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CMG901 induced responses with a manageable toxicity profile in patients with CLDN18.2-positive gastric or gastroesophageal junction cancer, according to updated data from the dose-expansion phase of the phase 1 KYM901 study.
The antibody-drug conjugate (ADC) CMG901 induced responses with a manageable toxicity profile in patients with CLDN18.2-positive gastric or gastroesophageal junction (GEJ) cancer, according to updated data from the dose-expansion phase (part B) of the phase 1 KYM901 study (NCT04805307) presented during the 2023 November ASCO Plenary Series.1
In the total patient population (n = 89), the confirmed objective response rate (cORR) was 33% (95% CI, 23.0%-43.3%), and the confirmed disease control rate (DCR) was 70% (95% CI, 59.0%-79.0%). At a median follow-up of 6.0 months (95% CI, 4.2-8.3%), the median duration of response (DOR) was 7.2 months (95% CI, 5.3-not reached [NR]).
When broken down by dose level, the cORRs achieved when CMG901 was administered at 2.2 mg/kg (n = 31), 2.6 mg/kg (n = 42), or 3.0 mg/kg (n = 16) were 42% (95% CI, 5%-60.9%), 24% (95% CI, 12.1%-39.5%), and 38% (95% CI, 15.2%-64.6%), respectively. The DCRs in these groups were 71% (95% CI, 52.0%-85.8%), 67% (95% CI, 50.5%-80.4%), and 75% (95% CI, 47.6%-92.7%), respectively.
At a median follow-up of 5.5 months (95% CI, 4.2-9.0) in the 2.2 mg/kg group, the median DOR was 6.3 months (95% CI, 4.2-NR). The median progression-free survival (PFS) and overall survival (OS) were 4.8 months (95% CI, 3.6-6.0) and NR (95% CI, 6.5-NR), respectively. The 9-month OS rate was highest in this group, at 70.7%. At a median follow-up of 6.0 months (95% CI, 3.8-8.1) in the 2.6 mg/kg group, the median DOR was 5.7 months (95% CI, 2.9-NR). The median PFS was 3.3 months (95% CI, 2.2-6.1) and the median OS was 8.5 months (95% CI, 6.2-NR). The 9-month OS rate was the lowest in this group, at 46.9%. Lastly, at a median follow-up of 7.7 months (95% CI, 5.2-9.7), the median DOR was 12.6 months (95% CI, 2.4-NR). The median PFS and OS were 14.5 months (95% CI, 3.0-NR) and NR (95% CI, 5.5-NR), respectively. The 9-month OS rate was 56.3%.
“CMG901 demonstrated promising clinical efficacy in patients with CLDN18.2-positive gastric/GEJ cancer [and] clinical activity was observed across all the subgroups,” Rui-Hua, Xu, MD, PhD, a professor of medical oncology and president of the Sun Yat-sen University Cancer Center in Guangdong 510060 China, said in a presentation on the data. “These results provide a strong rationale to further explore CMG901 as an ADC in CLDN18.2-expressing gastric/GEJ cancer.”
CMG901 is comprised of a humanized anti-CLDN18.2 antibody that is conjugated to monomethyl auristatin E (MMAE) through a protease cleavable linker.1 Preclinical data indicated that the agent had strong antitumor activity via MMAE-mediated cytotoxicity with bystander killing, antibody-dependent cellular cytotoxicity, and complement-dependent cytotoxicity.2
The KYM901 study enrolled patients with pathologically confirmed advanced solid tumors that were evaluable by RECIST v1.1 criteria.1 Patients were required to be refractory or intolerant to standard options and have an ECOG performance status of 0 or 1. For part A, CLDN18.2 expression was not required. For part B, patients needed to have CLDN18.2 expression of at least 2 positive membrane staining intensity in at least 5% of tumor cells.
In part A, CMG901 was evaluated at escalating doses ranging from 0.3 mg/kg to 0.6 mg/kg, to 1.2 mg/kg, to 1.8 mg/kg to 2.2 mg/kg to 2.6 mg/kg to 3.0 mg/kg to 3.4 mg/kg. All doses were administered intravenously every 3 weeks. The primary end points of this portion of the research were adverse effects (AEs) and dose-limiting toxicities (DLTs).
