Sacituzumab Tirumotecan Shows Early Efficacy in Gastric/GEJ Cancers

Sacituzumab tirumotecan elicited responses prominently in the second- and third-line and beyond setting and in those with high TROP2 expression.

The TROP2 antibody-drug conjugate sacituzumab tirumotecan (MK-2870/SKB264) showed encouraging responses in patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma with TROP2 expression, including in those in the second- and third-line and beyond setting, according to findings of the phase 1/2 KL264-01 trial (NCT04152499) that were presented during the 2024 American Association for Cancer Research Annual Meeting.¹

At a median follow-up of 14.2 months, the objective response rate (ORR) with sacituzumab tirumotecan was 22.0% (n = 9/48), which included 7 partial responses (PRs) and 2 pending PRs. The disease control rate (DCR) was 80.5%, and the median duration of response (DOR) was 7.5 months (95% CI, 3.1-not estimable); the 6-month DOR rate was 75.0% (95% CI, 12.8%-96.1%).

“We can see that this is a promising agent for gastric cancer. We saw preliminary activity in the second and third line, we see good responses in patients with high TROP2 expression, and the safety profile makes it very manageable, with good management of these [adverse] effects,” lead study author Jordi Rodon, MD, PhD, associate professor of investigational cancer therapeutics of The University of Texas MD Anderson Cancer Center, said in a presentation during the meeting.

Rodon noted that sacituzumab tirumotecan has the same antibody as sacituzumab govitecan (Trodelvy), but it has a different payload and linker.

Sacituzumab tirumotecan has a novel methyl sulfonyl pyrimidine linker that conjugates the payload, a belotecan-derivative topisomerase I inhibitor. Extracellular pH-sensitive cleavage and intracellular enzymatic cleavage in tumor cells affect the linker, which then releases the payload in the tumor cells and the tumor microenvironment.

Because there is high TROP2 expression in gastric cancer, investigators theorized that the mechanism of action with sacituzumab tirumotecan could lead to efficacy in this patient population of gastric/GEJ cancers. Preclinical data showed that the agent had dose-dependent tumor inhibition of gastric cancer and on those with low TROP2 expression and above.

In the first-in-human, phase 1/2 dose-escalation/-expansion KL264-01 trial, investigators enrolled patients in the United States and China with locally advanced unresectable/metastatic solid tumors refractory to standard treatment. In phase 1, dose-escalation portion, which has been completed, 30 patients received at least 1 every-2-week treatment of sacituzumab tirumotecan, with 4 weeks as 1 cycle of treatment, at doses of either 2 mg/kg (n =4), 4 mg/kg (n = 7), 5 mg/kg (n = 7), 5.5 mg/kg (n = 5), and 6 mg/kg (n = 7). The maximum-tolerated dose was identified as 5.5 mg/kg, and the recommended doses for expansion were 4 mg/kg and 5 mg/kg.

The phase 2 dose-expansion portion comprised patients with triple-negative breast cancer, epithelial ovarian cancer, non–small cell lung cancer, gastric adenocarcinoma, small cell lung cancer, and urothelial carcinoma. Four patients had gastric/GEJ cancer (cohort 4) who had measurable disease, an ECOG performance status of less than 1, and received at least 1 line of platinum-based chemotherapy, which was amended to the second line.

Sacituzumab tirumotecan was administered intravenously at 5 mg/kg every 2 weeks until disease progression or unacceptable toxicity. Tumors were assessed every 8 weeks per RECIST v1.1 criteria by investigators.

The primary end point was ORR, and secondary end points were DOR, progression-free survival (PFS), overall survival (OS), and safety.

At a data cutoff date of November 22, 2023, 48 patients were enrolled. Fifty percent of patients had received at least 2 prior lines of therapy, and 83.3% of patients received prior immunotherapy. The median age was 57 years (range, 24-76) and 79.2% of patients were male. Patients were Asian (77.1%), Caucasian (18.8%), or other (4.2%). A total of 14.6% of patients had an ECOG performance status of 0.

Investigators also evaluated the responses based on whether patients received sacituzumab tirumotecan in the second- or third-line and beyond setting. In the second-line setting (n = 22), the ORR was 27.3% with 4 confirmed PRs; the DCR rate was 77.3%. In the third-line and beyond setting (n = 19), the ORR was 15.8% with 3 confirmed PRs and the DCR was 84.2%.

Additionally, in the subset of 24 patients receiving therapy in the third-line and beyond, including 54.2% of patients with 4 or more prior lines of therapy and 75.0% of those with prior immunotherapy, the median follow-up was 14.6 months. In this subgroup, the median PFS was 3.7 months (95% CI, 2.6-5.4) and the median OS was 7.6 months (95% CI, 5.3-15.5). The 1-year OS rate was 32.6%.

The link between TROP2 immunohistochemistry (IHC) levels and responses was also tested. In those with a low and medium TROP2 IHC (n = 23), the ORR was 21.7% with 4 confirmed PRs and the DCR was 87.0%. In patients with high TROP2 IHC (n = 16), the ORR was 25.0% with 3 confirmed PRs and a 75.0% DCR.

Regarding safety, the most common treatment-related adverse effects (TRAEs; ≥30%) were anemia (all-grade, 64.6%; grade ≥3, 20.8%) white blood cell decrease (50.0%; 12.5%), neutrophil decrease (41.7% vs 18.8%), alopecia (all-grade, 41.7%), and nausea (all-grade, 33.3%). A total of 18.8% of TRAEs led to dose reductions, 33.3% led to dose interruptions, and 16.7% of patients experienced treatment-related serious adverse effects.

There were no deaths or treatment discontinuations due to TRAEs, nor were there any cases of neuropathy or treatment-related interstitial lung disease or pneumonitis.

Patients had previously received 1 (50.0%), 2 (12.5%), 3 (10.4%), 4 (18.8%), or more than 5 (8.3%) lines of therapy; 27.1% of patients previously were treated with irinotecan.

An international phase 3 trial is planned to evaluate sacituzumab tirumotecan compared with standard of care in patients with gastric/GEJ adenocarcinoma who have had at least 3 prior therapies.²

References

1. Rodon J, Wainberg ZA, Zhang M, et al. Preliminary efficacy and safety results of anti-TROP2 ADC SKB264 (MK-2870) in patients (pts) with previously treated advanced gastric (G) or gastroesophageal junction (GEJ) cancer from a phase 2 study. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT038.
2. AACR: Trio of studies highlights promising early results with new cancer therapies and targets. The University of Texas MD Anderson Cancer Center. News release. Published April 9, 2024. Accessed April 11, 2024. https://shorturl.at/oR069