These are our learning objectives. Briefly, we're going to review the epidemiology, risk factors, diagnosis, and staging for gastric and gastroesophageal junction cancers. We're going to have an emphasis on biomarkers, and then we're going to talk about the mechanism of action and clinical efficacy of zolbetuximab in treating tumors in this patient population that express CLDN18.2. We're also going to emphasize the safety profile and management strategies for adverse events associated with therapy. And finally, we're going to apply evidence-based data and review patient cases to inform treatment decision-making and optimize patient outcomes using zolbetuximab in clinical practice.

This is our program overview. We'll start with a brief introduction, then transition to the treatment landscape with a focus on biomarkers and CLDN18.2 targeting agents. We will then hone in on zolbetuximab as one of the newest agents in this patient population. And finally, we're going to focus on key studies for patients treated with zolbetuximab.

Dr. Strickland: The epidemiology of gastric and esophageal cancer in the US: there are just over 30,000 new cases of gastric cancer diagnosed in the US with just shy of 11,000 deaths. The epidemiology of esophageal cancer is not terribly different, with 22,000 new cases and approximately 16,000 deaths. I would point out that although in relative terms these incidences are lower within the US population, the global burden of gastroesophageal cancers is quite high.

One particularly alarming trend: despite a global decrease in incidence overall, there does seem to be increasing rates of young adult-onset gastroesophageal cancer. Our understanding of the etiology is incomplete, but this represents approximately a two-and-a-half-fold increase in this patient population since the early 1970s.

In terms of stage at diagnosis, for gastric cancer patients, approximately a third of the time the disease is localized, but it's really more like 50% that the disease is locoregional. Distant spread equates to a stage four advanced diagnosis, and that's just over a third of cases. The proportions for gastroesophageal junction cancer are, for the most part, similar with some subtle differences. In the medical oncology clinic, we're often seeing patients in a roughly 50/50 proportion for locoregional and advanced disease. For patients fortunate to have truly localized disease, the medical oncologist will often not meet these patients — they have very successful outcomes with endoscopic management alone.

Dr. Strickland: Major risk factors for gastric and GEJ cancer include environmental as well as dietary exposures like alcohol, tobacco, obesity. The Western diet is an increasingly relevant risk factor. There are genetic substrates that can increase risk — some of those germline mutations could include CDH1, TP53, or others. Epstein-Barr viral infection is a well-characterized risk factor. This is slightly more relevant outside of North American and Western populations, but it is a dominant risk factor worldwide. I would say the same for H. pylori — due to increased understanding of the mechanism as well as eradication programs, this has been an example of a successful decrease in H. pylori-mediated gastric and GEJ cancer incidence. Gastroesophageal reflux disease left unchecked and eventually developing Barrett's esophagus is also a well-characterized but still incompletely understood risk factor.

Dr. Strickland: Screening is not routinely recommended in the US or most Western countries. Because of that, we typically see patients come in with more advanced disease in relative terms. In countries with high incidence, mass screening has been implemented and has led to increases in overall survival. Great examples of such screening programs occur in Japan and Korea, where patients in their fourth or fifth decade will begin getting screening endoscopies on the order of every 2 to 3 years.

Standard TNM staging — as the audience is very likely familiar — depth of invasion as well as spread to lymph nodes and/or distant spread can make the difference between the final stage, the treatment selection, and ultimately the outcomes and survival.

Dr. Strickland: Some guiding principles: if a lesion is localized, we are hopeful that endoscopic management alone can ultimately lead to a successful outcome. If the depth of invasion is sufficient that there is high risk of spread to lymph nodes, we typically look at a multidisciplinary approach that broadly could include systemic therapy, possibly a role for radiation, and ultimately surgical resection for a localized or locoregional lesion. If advanced disease is confirmed, typically this is not amenable to surgical resection and the dominant treatment approach involves systemic therapy — which can be further subdivided into chemotherapy, immunotherapy, or possibly targeted therapy.

