Shitara and Xu Discuss Potential FDA Approval of Zolbetuximab in CLDN18.2+ Gastric/GEJ Adenocarcinoma

Phase 3 investigations have shown a clear survival benefit with zolbetuximab plus chemotherapy when used in the first line for patients with Claudin 18.2 (CLDN18.2)–positive, HER2-negative locally advanced unresectable or metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma, according to Rui-Hua Xu, MD, PhD, and Kohei Shitara, MD. These findings indicate its potential use as a new standard of care (SOC) for this patient population and support the exploration of other zolbetuximab combinations to expand the limited treatment armamentarium in this disease space.

The FDA granted priority review to a biologics license application (BLA) for zolbetuximab in July 2023 for patients with unresectable, locally advanced or metastatic, CLDN18.2-positive, HER2-negative, gastric, or GEJ adenocarcinoma.¹ Findings from the phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) trials supported the BLA by demonstrating zolbetuximab’s significant improvement of survival outcomes vs placebo in this population.

Patients in the SPOTLIGHT trial achieved a median progression-free survival (PFS) of 10.61 months vs 8.67 months with placebo plus mFOLFOX6 (leucovorin calcium, fluorouracil, and oxaliplatin). The median overall survival (OS) was 18.23 months in the zolbetuximab arm versus 15.54 months with placebo.²

In the GLOW trial, zolbetuximab capecitabine (Xeloda) plus oxaliplatin (CAPOX) produced a median PFS of 8.21 months compared with 6.80 months with placebo plus CAPOX. The median OS was 14.39 months in the zolbetuximab arm and 12.16 months in the placebo arm.³

“This significant improvement of PFS and OS was remarkable because of the limited treatment options for this disease. We believe these [results support] zolbetuximab as a new treatment option for the CLDN18.2-positive population in line with the findings from the GLOW study,” Shitara stated in an interview with OncLive^®.

In a joint interview, Shitara and Xu expand on the advantages of targeting CLDN18.2 with zolbetuximab in gastric/GEJ adenocarcinoma, key efficacy data from the GLOW and SPOTLIGHT trials in support of zolbetuximab’s potential FDA approval, and how this poised indication could address the historically low survival rates and limited treatment options for patients with this disease.

Shitara is a gastrointestinal (GI) medical oncologist in the Department of Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa City, Chiba, Japan. Xu is a professor of medical oncology and the president of Sun Yat-Sen University Cancer Center in Guangzhou, China.

OncLive: What is the unique mechanism of action of zolbetuximab?

Xu: Zolbetuximab is a first-in-class, investigational igG1 monoclonal antibody that targets CLDN18.2. It mediates antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in CLDN18.2–positive gastric or GEJ adenocarcinoma cells. [These processes] are needed to kill cancer cells. CLDN18.2 is a tight junction protein that is exclusively expressed in normal gastric mucosal cells. In both gastric and GEJ junction adenocarcinomas, some of them are expressed in the cancer cell. During malignant transformation, loss of gastric mucosal cell polarity may result in clothing 18.2 becoming more exposed and thus accessible to certain therapeutic antibodies. This means it can be a target. In the GLOW trial, 38.4% of screened patients with tumors assessed for CLDN18.2 expression had tumors that met the cutoff for CLDN18.2-positive [disease]. In SPOTLIGHT, a similar number of screened patients had CLDN18.2-positive tumors.

What makes CLDN18.2 an attractive target for drug development in gastric/GEJ adenocarcinoma?

Shitara: We still have a limited number of targets in gastric cancer. For example, HER2 is expressed in only 15% of gastric cancer and its incidence is higher in GEJ adenocarcinoma rather than stomach cancer. Especially in stomach cancer, we have a [need to identify more] targets for cancer treatment. As Dr. Xu mentioned, around 30% to 40% of patients maintain very high and homogeneous expression of CLDN18.2 in gastric cancers.

