36-month DFS rates were both estimated to be 34.9% (95% CI, 26.4%-43.4%). The median DFS was 7.7 months (95% CI, 5.5-13.6). Regarding DFS for any disease, the 12-month DFS rate was 41.7% (95% CI, 33.1%-50.0%), and the 24-, and 36-month DFS rates were both 33.0% (95% CI, 24.7%-41.5%). Of note, trial investigators called attention to patients with progressive disease at baseline (n = 18), for whom the 12-month DFS rate was 23.5% (95% CI, 7.3%-44.9%).

Progression-free survival (PFS) outcomes were also favorable for pembrolizumab in cohort B, with a 12-month PFS rate of 88.2% (95% CI, 80.0%-93.2%) for worsening of grade, stage, or death and 88.2% (95% CI, 79.4%-93.3%) for progression to metastatic disease or death. The median PFS for grade/stage was 44.5 months (95% CI, 34.6-not estimable [NE]) and 46.2 months (95% CI, 36.8-NE) for invasive or metastatic disease.

“There was very good disease control, a very high cystectomy-free rate,” Grivas noted adding that “the toxicity signal was what we would expect and there were no new safety signals. Something to look at in the non–muscle-invasive disease space.”

To build on these signals, novel combinations are being explored to boost efficacy with pembrolizumab. For example, the immune checkpoints TIGIT and LAG-3 are known to contribute to treatment resistance in many cancers, so investigators are seeking to leverage these with dual-inhibition approaches. Thus, cohort C of the KEYNOTE-057 trial will evaluate the efficacy and safety of pembrolizumab and the TIGIT inhibitor vibostolimab or the LAG-3 inhibitor favezelimab in patients with high-risk BCG-unresponsive NMIBC with CIS with or without papillary tumors. Tumor evaluations will take place every 12 weeks until year 2 and then every 24 weeks for up to 5 years. The primary efficacy end point is the 12-month complete response rate of high-risk NMIBC.

“There’s a lot of efforts right now in terms of intravesical therapy and trying to develop larger trials for BCG-unresponsive disease and studies that also include randomization,” Andrea B. Apolo, MD, said. “There’s a lot of activity right now for patients with NMIBC that are BCG unresponsive.”

Leveraging Findings From Adjuvant Therapy Trials

Patients with muscle-invasive urothelial carcinoma (MIUC) have a high recurrence rate despite treatment with neoadjuvant cisplatin-based chemotherapy, followed by radical cystectomy in eligible patients.

 Immunotherapy for patients with high-risk muscle-invasive disease has been established in the adjuvant setting with agents such as nivolumab (Opdivo) demonstrating durable improvements.

 Other treatment options, such as atezolizumab (Tecentriq), have missed the mark in this population, and the role of pembrolizumab in this setting remains to be seen.

The approval of nivolumab followed the DFS primary end point in the phase 3 CheckMate 274 trial (NCT02632409) being met in the intention-to-treat (ITT) group and in patients with PD-L1 expression of at least 1%.

 Specifically, CheckMate 274 enrolled patients with highrisk MIUC after radical resection. Patients were randomly assigned 1:1 to nivolumab (n = 353) or placebo (n = 356) for a maximum of 1 year of treatment. Patients had pathologic evidence of UC at high risk of recurrence and an ECOG performance status 1 or less. Primary end points were DFS in ITT patients and in patients with PD-L1 expression of at least 1%. DFS was also analyzed in prespecified subgroups.

At a median follow-up of 36.1 months, the median DFS was 22.0 months (95% CI, 18.8-36.9) with nivolumab arm vs 10.9 months (95% CI, 8.3-15.2) with placebo in ITT patients. Additionally, the median DFS was 52.6 months (95% CI, 25.8-NE) with nivolumab (n = 140) vs 8.4 months (95% CI, 5.6-17.9) with placebo (n = 142) in patients with PD-L1 expression of at least 1%. DFS benefit was seen in most subgroups analyzed. Safety data were consistent with the primary analysis. Overall survival (OS) will be evaluated. At follow-up, nivolumab continued to show DFS benefits vs placebo. These results further support adjuvant nivolumab as a standard of care for patients with high-risk MIUC after radical resection.

“Adjuvant chemotherapy has been used for years and has shown an improvement in PFS,” Apolo said. “There are important data showing that chemotherapy immediately after surgery does improve outcomes, although the trial did not fully accrue to give the OS benefit. We do see a benefit when patients are treated earlier with systemic therapy. If the patient already received neoadjuvant therapy, then we can talk about immunotherapy.”