Dr. Strickland: Gastric and GEJ adenocarcinoma has several conventional as well as emerging biomarkers. These include HER2; PD-L1 with various cutoffs relevant to clinical decision making — a threshold of ≥1 is seen in 67 to 82% of cancers, ≥5 in 29 to 60% of adenocarcinomas, and ≥10 in 16 to 49%. The next relevant biomarker is mismatch repair, which we often call MSI-high. CLDN18.2, at the conventional cutoff based on the latest approval, is approximately 38% of cancers. One example of an emerging biomarker that we cannot yet act on outside of a clinical trial would be FGFR2, with a proportion of 30% of these adenocarcinomas.

CLDN18.2 and PD-L1 overlap, particularly at a CPS threshold of five or greater, is highly clinically relevant based on subgroup analyses from landmark trials. In an ad hoc analysis using the Dako 28-8 assay in a subset of randomized patients from the SPOTLIGHT and GLOW studies — just shy of 600 patients with CLDN18.2-positive tumors — 17.4% of tumors had a PD-L1 expression level of five or greater. This illustrates the current state of overlap between CLDN18.2 expression and what we might consider a minimum threshold for PD-L1-high expression, which lends to some of the current clinical equipoise.

Dr. Strickland: The first question I ask in the clinic is: is the tumor positive for HER2 expression? There is a robust role for HER2-directed agents on a chemotherapy backbone, with or without an immunotherapy agent based on PD-L1 score. The next question is: is mismatch repair defective? For deficient mismatch repair and/or MSI-high tumors, there is a robust role for immunotherapy agents — often given with a chemotherapy backbone, though there is emerging data to support possibly a role for immunotherapy alone.

Moving on to HER2-negative tumors, the next most rational question is: what is the PD-L1 score? And similarly, what is the CLDN18.2 status? For CLDN18.2-positive tumors, we know that the current conventional definition of CLDN18.2 positivity is 2 to 3+ on immunohistochemistry in 75% or greater of cells on the tumor specimen. There is category one evidence for overall survival benefit by including the monoclonal antibody zolbetuximab on a chemotherapy backbone in these CLDN18.2-positive tumors.

Dr. Strickland: CLDN18.2 is an established biomarker in gastric and GEJ adenocarcinoma. It belongs to a family of at least 27 Claudin transmembrane proteins expressed throughout the body with tissue-specific expression patterns. These are major structural components of tight junctions, composed of four transmembrane helix domains and two extracellular loops, playing a critical role in cell polarity and selective paracellular permeability.

In normal gastric mucosa, CLDN18.2 is typically buried within the tight junctions. As a gastric mucosal cell undergoes transformation into a cancer cell — with hallmarks such as loss of polarity and increased epithelial-to-mesenchymal transition — there is increased exposure of CLDN18.2 on the transformed cell compared to the native gastric mucosal cells. Therein lies the therapeutic window and the rationale for CLDN18.2 as a target. CLDN18.2 may also be expressed in lymph node metastases of gastric adenocarcinoma as well as distant metastatic sites — this increased surface expression is retained as cancer spreads from its primary site.

Dr. Strickland: The emergence of CLDN18.2 as a rational target has led to a flurry of CLDN18.2-targeting agents in development. Types of therapies include CAR T-cell therapy, anti-CLDN18.2 monoclonal antibodies, antibody-drug conjugates, and bispecifics — in this case against CLDN18.2 and CD3. These agents are being studied in phase one and in some cases phase two, and we're excited to see how these studies may move the needle for patient outcomes. Early data show some activity by way of response and disease control rate, though numbers remain small.

In terms of toxicities from these developmental agents, CRS is a concern for the CAR T product — no different from other CAR T products for other cancer types. There is also a signal for nausea, vomiting, and in some cases hypoproteinemia or hypoalbuminemia.

Dr. Strickland: Zolbetuximab is a first-in-class immunoglobulin monoclonal antibody that targets CLDN18.2. The mechanism is mediated by antibody-dependent cellular cytotoxicity (ADCC) as well as complement-dependent cytotoxicity (CDC) in CLDN18.2-positive gastric/GEJ adenocarcinoma cells.

One of the first signals was in the phase 2b FAST study, where zolbetuximab given in the setting of a chemotherapy backbone was observed to prolong survival in patients whose tumors demonstrated higher expression of CLDN18.2. Subsequently, zolbetuximab was evaluated in two global phase three studies: GLOW and SPOTLIGHT. Both had a fluoropyrimidine and platinum chemotherapy backbone, with zolbetuximab in the experimental arm. PFS and OS were prolonged in both studies.