What other unmet needs exist for patients in this population?

Xu: Unfortunately, [early-stage patients tend to] have very light symptoms, so [they are] not as easily diagnosed. Most patients with gastric cancer are diagnosed at the advanced or metastatic stage. That means that many with the disease cannot be cured. The standard of care for a patient with this locally advanced, resectable, or metastatic gastric cancer. is platinum and 5-fluororacil. Chemotherapy [includes either] CAPOX, which was used in the GLOW trial, or FOLFOX, which was used in the SPOTLIGHT trial. Standard chemotherapy alone results in a median OS of approximately 1 year. That's not long enough, so that's an unmet clinical need. A gastric cancer patient with CLDN18.2-positive [disease treated with standard] chemotherapy is also likely to experience a lower median OS.We need to search for new agents to improve the survival [and/or] quality of life [of these patients]. [We may] even [allow some] unresectable diseases to [become] resectable so the patient [can potentially be] cured.

What key efficacy findings from the SPOTLIGHT trial may support the approval of zolbetuximab plus mFOLFOX6 in CLDN18.2-positive gastric/GEJ adenocarcinoma?

Shitara: This global phase 3 trial evaluated mFOLFOX6 plus zolbetuximab as a first-line treatment for patients with HER2-negative and CLDN18.2-positive gastric and GEJ adenocarcinomas. CLDN18.2 positivity was assessed by immunohistochemistry and was defined as a moderate to strong expression of more than 75% in the tumor. More than 2700 patients were screened, and nearly 40% of patients had CLDN18.2 expression. [A total of] 565 patients were [enrolled onto] the study.

This study met the primary end point, with PFS being significantly improved with zolbetuximab plus mFOLFOX6 according to central assessment. The median PFS was [10.61] months vs [8.67] months [with chemotherapy alone], with a hazard ratio [HR] of 0.751 and a significant P value [ of .0066]. This trial also showed significant improvement of OS as a key secondary end point.The median OS was [18.23] months with the zolbetuximab regimen vs [15.54] months with placebo, with an HR of 0.75.

The control arm result was better than that of previous global studies. This may be partially based on the different country distribution, with a higher number of patients from Japan and Korea [included in the study]. Despite that, [the experimental regimen] showed a clinically meaningful improvement of OS, and the 18.23-month median OS [may] be the longest median OS in a global phase 3 trial [in gastric cancer]. Interestingly, there was no difference in response rate [between arms].

How do efficacy findings from the GLOW trial similarly support the use of zolbetuximab plus CAPOX in this population?

Xu: We can see the results from the trial are similar to those from SPOTLIGHT. The primary end point was PFS in this trial. PFS was significantly prolonged by zolbetuximab plus CAPOX vs placebo plus CAPOX. The median PFS [with the experimental regimen was] 8.2 years vs 6.8 months in the control group. [This result was] statistically significant. Additionally, OS was also significantly prolonged in patients who received the zolbetuximab regimen vs placebo, at 14.39 months vs 12.16 months, [respectively]. PFS and OS were also prolonged across most subgroups. Both the GLOW and SPOTLIGHT trials demonstrate that zolbetuximab can prolong PFS and OS. We do not see a higher response rate in the [experimental] group, which is similar to data from the SPOTLIGHT trial, but we see a survival benefit. These are good data for the clinical oncologist.

What should be known about the safety profile of zolbetuximab?

Shitara: Nausea and vomiting are [common] on-target toxicities for CLDN18.2-positive patients. They are more commonly observed with zolbetuximab vs placebo, with a 20% higher incidence of any-grade adverse effects [AEs] and 10% higher incidence of grade 3 or higher Aes. These events usually occur during the first cycle, especially during treatment administration. Sometimes we need a dose interruption or adjustment.

