Claudin 18.2 Represents New Druggable Target for CLDN18.2+/HER2-, Advanced/Metastatic Gastric and GEJ Adenocarcinoma

Samuel Klempner, MD

The use of claudin 18.2 (CLDN18.2) antibody, zolbetuximab in combination with standard-based chemotherapy for the treatment of patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) cancer, was shown to significantly prolong survival.¹

In the phase 3 SPOTLIGHT study (NCT03504397), zolbetuximab 800 mg/m2 was administered with a standard dose of 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) and compared with placebo plus mFOLFOX6. The study explored progression-free survival (PFS) as the primary end point, and the secondary end points included overall survival (OS), objective response rate (ORR), and safety.

Results presented during the 2023 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI) showed a median PFS of 10.61 months with the addition of zolbetuximab to mFOLFOX vs 8.67 months with placebo/mFOLFOX (HR, 0.751; 95% CI, 0.598-0.942; P = .0066). The median OS was 18.23 with zolbetuximab and chemotherapy vs 15.54 months with placebo and chemotherapy (HR, 0.750; 95% CI, 0.601–0.936; P = .0053). the ORR observed with zolbetuximab and mFOLFOX6 was not significantly different from the placebo arm.

In the zolbetuximab and mFOLFOX6 arm vs placebo arm, the most common treatment-emergent adverse events (TEAEs) observed with nausea (82.4% vs 60.8%), vomiting (67.4% vs 35.6%), and decreased appetite (47.0% vs 33.5%). Serious TEAEs occurred in 44.8% of zolbetuximab arm vs 43.5% of the placebo arm.

“This was potentially a practice-changing trial. The 18-month+ is the longest survival we've seen in a global phase 3 trial. I would point practicing clinicians to the idea that this is a new target on the block. It’s anticipated to be coming to our clinics, pending FDA review, and presumed approval based on the trial,” Samuel Klempner, MD, told Targeted Oncology™, in an interview.

In the interview, Klempner, gastrointestinal medical oncologist, Oncology, Massachusetts General Hospital and faculty, Medicine, Harvard Medical School, discussed the significance of the phase 3 SPOTLIGHT study and the future of impact of CLDN18.2 as a biomarker to treat cancers of the stomach and esophagus.

TARGETED ONCOLOGY: Can you talk about zolbetuximab and what rationalizes it’s use in patients with CLDN18.2+ HER2-negative, locally advanced, unresectable, or metastatic gastric or GEJ /GEJ cancer?

Klempner: The whole field of stomach and esophageal cancers is moving towards biomarker selection strategies, and this is great for patients. It helps us match patients to drugs that are ideally suited to have the greatest chance of benefit. That's the idea behind it. The SPOTLIGHT trial, which was presented at ASCO GI 2023, is the latest addition to the biomarker world of gastric and GEJ adenocarcinomas.

There were some earlier clues about the activity of this approach in prior work. CLDN18.2 is overexpressed to varying levels in a large portion of patients with stomach and esophageal cancer. It’s seen in roughly around 40% of patients, depending on what cut off you use. There was a prior trial using monoclonal antibody against CLDN18.2 in combination with an anthracycline-based chemotherapy. It showed that the patients who got the zolbetuximab precursor in this case, IMAB362, added to chemotherapy had an improved survival. It was a phase 2 trial called the FAST study [NCT01630083]. It suggested that this strategy of targeting CLDN-high patients for treatment with a CLDN-directed antibody was something that had a lot of potential. That was the background and rationale for the phase 3 SPOTLIGHT trial presented at ASCO GI 2023.

What was the key purpose of this study? What is important to highlight about the patient population in SPOTLIGHT?

The phase 3 SPOTLIGHT trial asked quite a straightforward question, which is an important thing. We'd like to have our phase 3 trials be relatively simple to answer a straightforward and clinically relevant question. It was asking whether the addition of zolbetuximab to standard chemotherapy improved the progression-free survival and secondary end point of overall survival in patients with frontline gastric and GEJ adenocarcinoma.