GLOW Study Design: Patients with previously untreated, locally advanced unresectable or metastatic gastric/GEJ adenocarcinoma. CLDN18.2 positivity was defined as ≥75% of tumor cells demonstrating moderate to strong membranous CLDN18 staining by IHC. Tumors were also HER2-negative. Patients were randomized 1:1 to capecitabine + oxaliplatin alone or with zolbetuximab. Primary endpoint was progression-free survival. Key secondary endpoints included overall survival, quality of life metrics, and disease control.

SPOTLIGHT Study Design: Very similar patient population with the same CLDN18.2 expression cutoff. Patients were randomized 1:1 with a chemotherapy backbone of modified FOLFOX6, either with or without zolbetuximab.

GLOW Results: Median PFS in the control arm was 8.9 months. In the experimental arm, the median was 11 months — hazard ratio 0.73, which was statistically significant.

SPOTLIGHT PFS (per-protocol set): Median PFS in the control arm was 10.3 months compared to 12.5 months in the experimental arm, hazard ratio 0.65, statistically significant. The separation of the PFS curve occurred earlier in the per-protocol set (approximately 2 months) compared to the full analysis set (approximately 4 months).

SPOTLIGHT OS (full analysis set): Median OS in the control arm was 15.6 months compared to 18.2 months in the experimental arm — hazard ratio 0.78, statistically significant.

SPOTLIGHT OS (per-protocol set): Median OS in the control arm was 16.4 months compared to 21.5 months in the experimental arm — hazard ratio 0.69, statistically significant. The separation in the OS curve occurred at approximately 5 months in the per-protocol set compared to approximately 9 months in the full analysis set.

Dr. Strickland: Looking at treatment-related adverse events occurring in at least 15% of patients from the SPOTLIGHT safety analysis set: the higher proportions in the experimental arm include nausea and vomiting — these are considered on-target treatment-related adverse events. Other adverse events are very similar to what we would consider a chemotherapy toxicity profile. I would also like to point out that hypoalbuminemia had a higher proportion compared to the control arm, although the overall proportion was quite small — about 4% of patients.

Leslie Swanson, NP: Hi, I'm Leslie Swanson, and I'm a Nurse Practitioner at the Fred Hutch Cancer Center in Seattle, Washington. I'm excited to be here today to talk to you about zolbetuximab. We are going to focus on dosing and administration.

Leslie Swanson, NP: Zolbetuximab should be administered in combination with a fluoropyrimidine and platinum-containing chemotherapy regimen. If zolbetuximab and its chemotherapy backbone are administered on the same day, zolbetuximab must be administered first. Dosing frequency is aligned with the chosen chemotherapy backbone — for example, FOLFOX plus zolbetuximab is given every two weeks, or CAPOX plus zolbetuximab is every three weeks.

Zolbetuximab should be administered as an intravenous infusion only — do not administer as an IV push or bolus. Patients should be monitored during their infusion and for two hours after completion, or longer if clinically indicated. We are monitoring for hypersensitivity reactions with symptoms and signs highly suggestive of anaphylaxis — for example, urticaria, repetitive cough, wheeze, and throat tightness. This observation period can occur while other chemotherapy agents are being administered. The prepared infusion bag should not be kept for greater than six hours at room temperature or greater than 16 hours under refrigeration.

To minimize the risk of adverse reactions, begin each zolbetuximab infusion at a slower rate for 30 to 60 minutes. If tolerated, gradually increase the rate as described in the prescribing information.

Leslie Swanson, NP: There are no recommended dose reductions. For patients experiencing nausea or vomiting, this is managed by reducing the infusion rate, infusion interruption, withholding the dose, or permanently discontinuing the drug. Most importantly, zolbetuximab should not be discontinued without first attempting to modify or temporarily interrupt the infusion, or without providing additional treatment for nausea and vomiting.

As we're monitoring our patients, what we're looking for most is a hypersensitivity or infusion-related reaction, or treatment-related events such as nausea and vomiting.

