Overall survival (OS) in heavily pretreated gastroesophageal carcinoma (GEC) doubled in patients who received an investigational antibody-drug conjugate (ADC) targeting claudin (CLDN) 18.2, a randomized trial showed.
Patients treated with sonesitatug vedotin (Sone-Ve) in the third line and beyond had a median OS of 10 months as compared with 5 months for patients treated with a standard-of-care therapy. Twice as many patients remained alive at 12 months (38.1% vs 18.1%). The trial did not meet the second primary endpoint of progression-free survival (PFS) by independent review but met a key secondary endpoint of PFS among patients in third-line or later therapy. The secondary endpoint of median OS did improve significantly with Sone-Ve (10.6 vs 6.4 months).
Adverse events (AEs), serious AEs, and grade ≥3 AEs occurred in a similar proportion of patients in each treatment arm, reported Rui-Hua Xu, MD, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China, at the European Society for Medical Oncology congress in Madrid.
“CLARITY-Gastric01 is the first global phase III trial to demonstrate a statistically significant improvement in overall survival and a manageable safety profile with a claudin 18.2-targeted ADC in patients with previously treated advanced or metastatic claudin 18.2-positive GEC,” said Xu. “Sone-Ve showed a statistically significant and clinically meaningful improvement in overall survival versus investigator’s choice of therapy in both third or later line and the ITT [intention- to-treat] populations. Overall survival was maintained across claudin 18.2 expression subgroups.”
“Sone-Ve is a potential new standard of care in the second- or later-line setting for patients with advanced or metastatic claudin 18.2-positive gastroesophageal carcinoma,” he added.
The most important finding from the trial is the OS improvement in patients treated with Sone-Ve in third line and beyond, said ESMO invited discussant Salah-Eddin Al-Batran, MD, of the Frankfurt Institute of Clinical Cancer Research in Germany.
“I think the valid and fair description of this result is, at least, impressive,” said Al-Batran. “Median survival was more than doubled, from 5 months with investigator choice of therapy, to 10 months with Sone-Ve, and the hazard ratio was less than 0.5. These are good news for our patients who have few options in this setting.”
However, analyses that combined patients who received the ADC in second line or beyond complicate interpretation of the results.
“When including the second-line patients, who make up approximately 30% of the population, the overall survival result remains positive and clearly relevant, but it’s less pronounced,” said Al-Batran. “This leads us to believe that the overall survival seen in the second-line-and-beyond population could be largely driven by patients treated in the third line and beyond.”
“This is supported by the fact that the co-primary endpoint, PFS by [independent review] in the second line and beyond, did not achieve statistical significance,” he continued. “The hazard ratio for the second-line-setting patients was not reported, so I think that the treatment effect in this group requires more data and a dedicated subgroup analysis to draw final conclusions.”
By way of introduction, Xu noted that second-line therapy for GEC is associated with a median OS of <10 months, decreasing to <6 months for third-line options. CLDN 18.2 is highly expressed in about 40% of GEC, but no CLDN 18.2-targeted therapy had global approval for second line and beyond. Sone-Ve consists of an anti-CLDN 18.2 antibody and a microtubule-disrupting payload that might help fill that void.
Investigators in the multinational CLARITY-Gastric01 trial enrolled patients with second-line or later advanced/metastatic GEC associated with CLDN 18.2 expression (≥25% tumor cells with membrane staining). Patients initially were randomized to one of two doses of Sone-Ve or investigator’s choice of therapy. Enrollment in the lower-dose Sone-Ve arm was closed early, and data analysis included only the patients enrolled in the remaining two arms.
The trial had dual primary endpoints: PFS in the ITT population and OS in patients treated in third line or later. The ITT population included 594 randomized patients. The population had a median age of 57, men accounted for 55-60% of the patients, and about 60% of the patients were enrolled in Asia. Gastroesophageal junction/esophageal cancer represented 20-25% of the population. Two-thirds of the patients received treatment in third line or beyond.
The primary analysis showed a 53% reduction in the survival hazard in the Sone-Ve arm (95% CI 0.36-0.62, P<0.000001). Median OS in the ITT population, a secondary endpoint, was 10.6 months with Sone-Ve and 6.4 months with comparators (HR 0.58, 95% CI 0.47-0.73, P=0.000004).
The trial just missed statistical significance for the second primary endpoint, showing a median PFS of 4.2 months with Sone-Ve versus 3.8 months with control therapy (HR 0.77, 95% CI 0.62-0.96, P=0.053193). Investigator-assessed PFS did achieve statistical significance (4.4 vs 3.0 months; HR 0.59, 95% CI 0.48-0.73).
Rates of grade ≥3 adverse events (AEs) “possibly related to treatment” were 36.4% with Sone-Ve and 44.8% with comparator therapies. Rates of discontinuation possibly related to treatment were 3.1% versus 4.4%.