The highlight is that this is a real-world population in a phase 3 study. These are patients who have not received prior therapies and it's selecting on the presence of a biomarker. Patients had to be screened and they had to have CLDN18.2 overexpression. In this case, the expression had to be present in greater than or equal to 75% of the cells. Then if they met the CLDN18.2 overexpression, they could be randomized into the trial. It’s a relatively straightforward and clean design. There were some additional stratification factors [including]Asia vs non-Asia, the number of organs with metastases, and people who had prior stomach removal. Also, patients had to be HER2-negative if their HER2 status was known.

What should oncologist know about the study results?

This was potentially a practice-changing trial. The 18-month+ is the longest survival we've seen in a global phase 3 trial. I would point practicing clinicians to the idea that this is a new target on the block. It’s anticipated to be coming to our clinics, pending FDA review, and presumed approval based on the trial.

How could the introduction of a CLDN18.2 antibody impact treatment decisions?

It's going to be a lot about learning to test our patients for this biomarker because we now only test patients for mismatch repair deficiency, HER2, and PD-L1 expression.

Soon, we're going to be needing to test them for CLDN expression, because only the high patients are the ones that met the trial criteria, were included, and seem to be deriving the benefit. I think it's like any new drug when there's a new target and a new drug. There's a learning curve, we have to learn to do the testing, we have to gain experience with the drug in the clinic, manage [adverse events], and support our patients during therapy. But this is going to be a new tool in the toolbox for oncologist taking care of stomach and esophageal cancers.

How do you see this combination fitting into the treatment landscape overall?

The landscape of stomach and esophagus cancer is rapidly evolving, and that's a good thing for patients. Even in the past couple of years, we've had approvals for new HER2 agents like trastuzumab deruxtecan [Enhertu]. We've had immunotherapy added to the frontline, we've had neoadjuvant immunotherapy for MSI-high patients, and there are all great things for patients.

The area that's the most complex is that in patients that have expression of multiple biomarkers [and deciding] how we're going to manage or choose an approach. Let's say a patient walks into your clinic 9 months from now and they're PD-L1 positive and they're CLDN18.2-positive. How do we decide between giving them chemotherapy with immunotherapy or chemotherapy with zolbetuximab. Right now, we don't have head-to-head comparison to pick that. We have to look at the patient factors, we have to look at the [adverse events] of the drugs, we have to have shared decision-making and discussions with the patients, and then we need to look at the relative benefit in the areas that we do have data. For example, someone who is PD-L1-low, but CLDN-positive is someone that I envision using a CLDN antibody in the front-line setting. For someone who's had very high PD-L1 expression, perhaps you might use immunotherapy, or you could do both, but you could choose immunotherapy plus zolbetuximab plus chemotherapy. There are some ongoing trials to test that to see if it's safe and active.

Someday, we may be using triplet combinations of targeted plus immunotherapy plus chemotherapy. But right now, we’re trying to tease apart the data and decide what we think is best for our patients.

What other advice do you have for oncologists who maybe use this drug in the near future?

Like with learning any new drug or any new approach for practicing oncologists, it's all about familiarizing yourself with the data so that we can educate our patients about expectations around things like [adverse events]. When we first started using immune therapy several years ago, we all had to learn about managing immune-related adverse events. Now, we're all pretty comfortable with that. When we started using trastuzumab a year or 2 ago, we all had to be aware of the potential for lung toxicity.

I think that we'll all share strategies that work. This will get spread around by word of mouth and social media as data dives from SPOTLIGHT to understand what management strategies were effective.

_REFERENCE:

_{Shitara K, Lordick F, Bang Y, et al. Zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) 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; (suppl 4; abstr LBA292). doi:10.1200/JCO.2023.41.3_suppl.LBA292}