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Astellas Bullish on Zolbetuximab's Prospects in Gastric Cancer After Two Positive Phase III Readouts

Gastric cancer

NEW YORK – Back-to-back positive Phase III data readouts from the SPOTLIGHT and GLOW trials have given Astellas Oncology confidence in zolbetuximab's approval in gastric cancer.

Data from both the Phase III SPOTLIGHT trial presented in January and the Phase III GLOW trial presented Wednesday show that zolbetuximab, a CLDN18.2-directed monoclonal antibody, plus chemotherapy improves progression-free survival and overall survival versus placebo plus chemotherapy in treatment-naïve patients with CLDN18.2-expressing HER2-negative advanced gastric or gastroesophageal junction cancers.

"These two statistically significant Phase III trials, GLOW and SPOTLIGHT, will serve as the basis for global regulatory submissions, marking remarkable progress in our gastric cancer development program," Ahsan Arozullah, Astellas' senior VP and head of development therapeutic areas, said in a statement on Wednesday.

The patient population was similar in SPOTLIGHT and GLOW, though not identical. Patients in SPOTLIGHT were primarily Japanese and Korean, whereas many of the patients in GLOW were from China, where gastric cancer biology is similar to Western patient populations. The chemotherapy paired with Astellas' zolbetuximab differed, too; in SPOTLIGHT, patients received FOLFOX with zolbetuximab, and in GLOW, the chemo regimen was CAPOX. Astellas will submit the data from both these trials to regulatory authorities and seek approval for zolbetuximab plus chemo in CLDN18.2-positive, HER2-negative gastric cancer patients.

"Across the two studies, in over 1,000 patients, you see a real benefit with the addition of zolbetuximab to chemotherapy," said Manish Shah, a GLOW investigator and a medical oncologist at Weill Cornell Medical College, during an American Society of Clinical Oncology (ASCO) virtual plenary presentation Wednesday afternoon. "This [readout] was a very encouraging result for all of us and for our patients with gastric cancer."

In the GLOW study, investigators randomized 500 patients with previously untreated, advanced gastric or gastroesophageal junction (GEJ) cancer to receive either zolbetuximab plus CAPOX or placebo plus CAPOX. To be eligible for the trial, patients' tumors had to express CLDN18.2 in at least 75 percent of cells, as determined by central immunohistochemistry testing.

For patients on the zolbetuximab-chemotherapy combination, investigators saw a median progression-free survival benefit of 8.21 months versus 6.8 months in patients on placebo plus chemo. After one year on treatment, 35 percent of patients who had received zolbetuximab-chemo were alive without cancer progression versus 19 percent in the comparator arm; two-year progression-free survival rates were 14 percent versus 7 percent, respectively.

The drug also improved overall survival. Patients who received zolbetuximab-chemo lived a median of 14.39 months versus 12.16 months on just chemo. After one year, 58 percent of zolbetuximab-chemo-treated patients were alive versus 51 percent of chemo-treated patients; two-year overall survival rates were 29 percent versus 17 percent, respectively.

According to Shah, the zolbetuximab-containing treatment regimen benefitted patients across all subgroups. The overall response rate improved with the monoclonal antibody, albeit modestly: 53.8 percent in the zolbetuximab-chemo arm versus 48.8 percent in the chemo arm. Importantly, the toxicities were about equal across the arms, with nausea and vomiting being the most common adverse event.

"Zolbetuximab successfully targets CLDN18.2 and meets a truly unmet medical need," Shah said. "GLOW confirmed that zolbetuximab plus chemotherapy is a new standard of care for patients with CLND18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric and GE junction adenocarcinoma."  

Prioritizing first-line therapy with biomarker testing

While Astellas' drug addresses a patient population with unmet need, there are other drugs on the market to treat advanced gastric cancer patients that overlap with the GLOW and SPOTLIGHT study populations. These include Bristol Myers Squibb's Opdivo (nivolumab), which is approved in combination with chemo for patients with advanced gastric or GEJ cancers. The US Food and Drug Administration approved the checkpoint inhibitor for an allcomers population, but as Shah noted, oncologists treating gastric cancer patients take into account data from the CheckMate-649 trial, which showed that patients with PD-L1 expression greater than a combined positive score of 5 derived the most benefit from the checkpoint inhibitor.

The latest data from GLOW surely have oncologists wondering whether a patient with high PD-L1 expression might benefit more from Opdivo-chemo or zolbetuximab-chemo. Merck's checkpoint inhibitor Keytruda also has tumor-agnostic approvals and may be an option for gastric cancer patients with high tumor mutational burden or high microsatellite instability.

Shah emphasized that although the GLOW trial did not enroll patients on the basis of PD-L1 expression scores, the biomarker was a key consideration and warranted a post hoc analysis given the Opdivo approval. In a post hoc analysis of 288 patients in the GLOW trial, Shah pointed out that 78 percent had a PD-L1 combined positive score below 5. "We truly are targeting an unmet need population," he said. However, the uncertainty remains about the other 22 percent with a PD-L1 score above 5.

When it comes to prioritizing treatment, Yelena Janjigian, a medical oncologist at Memorial Sloan Kettering Cancer Center, said during a discussion of the GLOW data that she might still be inclined to use BMS's immunotherapy for patients with both CLDN18.2 positivity and PD-L1 scores greater than 5. This is due in part to the fact that the response rates were a bit better with Opdivo-chemo than with chemo-placebo in BMS's registrational trial than they were for zolbetuximab-chemo in GLOW. Looking ahead, she acknowledged that new treatment strategies are nonetheless on their way to patients with CLDN18.2-positive gastric cancers, including antibody-drug conjugates targeting CLDN18.2, treatments simultaneously blocking PD-L1 and CLDN18.2, and even CAR T-cell therapies.

Given the increased focused on targeting this relatively new biomarker, Janjigian said the primary takeaway from the GLOW and SPOTLIGHT trials should be the importance of adding CLDN18.2 to the list of routinely tested gastric cancer biomarkers. Janjigian said that most oncologists will routinely perform several biomarker tests for advanced gastric cancer patients, including assessing HER2 and DNA mismatch repair deficiency using IHC; microsatellite instability testing with PCR or next-generation sequencing; and occasionally, as is the case at MSK, gauging PD-L1 expression.

"Biomarker testing is critical," she said. "We need to reflexively test all of our patients in all tumors and then prioritize therapy."

As of now, while drugs like zolbetuximab are still investigational, there's no commercially available CLDN18.2 companion diagnostic that oncologists can routinely order for patients, though labs do perform analysis of this biomarker. Widespread uptake will rely on a commercially available diagnostic, Janjigian said.

"We need to wait for an FDA-approved IHC test before testing begins in the clinic," she said, adding that this would standardize the CLDN18.2-positivity cutoff at biomarker expression in 75 percent of cells.

The market entry of drugs that rely on new biomarkers often drive demand for testing. As such, Shah anticipates that as drugs for cancer patients with CLDN18.2 expression become available, so will the biomarker tests.