For hypersensitivity — if a patient experiences grade 3, 4, or anaphylaxis, we should immediately stop and permanently discontinue the infusion. For a grade 2 reaction, we can interrupt the infusion, provide symptom management, and resume once recovered to grade 1 or less.

For nausea and vomiting, I want to point out a difference in grading from CTCAE criteria. Nausea during an infusion is graded differently — we're looking at the incidence of how many episodes of nausea, how severe, versus how many episodes of vomiting. For anything grade 2 or higher for nausea, we interrupt the infusion, provide symptomatic support, and once recovered to grade 1 or less, resume at a reduced rate for the remaining infusion. For vomiting grade 2 or 3, we do the same — interrupt, provide symptomatic support, resume at a slower rate. Grade 4 vomiting — which is identified as life-threatening or severe — we should immediately stop and permanently discontinue. Keeping in mind how we approach the infusion, how many times we had to interrupt, and what extra medications were needed, we may want to consider pre-medicating and adjusting the infusion rate for the next infusion.

Leslie Swanson, NP: Some key points to think about related to nausea and vomiting with treatment: the occurrence of nausea and/or vomiting is highest during the first treatment cycle, with a median time of first onset of less than one hour. From SPOTLIGHT and GLOW: about three-quarters of patients on SPOTLIGHT and two-thirds of patients on GLOW experienced nausea and vomiting.

For prevention, administer a combination of antiemetics before each zolbetuximab infusion. For maximal mucosal protection, administer anti-ulcer medications such as PPIs or H2 blockers beginning a few days prior to treatment.

During the actual infusion, consider interrupting, slowing the infusion rate, withholding the dose, or permanently discontinuing based on severity. Always consider administering rescue antiemetics and providing IV fluids as clinically indicated. When thinking about slowing the infusion rate: if running at the PI rate, slow by 50%. If the infusion rate has already been slowed to 50%, slow by an additional 50% (down to 25% of the initial rate).

Leslie Swanson, NP: Leading up to the approval of zolbetuximab, there was very little guidance on the management of treatment-related nausea and vomiting. This prompted the Modified Delphi Panel on the Prevention and Management of Nausea and Vomiting in patients treated with zolbetuximab and chemotherapy. This was an international RAND/UCLA modified panel consisting of 15 clinicians selected based on their experience in the zolbetuximab phase two and three clinical trials.

Prophylaxis prior to the first infusion: Given the high risk for nausea and vomiting, prophylaxis before the first infusion is key. The recommendation is to provide one of the following NCCN-recommended high-risk antiemetic drug regimens — all multidrug regimens using different pathways for mitigation: (1) NK-1 receptor antagonist + 5-HT3 receptor antagonist + dexamethasone + olanzapine; (2) NK-1 receptor antagonist + 5-HT3 receptor antagonist + dexamethasone; or (3) palonosetron + dexamethasone + olanzapine. It is also important to consider anti-ulcer medications or antacids for patients with dyspepsia who have not had a prior total gastrectomy — these should be administered a few days to a week prior to zolbetuximab for maximal mucosal protection. Key takeaway: zolbetuximab should not be discontinued without first attempting to modify or temporarily interrupt the infusion, and/or without providing additional treatment for nausea and vomiting.

Management during infusion: For patients experiencing nausea alone: consider either making no modification, or stopping the infusion for 30 to 60 minutes and restarting at the same rate. If symptoms improve after the first hour, we can also consider slowing the infusion rate without stopping it first. For patients experiencing any vomiting: add antiemetic treatment, stop the infusion for 30 to 60 minutes, and restart at a slower rate if symptoms improve. When modifying the infusion rate, cut by 50% from the target rate. If already at a reduced rate, reduce by an additional 50% (down to 25% of the rate).

Planning for second and subsequent infusions: Take into consideration how previous infusions went. If the patient experienced nausea alone or one episode of vomiting, continue with the rate recommended in the prescribing information — no changes needed, but the antiemetics regimen can be escalated if additional medications were needed. For patients who experienced repeated vomiting, consider slowing the rate and escalating the antiemetics regimen.