Usually these AEs are manageable, and re-administration is almost always possible in my experience. The incidence of nausea and vomiting apparently decreased in subsequent cycles, so management during the first cycle is very important. Otherwise, there were no major differences in toxicities [with zolbetuximab vs placebo.] If we can [get past] the first or second treatment cycle, the [zolbetuximab] combination is very feasible.

Given these data, are there any patients in whom you would hesitate to use this agent?

Xu: In my practice, I'm definitely going to treat a patient with CLDN18.2-positive advanced gastric cancer with zolbetuximab plus CAPOX or FOLFOX. This regimen could be a new SOC first-line regimen if [it gains] FDA approval, as both trials demonstrated PFS and OS benefit. The combinations have good safety profiles as mentioned by Dr Shitara. Some patients with CLDN18.2-positive, [PD-L1–positive] disease and a tumor positive score (TPS) more than 5...those patients may have more options. A PD-1 inhibitor plus chemotherapy is one of them.

If zolbetuximab gains FDA approval in CLDN18.2–positive gastric/GEJ adenocarcinoma, how might it influence the treatment paradigm going forward?

Shitara: These 2 trials clearly support zolbetuximab plus chemotherapy as a new treatment option for a HER2-negative and CLDN18.2–positive population. As Dr Xu mentioned, there should be debate whether chemotherapy plus zolbetuximab should be used for patients with high PD-L1 and high CLDN18.2 expression.

Chemotherapy plus zolbetuximab may be the best choice for patients with CLDN18.2-positive and [low PD-L1 expression]. [For] a patient with microsatellite instability [MSI]–high and CLDN18.2-positive disease, I prefer chemotherapy plus a checkpoint inhibitor because of the benefit of checkpoint inhibition in this population. Otherwise, I prefer chemotherapy plus zolbetuximab for patients with CLDN18.2-positive and a TPS score of 5 or higher because we can use nivolumab [Opdivo] in Japan [as a later-line] treatment option. Even after the approval of zolbetuximab, we would only be able to use it in the first line, so my preference is to use chemotherapy first for most patients. However, [the optimal choice of regimen] should be debated in each country and should be dependent on the availability of checkpoint inhibitors. Overall, more options are always good for us and our patients.

What future directions do you envision for the investigation of zolbetuximab in gastric/GEJ adenocarcinoma?

Xu: It would be interesting to develop a new combination in a HER2-negative, CLDN18.2–positive subpopulation. We are looking forward to higher response rates [with zolbetuximab regimens]...in clinical trials. Another consideration [is to explore this agent] in the neoadjuvant or adjuvant settings for this subpopulation. In the future, these are directions for the new anti-cancer drugs [to potentially] improve survival, even for the patients with resectable disease.

Shitara: I agree with Dr Xu that [zolbetuximab in] combination with other treatments, especially immune checkpoint inhibitors, would be very attractive. We performed a treatment biopsy during treatment with zolbetuximab and it showed some change of the tumor microenvironment. Preclinical studies support the combination with chemotherapy, a checkpoint inhibitor, and zolbetuximab. Trials to evaluate such a combination are currently ongoing. Also, one of the very attractive aspects of this development is that we can target this marker without a druggable gene alteration. Previously we hadn't found a good driver or genomic alteration in gastric cancer, such as EGFR. CLDN18.2 is just a protein, but it can be targeted by antibodies or other treatments. For this population, there are so many other compounds that are being tested, [including] CAR T cells, antibody-drug conjugates, and bispecific antibodies. This is a very attractive field [for drug development].

References

1. Astellas announces US FDA grants priority review for zolbetuximab biologics license application. News release. Astellas. July 6, 2023. Accessed November 22, 2023. https://www.astellas.com/en/system/files/news/2023-07/81743d9407/20230706_en_1.pdf
2. Shitara K, Lordick F, Bang YJ, 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 trial. J Clin Oncol. 2023;41(suppl 4):LBA292. doi:10.1200/JCO.2023.41.3_suppl.LBA292
3. Xu R, 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