The phase 3 IMvigor010 trial (NCT02450331) compared atezolizumab with observation as adjuvant therapy in patients with high-risk MIUC. IMvigor010 is, to our knowledge, the largest, first-completed phase 3 adjuvant study to evaluate the role of a checkpoint inhibitor in MIUC, Shilpa Gupta, MD, explained. The trial did not meet its primary end point of improved DFS with adjuvant atezolizumab, and the use of adjuvant checkpoint inhibitor therapy in the setting evaluated in IMvigor010 is not supported at this time.

“It’s important to enroll on trials…to address some of these unmet needs,” Gupta said. “We learned a lot from IMvigor010. Although it was a negative trial for the primary end point, it did teach us a lot about minimal residual disease [MRD] in these patients.”

Gupta noted a poster presentation on circulating tumor DNA (ctDNA) analysis in the IMvigor010 study given during the 2023 ASCO GU Symposium.

 Investigators reported that ctDNA detection at a postsurgical time point was prognostic for DFS and OS. In the observation arm of the trial, patients were stratified by positive (n = 66) or negative (n = 118) ctDNA status. The median DFS was 3 months for those with ctDNA positivity vs not reached for those with ctDNA negativity (HR, 4.86; 95% CI, 3.09-7.60; 

 < .0001). The median OS was 13 months vs not reached, respectively (HR, 5.47; 95% CI, 3.19-9.40; 

“We’re working in exciting times right now where we have some biomarkers that may be able to select the patients that respond better or benefit the most,” Apolo said. “The problem with adjuvant therapy is that we overtreat patients. That’s why it’s hard to see the benefit that the therapy does because a lot of the patients may be cured, and that’s true of all forms. It’s hard to select the patients [who] meet the [criteria for] therapy. That’s why I think ctDNA is very exciting.”

“I have not started using the FDA-approved ctDNA test in clinical practice,” Parihk said. “We have some trials that are evaluating this, but as of now I think that it’s a fascinating area and the IMvigor data are interesting, but I’m not ready to allow it to guide my clinical practice quite yet. We need more trials that will help us further determine how to incorporate MRD into our practice.”

Other trials examining adjuvant immunotherapy include the phase 3 AMBASSADOR trial (NCT03244384), which is exploring the use of pembrolizumab in patients with localized MIBC and locally advanced UC. Monoclonal antibodies can enhance the immune response and help fight cancer by recognizing and blocking checkpoint molecules. OS and DFS are the primary outcome measures in this study, which is expected to complete in 2025.

 “I’m awaiting the AMBASSADOR trial results and would be very excited to report that out,” Apolo said. “It’s such an important trial because the CheckMate-274 [trial] is showing an improvement in DFS. We really want to see what other agents show since the IMvigor010 did not show the data. I’m excited about the AMBASSADOR trial.”

In the clinic, Apolo said that she discusses adjuvant therapy options based on established findings and takes the patient’s prior courses of therapy into consideration. “I do discuss adjuvant chemotherapy with patients if they have not received chemotherapy,” she said. “If they’ve already received chemotherapy, then I discuss adjuvant checkpoint inhibitor [therapy] with nivolumab and discuss the PFS data. We still don’t have survival data, but the PFS data are positive, and it does look like it improves outcomes in patients in terms of DFS in the adjuvant setting, so it is something that I will discuss with patients and offer it to them.

“In terms of upper tract [disease] that’s a little harder. We don’t want to base decisions on subgroup analyses, and that’s what we have right now for adjuvant checkpoint [inhibitors]. The subgroup analysis in patients with upper tract disease did not look like it benefitted them as much as the bladder primaries. If a patient has already received chemotherapy, then I also discuss adjuvant nivolumab; if they haven’t, then I discuss adjuvant chemotherapy.”

On April 3, 2023, the FDA granted accelerated approval to enfortumab vedotin-ejfv (Padcev) in combination with pembrolizumab for patients with locally advanced or metastatic UC and who are ineligible for cisplatin chemotherapy. The second indication for the antibody-drug conjugate highlights the role of nectin-4 as a clinically actionable target in this patient population.

The most recent approval was supported by findings from the phase 1/2 KEYNOTE-869 trial (NCT03288545), which showed that the objective response rate in patients that received enfortumab vedotin and pembrolizumab (n = 121) was 68% (95% CI, 59%-76%), including a 12% CR rate.

 The recommended enfortumab vedotin dose given with pembrolizumab is 1.25 mg/kg (up to 125 mg for patients with a body weight ≥ 100 kg) via intravenous infusion over 30 minutes on days 1 and 8 of a 21-day cycle until disease progression or unacceptable toxicity. The recommended pembrolizumab dose, administered after enfortumab vedotin on the same day, is 200 mg every 3 weeks or 400 mg every 6 weeks.