Key takeaways: always consider administering antiemetics not used for prophylaxis in patients experiencing nausea or vomiting. Think about the patient's ability to take medications — oral versus topical. Consider a scopolamine patch for refractory nausea and/or vomiting where pre-medication options have already been escalated. Clinicians should avoid zolbetuximab discontinuation and retain flexibility for individual patient management.

Management during second and subsequent infusions: Use information from previous treatments; adjust antiemetics regimens and rates as needed. If experiencing nausea alone, no modifications are necessary. For any vomiting, stop the infusion for 30 to 60 minutes and restart at a slower rate if symptoms improve. As the incidence of nausea and vomiting during infusion does decrease as patients continue to receive therapy, for patients receiving infusion at a slower rate and tolerating well, consider escalating the infusion rate in increments of 25% back up to the full rate.

Leslie Swanson, NP: Consensus-based guidelines can help guide clinicians to prevent and manage nausea and vomiting in patients treated with zolbetuximab plus chemotherapy. This may help patients continue receiving treatment and achieve the benefit it offers. Recommendations for prophylaxis prior to the first infusion: NCCN regimens for high risk of nausea and vomiting — examples include: (1) NK-1 receptor antagonist + 5-HT3 receptor antagonist + dexamethasone + olanzapine; (2) NK-1 receptor antagonist + 5-HT3 receptor antagonist + dexamethasone; or (3) palonosetron + dexamethasone + olanzapine.

Recommendations for management during infusion: interrupt zolbetuximab infusions temporarily for 30 to 60 minutes; administer antiemetics not used for prophylaxis; adjust the zolbetuximab infusion rate (slow by 50% from PI rate; if already at 50%, slow by an additional 50%); and always consider providing additional support such as IV fluids.

Leslie Swanson, NP: So we'll start with our first case. We have a 64-year-old male who presented with a growing right chest wall mass. He underwent extensive surgery with an en bloc resection of the lesion in his anterior three ribs. The pathology came back adenocarcinoma with immunostains suggestive of potentially upper GI origin. He then went on to receive baseline staging with a PET CT, which showed an FDG avid extension lesion in the gastroesophageal junction, as well as supraclavicular and mediastinal lymphadenopathy, making him a stage four esophageal cancer. He had a subsequent EGD which did confirm the ulcerated mass in the gastroesophageal junction. We sent off his tissue for molecular profiling, which came back with HER2 negative and CLDN18.2 positive. And as we were strategizing his treatment options, he was interested in a clinical trial. And so we enrolled him on the phase three trial consisting of zolbetuximab and placebo plus mFOLFOX6.

Dr. Strickland: That's a really great case. And, you know, the first thing that stands out to me is that it reflects a lot of the experiences of the patients that come to our clinics where not only are they symptomatic, but unfortunately after workup, they have advanced disease. Maybe my first question is, what other biomarkers were tested at the baseline? And in your typical practice, which are the biomarkers that are completed for every new patient?

Leslie Swanson, NP: Yeah. So we know that as we are trying to make treatments more precise for our patients and understand what's driving their malignancies, we do want to send the tissue for molecular profiling. And for patients with metastatic GEJ or gastric cancer, we should be sending all of that tissue off for HER2, PD-L1, MSI, and now CLDN18.2.

Dr. Strickland: That's great. And I would say that mirrors our practice at Massachusetts General Hospital. So tell me more about how the patient started treatment and how did they respond?

Leslie Swanson, NP: Yeah. So he went on to the protocol for the trial. He was on zolbetuximab and placebo on day one and day 22, every 42 days. The initial dose of zolbetuximab, or the placebo, was 800 mg/m². And then subsequent infusions every two weeks with 600 mg/m². We had a chemo backbone of modified FOLFOX and the pre-medications that we had planned were palonosetron and fosaprepitant. And so looking at his treatment course, during his initial infusion, he did have grade two nausea that resulted in needing to hold the infusion briefly. We were able to restart and give additional antiemetics for the first hour or two, but because of the nausea and the six-hour window within which zolbetuximab could be kept at room temperature, we were unable to complete the infusion because we ran out of time.

Dr. Strickland: That resonates a lot with some of our early experiences. We definitely had to work out some logistical aspects, particularly with scheduling, and we ended up moving more towards having any patient receiving zolbetuximab in some of the earliest slots in the day — for the exact same reason that you're illustrating. So that definitely resonates. Tell me more about the patient.

