SHR-A1921 Demonstrates Early Efficacy in Platinum-Resistant Ovarian Cancer

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Treatment with the antibody-drug conjugate (ADC) SHR-A1921 showed activity with manageable safety in patients with platinum-resistant ovarian cancer, according to data from a first-in-human phase 1 study (NCT05154604) that were presented during the 2024 ESMO Congress.¹

Evaluable patients treated with SHR-A1921 at a dose of 3.0 mg/kg once every 3 weeks (n = 26) experienced an overall response rate (ORR) of 42.3% (95% CI, 23.4%-63.1%), which included a complete response (CR) rate of 3.8% and a partial response (PR) of 38.5%; 57.7% of patients had stable disease (SD). The disease control rate (DCR) was 100.0% (95% CI, 86.8%-100.0%) in this group. The median duration of response (DOR) was 9.9 months (95% CI, 4.5-not reached [NR]). Additionally, the median progression-free survival (PFS) was 7.9 months (95% CI, 4.2-NR).

In the evaluable patients who received the agent at a dose of 2.0 mg/kg twice every 3 weeks (n = 17), the ORR was 58.8% (95% CI, 32.9%-81.6%); the PR was 58.8% and 35.3% of patients had SD. Moreover, 5.9% of patients experienced progressive disease. The DCR in this group was 94.1% (71.3%-99.9%). The median DOR was 6.3 months (95% CI, 3.0-NR). The median PFS was 6.9 months (95% CI, 4.2-9.6).

“SHR-A1921 demonstrated promising efficacy in heavily pretreated patients with platinum-resistant ovarian cancer,” Professor Dihong Tang, MD, of the Department IV of Gynecology at Hunan Cancer Hospital in Changsha, China, and colleagues, wrote in the presentation. “Safety in [this] cohort was manageable.”

For patients with epithelial ovarian cancer who receive platinum-based chemotherapy, approximately 85% will go on to develop resistance. This disease is known to have a poor prognosis, and few effective treatment options are available to these patients who previously received systemic therapy. SHR-A1921 is comprised of a humanized anti–TROP-2 IgG1 monoclonal antibody that is attached to a DNA topoisomerase I inhibitor by way of a tetrapeptide-based cleavable linker. Previously, the maximum tolerated dose of the ADC was determined to be 4.0 mg/kg given once every 3 weeks.² Doses of 3.0 mg/kg once every 3 weeks and 2.0 mg/kg twice every 3 weeks were identified for dose optimization in this population.

Patients were eligible for this cohort of the study if they had histologically confirmed recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer and had experienced disease progression during or within 6 months after platinum-based therapy was completed.¹ Patients were required to have measurable disease per RECIST 1.1 criteria, an ECOG performance status 0 or 1, a life expectancy of 12 weeks or more, and acceptable organ function. They also needed to be able to provide tumor tissues to determine TROP-2 expression level.

Participants received intravenous SHR-A1921 at 3.0 mg/kg on day 1 of each 21-day cycle or at 2.0 mg/kg on days 1 and 8 of each 21-day cycle. Treatment continued until disease progression, intolerable toxicity, patient withdrawal, or investigator decision.

Of the 61 patients who were screened, 46 were enrolled to the cohort. Of the 15 patients who were excluded from study, 13 were ineligible, 1 withdrew, and 1 were excluded for other reasons that were not specified. Twenty-six patients went on to receive treatment with SHR-A1921 at 3.0 mg/kg with 9 still receiving treatment at the data cutoff date of March 20, 2024. In this group, 17 patients discontinued treatment; 10 did so because of radiographical progression, 2 due to clinical progression, 2 due to patient withdrawal, 1 because of adverse effects (AEs), 1 due to death, and 1 due to other reasons. In the 2.0-mg/kg group, 20 patients were treated and 4 were still on treatment at the time of data cutoff. Sixteen patients discontinued treatment due to radiographical progression (n = 9), patient withdrawal (n = 5), clinical progression (n = 1), and AEs (n = 1).

The median follow-up in the 3.0-mg/kg and 2.0 mg/kg groups was 7.2 months (range, 3.0-23.0) and 7.5 months (range, 1.0-13.0), respectively.

The median age of patients enrolled in the 3.0-mg/kg group was 55 years (range, 40-71) vs 54 years (range, 38-61) in the 2.0-mg/kg group. Most patients in both groups had an ECOG performance status of 1 (96.2%; 95.0%). In the 3.0-mg/kg group, most patients (96.2%) had a primary diagnosis of ovarian cancer and 3.8% had fallopian tube cancer. All patients in the 2.0-mg/kg group had a primary diagnosis of ovarian cancer.

