SPOTLIGHT shines on zolbetuximab-chemo potential for gastric/GEJ cancer
A combination regimen comprising zolbetuximab and mFOLFOX6* chemotherapy (CT) regimen showed potential as first-line treatment for claudin-18.2-positive**/HER2-negative (CLDN18.2+/HER2–) locally advanced unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma, according to the primary findings of the phase III SPOTLIGHT trial.
“Zolbetuximab + mFOLFOX6 led to statistically significant and clinically meaningful improvements in both progression-free survival (PFS) and overall survival (OS),” reported primary investigator Dr Kohei Shitara from the National Cancer Center Hospital East, Kashiwa City, Chiba, Japan, at ASCO GI 2023.
Median PFS was significantly longer with zolbetuximab-CT vs placebo-CT (10.6 vs 8.7 months; hazard ratio [HR], 0.75; p=0.0066). “Kaplan-Meier (KM) curves showed a relatively early separation, which was maintained until the tail of the curves … Our trial met its primary endpoint,” Shitara said.
One-year PFS rates were higher with zolbetuximab-CT vs placebo-CT (49 percent and 35 percent). The corresponding 2-year rates were 24 percent and 15 percent, underpinning the long-term benefit of zolbetuximab. [ASCO GI 2023, abstract LBA292]
Subgroup analyses also favoured zolbetuximab-CT over placebo-CT in most of the prespecified subgroups***, yielding HRs between 0.56 and 0.84.
OS was also longer in the zolbetuximab-CT vs placebo-CT arm (median 18.2 vs 15.5 months). “I believe this [is] the longest median OS seen in a global phase III trial for gastric cancer,” Shitara stressed. HR was also 0.75 with a p value of 0.0053, which was lower than the predefined significant threshold.
The KM curves for both arms were similar until month 8 when a nice separation became evident, Shitara noted.
OS rates were also higher with zolbetuximab-CT vs placebo-CT, both at 1 year (68 percent vs 60 percent) and 2 years (39 percent vs 28 percent). “Again, this suggests a long-term benefit with zolbetuximab,” he added.
The OS benefit of zolbetuximab remained consistent across most subgroups.
Other secondary endpoints, safety
Objective response rates were similar between the zolbetuximab-CT and placebo-CT arms (61 percent vs 62 percent), as was median duration of response (8.5 vs 8.1 months).
Regarding patient-reported outcomes (PROs), formal analysis is still underway, but the initial descriptive analysis did not signify any major difference between arms, noted Shitara. “This suggests that zolbetuximab has no negative impact on PROs or quality of life.”
Serious treatment-emergent adverse event (TEAE) rates were similar between arms (45 percent vs 44 percent), but there were more discontinuations owing to treatment-related AEs (TRAEs) with zolbetuximab-CT vs placebo-CT (14 percent vs 2 percent). The rates of TRAEs leading to death were low at <2 percent in both arms.
More grade ≥3 nausea and vomiting events were observed with zolbetuximab-CT vs placebo-CT (16 percent vs 6 percent), typically occurring during the first or second cycles of zolbetuximab. These events were managed by infusion adjustments, with rates dropping at subsequent cycles, Shitara noted.
CLDN18.2 a promising target
A total of 565 participants (median age 61 years, 62 percent male) were randomized 1:1 to receive mFOLFOX6 IV Q2W combined with either zolbetuximab 800/600# mg/m2 or placebo IV Q3W for four 42-day cycles. Following which, participants were given zolbetuximab 600 mg/m2 or placebo IV Q3W in combination with 5-FU and folinic acid IV Q2W.
A third of participants were from Asia. The stomach was the primary cancer site in three-quarters of participants. About half of the overall cohort received subsequent anticancer therapies.
G/GEJ cancer patients have a high unmet medical need. Apparently, median OS with standard-of-care (SoC) CT is only about a year, with low long-term survival rates. [Ann Oncol 2022;33:1005-1020; Ann Oncol 2022;33:992-1004; Gastric Cancer 2021;24:1-21]
Moreover, targeted therapies (ie, nivolumab, trastuzumab), when combined with CT, only prolong survival in certain subsets of patients. [NEJM 2021;384:1191-1203; Lancet 2021;398:27-40; Nature 2022;603:942-948; Chin J Cancer Res 2022;34:207-237] “[Hence,] there is a need to identify additional subsets of G/GEJ cancer that can be therapeutically targeted for benefit,” said Shitara.
CLDN18.2, a tight junction protein, is normally expressed in gastric mucosa cells and retained in metastatic G/GEJ tumour cells. They may be exposed on the surface of G/GEJ cancer cells, making it a promising target. “We may be able to use a treatment that targets this protein to kill the cancer cells,” noted Shitara. [clinicaltrials.gov/ct2/show/NCT03504397, accessed February 6, 2023]
Zolbetuximab, a first-in-class chimeric IgG1 monoclonal antibody targeting CLDN18.2, has shown promise in the treatment of G/GEJ cancer when combined with CT. [Eur J Cancer 2018;100:17-26; Ann Oncol 2019;30:1487-1495; Ann Oncol 2021;32:609-619]
Together with previous evidence, the SPOTLIGHT findings support the potential of zolbetuximab + mFOLFOX6 as a new SoC treatment for a biomarker-based subgroup of G/GEJ cancer patients, Shitara concluded.