Previous data from part A showed that the agent was generally well tolerated with most AEs being grade 1 or 2.2 The maximum tolerated dose was not yet reached, and no treatment-related grade 4 or 5 toxicities occurred. One patient who received the agent at 2.2 mg/kg experienced a DLT. In 8 patients with CLDN18.2 positivity, the ORR was 75% and the DCR was 100%. The median PFS and OS were NR.
In part B, CMG901 was evaluated at 2.2 mg/kg, 2.6 mg/kg, and 3.0 mg/kg. The primary end points for this portion of the research were ORR and establishing the recommended phase 2 dose.1
In the presentation delivered during the ASCO Plenary Series, Xu shared findings from 113 patients who had gastric/GEJ cancer and received the agent at those 3 doses; 107 patients were from part B and 6 were from part B.
The median age in the total population was 56.0 years (range, 44.0-64.0), and 52% were male. All patients were Asian, 84% had an ECOG performance status of 1, and 90% had gastric cancer. Eighty-three percent of patients had CLDN18.2 expression of 2 or more positive membrane staining in at least 20% of tumor cells. Regarding HER2 expression, 11% had high expression and 89% had low or no expression; this information was missing for 22 patients. The median number of prior lines of therapy received was 2 (range, 1-6), with 74% of patients previously receiving PD-1 or PD-L1 therapy, 64% who had prior taxane therapy, and 4% who were previously exposed to an anti-claudin 18.2 therapy.
A subgroup analysis revealed that the ORRs achieved with CMG901 were comparable across the different subsets analyzed, including those with an ECOG performance status of 1 (n = 75) vs 0 (n = 14; 30.7% [95% CI, 20.5%-42.4%] vs 42.9% [95% CI, 17.7%-71.1%]), those with peritoneal metastases (n = 51) vs none (n = 38; 35.3% [95% CI, 22.4%-49.9%] vs 28.9% [95% CI, 15.4%-45.9%]), and other groups that are known to have a poor prognosis, according to Xu.
Responses were observed irrespective of the number of prior lines of treatment received. The ORRs in those who received 1 (n = 37), 2 (n = 28), or 3 or more (n = 24) prior lines were 35.1% (95% CI, 20.2%-52.5%), 25.0% (95% CI, 10.7%-44.9%), and 37.5% (95% CI, 18.8%-59.4%), respectively. Similar ORRs were also observed irrespective of prior taxane or PD-1 therapy. In those who had prior taxane (n = 59), the ORR was 30.5% (95% CI, 19.2%-43.9%); in those who did not (n = 30), the ORR was 36.7% (95% CI, 19.9%-56.1%). In those with prior PD-1 exposure (n = 63), the ORR was 31.7% (95% CI, 20.6%-44.7%); in those without (n = 26), the ORR was 34.6% (95% CI, 17.2%-55.7%).
Regarding safety, all patients in the total population experienced treatment-emergent AEs (TEAEs), and 99% experienced treatment-related AEs. Grade 3 or higher TEAEs were reported in 64% of patients; these were treatment related in 54% of patients. Serious AEs (SAEs) occurred in 47% of patients and treatment-related SAEs were experienced by 31% of patients. Thirteen percent of patients required a dose reduction due to a TEAE, and 8% required discontinuation due to a TEAE. Three patients died from TEAEs; 1 was due to drug-related cerebral hemorrhage and 2 died from unknown reasons.
The most common TEAEs reported in at least 20% of patients included anemia (any, 63%; grade ≥3, 13%), vomiting (58%; 10%), hypoalbuminemia (58%; 0%), decreased weight (56%; 3%), nausea (55%; 4%), decreased neutrophil count (52%; 19%), decreased white blood cell count (50%; 7%), reduced appetite (50%; 7%), increased aspartate aminotransferase (42%; 0%), asthenia (29%; 4%), proteinuria (27%; 1%), increased alanine aminotransferase (27%; 0%), hyponatremia (26%; 0%), diarrhea (21%; 1%), and hypoesthesia (20%; 0%).
In April 2022, the FDA granted a fast track designation to CMG901 for use as a monotherapy in patients with unresectable or metastatic gastric or GEJ cancer that is relapsed or refractory to approved therapies.3
Editor’s Note: Dr Xu disclosed having a consulting or advisory role with HenRui, BeiGene, AstraZeneca, Junshi Biosciences, Bristol Myers Squibb, Merck Serono, Roche, Astellas Pharma, and KYM Biosciences.