Regarding histology, most patients in the 3.0- and 2.0-mg/kg groups, respectively had serous carcinoma (73.1%; 80.0%). Other histologies included clear cell carcinoma (15.4%; 5.0%), mucinous carcinoma (7.7%; 5.0%), or other (3.8%; 10.0%). A majority of patients underwent prior surgery (92.3%; 100%). With regard to platinum resistance, 42.3% of patients in the 3.0-mg/kg group and 35.0% of those in the 2.0-mg/kg group had primary resistance; 57.7% and 65.0% of patients, respectively, had secondary resistance. The platinum-free interval of the latest line of platinum therapy was less than 4 weeks for 26.9% of those in the 3.0-mg/kg group and 45.0% of those in the 2.0-mg/kg group; it was at least 4 weeks but under 6 months for 73.1% and 55.0% of patients, respectively.

With regard to prior lines of treatment in the 3.0-mg/kg group, 7.7% had 1 prior line, 19.2% had 2 prior lines, 34.6% had 3 prior lines, and 38.5% had 4 or more prior lines; in the 2.0-mg/kg group, these respective rates were 15.0%, 35.0%, 15.0%, and 35.0%. All patients in both cohorts had received platinum-based chemotherapy. Additionally, patients had also received bevacizumab (Avastin; 76.9%; 60.0%) or a PARP inhibitor (65.4%; 50.0%).

Regarding TROP-2 expression levels in the 3.0-mg/kg group, 26.9% had high expression (defined as 200 ≤ H-score ≤ 300), 34.6% had medium expression (defined as 100 ≤ H-score ≤ 200), and 38.5% had low expression (0 ≤ H-score < 100); these respective rates in the 2.0-mg/kg arm were 20.0%, 30.0%, and 50.0%.

Regarding safety, 100% of patients in the 3.0-mg/kg group had any-grade treatment-related AEs (TRAEs), with 42.3% experiencing grade 3 or 4 effects. Moreover, 38.5% of patients experienced TRAEs that led to treatment interruption, and 23.1% experienced TRAEs resulting in dose reduction. Moreover, 15.4% of patients experienced serious TRAEs. In the 2.0-mg/kg group, all patients had any-grade TRAEs, 60.0% of which were grade 3 or 4. Moreover, 65.0% and 30.0% of patients experienced TRAEs that led to dose interruption or reduction, respectively. Five percent of patients had TRAEs that led to treatment discontinuation. Serious TRAEs occurred in 35.0% of patients. No TRAEs proved to be fatal in either group.

The most common grade 3 or 4 TRAEs that occurred in both the 3.0- and 2.0-mg/kg groups included stomatitis (11.5%; 50.0%), anemia (3.8%; 15.0%), vomiting (7.7%; 0%), nausea (0%; 5.0%), white blood cell count decrease (3.8%; 5.0%), neutrophil count decrease (3.8%; 10.0%), amylase increase (3.8%; 5.0%), increased aspartate aminotransferase level (0%; 5.0%), rash (0%; 5.0%), hypokalemia (0%; 5.0%), platelet count decrease (0%; 10.0%), lymphocyte count decrease (7.7%; 0%), decreased appetite (0%; 5.0%), C-reactive protein increase (3.8%; 5.0%), leukopenia (3.8%; 5.0%), and increased alanine aminotransferase level (0%; 5.0%).

The efficacy and safety of SHR-A1921 are being compared with investigator’s choice of chemotherapy in patients with platinum-resistant epithelial ovarian cancer in a phase 3 study (NCT06394492) that is currently recruiting.

Disclosures: Dr Tang did not declare any conflicts of interest.

References

1. Tang D, Song Z, Chen L, et al. SHR-A1921 in platinum-resistant ovarian cancer (PROC): data from a first-in-human phase 1 study. Ann Oncol. 2024;35(suppl 2): S549. doi:10.10.1016/j.annonc.2024.08.779
2. Wang J, Wu L, Song Z, et al. A first-in-human (FIH) phase 1 study of SHR-A1921, a TROP-2 targeted antibody-drug conjugate (ADC), in patients with advanced solid tumors. Cancer Res. 2023;83(suppl 8):CT181. doi:10.1158/1538-7445.AM2023-CT181