Leslie Swanson, NP: Yeah. So based off of his initial treatment, we did some planning to think about how we wanted to strategize for future treatments. And because he was on the clinical trial, we did have some stipulations about not using dexamethasone in the initial infusion, but we could consider adding it to subsequent ones. So we did decide to add IV dexamethasone as a pre-medication for subsequent infusions. When he came back for his next infusion, in addition to palonosetron and fosaprepitant, he received dexamethasone. We ended up giving him additional antiemetics, including lorazepam, an H2 blocker, and some Benadryl, which did help him get through the infusion. And we were able to complete everything within the required time window.

Dr. Strickland: Really hearing the importance of being aggressive with anti-nausea management. And I'm curious — at any point, did you consider actually modifying the dose of zolbetuximab, which presumably is the driver of the symptoms in this case?

Leslie Swanson, NP: Yeah. We didn't actually make any dose modifications to zolbetuximab. And as we've seen, there are actually no recommended dose modifications for zolbetuximab. It was really about strategizing which antiemetics we could utilize to help mitigate symptoms. If we were going to consider dose modifications, more likely it would be in the chemotherapy backbone — and in our experience, it would be more relevant in the days after they're not in clinic, rather than on an actual infusion day.

Dr. Strickland: That sounds very reasonable. So how did the patient end up doing towards the end of their known course?

Leslie Swanson, NP: Yeah. So after we got through the initial two cycles, we did end up having to escalate a little bit more. We added a scopolamine patch that we had him apply the night before his infusion to try and maximize all the medications we could use. And starting with cycle three, he was able to continue with infusions for up to 18 months.

Dr. Strickland: That's really remarkable. Do you think now that your experience has grown, that a multi-antiemetic agent regimen is a one-size-fits-all approach, or do you start with the standard and then titrate as needed based on the individual?

Leslie Swanson, NP: Yeah. So I think for zolbetuximab in particular, a high antiemetic regimen is key. Using multiple modalities for blocking those chemotherapy-induced nausea and vomiting pathways — I do try to limit the amount of medications for our patients, both for adherence (making sure they can take their medications as needed when they go home) and also to preserve interventions we can give them in clinic should they have symptoms.

Dr. Strickland: And actually, I want to go back to some of the logistical aspects of delivering zolbetuximab. Would you say that qualitatively, was there a steep learning curve with the infusion nurses in particular, as well as other important team members like pharmacy?

Leslie Swanson, NP: Yeah. You know, I think it definitely takes an entire team approach. The infusion nurses' familiarity with not only the protocols, but as we move into routine clinical practice of administering zolbetuximab — how to identify an infusion-related reaction versus just a side effect of the drug and how to intervene. I work in an academic center, so we also have infusion APPs who are not routinely interacting with our GI patient population but may get called into an infusion and may not be as familiar with what to expect. So it's definitely a matter of education, collaboration, and making sure that patients are aware of what to expect and how to manage it.

Dr. Strickland: Absolutely. That makes perfect sense. And by extension, just curious — do you liaise often with community providers where you might see a patient for a baseline evaluation or trial consideration, but they end up getting their treatment with a zolbetuximab-containing regimen in the community?

Leslie Swanson, NP: Not too often, but we do always try to keep an open line of communication — as I'm sure at Mass General as well. Patients come to you for that opinion, make sure they're on the right track, but then would like to get treatment closer to home. So we do try to provide guidance on what we've found that works. We make sure our recommendations and notes are clear regarding the regimens we would use, to set those patients up for the best success.

Dr. Strickland: It makes perfect sense. And you know, I think you probably feel similar — but we're lucky that we get to practice at tertiary academic centers with a ton of support and resources. In some ways, our job at MGH was easier because of that support. It's just by definition a little more challenging to administer a new agent after a new approval in the community. But I totally agree with the points you made — it's really about a tight bond with those community providers and upholding the multidisciplinary approach at every step.

Leslie Swanson, NP: Yeah. It was great to see this patient do so well on treatment for so long and be able to mitigate symptoms so that he was able to successfully receive the therapy that helped him for quite a significant amount of time.

Dr. Strickland: That's wonderful.