CMG901 Elicits Responses in CLDN18.2-Expressing Gastric/GEJ Cancer

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.

References

1. Xu R-H, Ruan D-Y, Zhang D-S, et al. A phase 1 trial of claudin 18.2-specific antibody-drug conjugate CMG901 in patients with advanced gastric/gastroesophageal junction cancer. J Clin Oncol. 2023;41(suppl 36):434420. doi:10.1200/JCO.2023.41.36_suppl.434420
2. Xu R-H, Wei X, Zhang D, et al. A phase 1a dose-escalation, multicenter trial of anti-claudin 18.2 antibody drug conjugate CMG901 in patients with resistant/refractory solid tumors. J Clin Oncol. 2023;41(suppl 4):352. doi:10.1200/JCO.2023.41.4_suppl.352
3. FDA granted CMG901 fast track designation for unresectable or metastatic gastric and gastroesophageal junction cancer which have relapsed and/or are refractory to approved therapies. News release. Keymed Biosciences. April 19, 2022. Accessed November 7, 2023. https://prn.to/3jXET0G