“We have data in the metastatic setting that enfortumab vedotin is active,” Apolo said. “It’s active on its own as monotherapy and it’s active in combination with checkpoint inhibitor pembrolizumab. This year we saw several trials in progress that are comparing enfortumab vedotin alone with enfortumab vedotin in combination with pembrolizumab. The KEYNOTE-905/EV-303 study [NCT03924895] is evaluating neoadjuvant pembrolizumab alone compared with pembrolizumab plus enfortumab vedotin. KEYNOTE-B15/EV-304 [NCT04700124] is a randomized phase 3 trial comparing enfortumab vedotin plus pembrolizumab with platinum-based chemotherapy in the neoadjuvant setting for patients with muscle-invasive disease. It’s going to be very interesting to move these therapies forward and to see what the outcomes are in these trials.”

The phase 2 TROPHY U-01 trial (NCT03547973) is a multicohort, open-label, study that led to the accelerated FDA approval of sacituzumab govitecan-hziy (Trodelvy) for patients with locally advanced or metastatic UC who previously received a platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor.

 Neutropenia and diarrhea are the most frequent toxicities associated with sacituzumab govitecan, an active medication with a controllable safety profile.

“The TROPHY U-01 cohort 5 study investigated sacituzumab govitecan plus zimberelimab, which is a PD1 inhibitor, vs zimberelimab alone vs avelumab [Bavencio],” Parikh said. “It will give us interesting data. It will be challenging for patients to be on that kind of intensified therapy. There are more challenges in terms of weekly infusions, potential for cytopenias, and gastrointestinal [adverse] effects, so we’ll have to see if the tolerability is acceptable. It will be interesting to see the duration of therapy for all these regimens, including with intensified approaches.”

Taking the Whole Patient Into Consideration

Parikh noted that bladder-preserving efforts are something that should be given more focus because patients’ quality of life is greatly affected with radical cystectomies (

 “There are a lot of really exciting things that are around the corner for bladder cancer [and] one thing that’s very inspiring in our field is that we’re listening to the patients about what they want,” she said. “We have heard that cystectomies are [procedures] they would like to avoid, as they are impacting their quality of life. It’s wonderful to see the field listening to that and looking in both the non–muscle-invasive space as well as the muscle-invasive space to find patients for whom we can spare their bladders and looking at approaches that potentially could get us to bladder preservation for all.”

Grivas also noted that novel preservation approaches are actively being discussed in the clinic using the tools that are available. “This is a very important and rapidly evolving theme [as] we see a trend toward a higher desire and willingness to go for bladder preservation,” he said. “This has been evolving with our urologist [colleagues] being strong advocates for that in well-selected patients. The way we navigate discussions in a busy multidisciplinary clinic is we try to think about the individual in front of us. What is the best local regional definitive therapy assuming no metastasis of course and curative intent? Is radical surgery or trimodality therapy the best approach for bladder preservation? This has to do with a number of patient-related characteristics but also cancer-related characteristics.”

Counseling the patient on the best course of action is the next step, and keeping the patient part of the decision-making process is paramount. “With this approach I would say that approximately 15% to 20% of patients may undergo bladder preservation using anecdotal statistics and of course it’s a method of selection based on the criteria we use for bladder preservation,” Grivas said.

Necchi A, Roumiguié M, Esen AA, et al. Pembrolizumab (pembro) monotherapy for patients (pts) with high-risk non-muscle-invasive bladder cancer (HR NMIBC) unresponsive to bacillus Calmette-Guérin (BCG): results from cohort B of the phase 2 KEYNOTE-057 trial. 

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FDA approves pembrolizumab for BCG-unresponsive, high-risk non-muscle invasive bladder cancer. FDA. Updated January 8, 2020. Accessed May 10, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-bcg-unresponsive-high-risk-non-muscle-invasive-bladder-cancer 

Shore ND, Gupta S, Kulkarni GS, et al. Phase 2 KEYNOTE-057 cohort C: pembrolizumab (pembro) with vibostolimab or favezelimab for patients (pts) with high-risk (HR) bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC). 

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FDA approves nivolumab for adjuvant treatment of urothelial carcinoma. FDA. Updated February 1, 2022. Accessed May 11, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-adjuvant-treatment-urothelial-carcinoma 

Bellmunt J, Hussain M, Gschwend JE, et al; IMvigor010 Study Group. Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial. 

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FDA grants accelerated approval to sacituzumab govitecan for advanced urothelial cancer. FDA. April 13, 2021. Accessed May 10, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sacituzumab-govitecan-advanced-urothelial-cancer 

Vol. 24/ No. 10 | Oncology Live®

Colocation Approach Leads to Decreased Time to Diagnosis, Stimulates Clinician Collaboration

Clinical Updates for the Management of Lung Cancer Brain Metastases

Claudin-18.2 Emerges as a Novel Therapeutic Target in GI Malignancies

Advances Across Urothelial Carcinomas Highlight Need for Shared Decision-making

OncLive Honors 12 Cancer Care Pioneers

The Placebo: A Controversial Element of Randomized Cancer Clinical Trials