Editor’s Note: At the 2025 ESMO Annual Congress in Berlin, multiple innovative therapies attracted wide attention. Among them, the selective PI3K-α inhibitor JS105 released the first results from two Phase I clinical studies (Abstract #466P), comprehensively presenting the drug’s preliminary efficacy, safety, and pharmacokinetic (PK) profiles in Chinese patients with advanced solid tumors, both as monotherapy and in combination therapy.
The results showed that JS105 demonstrated encouraging antitumor activity and manageable safety, particularly among patients with PIK3CA mutations. Specifically, in patients with PIK3CA-mutant advanced solid tumors, JS105 monotherapy achieved an objective response rate (ORR) of 28.1% and a disease control rate (DCR) of 87.5%. In HR+/HER2– advanced breast cancer, JS105 combined with dalpiciclib and fulvestrant achieved an ORR of 50% and a DCR of 88.5%. The median duration of response (DoR) and progression-free survival (PFS) were not yet reached, suggesting the potential for long-lasting responses.
Oncology Frontier invited Prof. Min Yan from Henan Cancer Hospital, principal investigator of the JS105 study, to interpret the clinical implications and future development prospects of this research.
Study Background
Activating mutations of the PIK3CA gene are common in many cancers and are closely linked to resistance to endocrine therapy, targeted therapy, and chemotherapy. Therefore, PI3Kα has become a key target in anticancer drug development.
This report presents the preliminary efficacy and safety results from two studies conducted in China: the JS105 monotherapy study (NCT06846099) and the combination therapy study (NCT06208410).
Study Design
The monotherapy study (NCT06846099) included dose-escalation and dose-expansion phases, enrolling patients with advanced solid tumors who had failed standard treatments. Patients received JS105 50–350 mg once daily in 28-day cycles.
The combination therapy study (NCT06208410) enrolled patients with HR+/HER2– advanced breast cancer, who received JS105 150–250 mg in combination with dalpiciclib and fulvestrant, also in 28-day cycles.
The primary endpoints were safety, tolerability, maximum tolerated dose (MTD), and recommended Phase II dose (RP2D); secondary endpoints included efficacy and pharmacokinetic profiles.
Study Results
As of May 30, 2025, 69 patients had been enrolled in the monotherapy study. Of these, 44 (63.8%) had PIK3CA mutations, and 41 (59.4%) had received two or more prior lines of therapy.
As of August 19, 2025, 33 patients were enrolled in the combination therapy study; 30 (90.9%) had PIK3CA mutations, and 22 (66.7%) had not received any systemic anticancer therapy other than adjuvant endocrine treatment.
Across both studies, nearly half of the patients had diabetes or pre-diabetes.
Efficacy
In the monotherapy study, no dose-limiting toxicities (DLTs) occurred, and RP2D was determined as 250 mg daily. Among 32 PIK3CA-mutant patients, the ORR was 28.1% (95% CI: 13.7–46.7%), the median PFS was 4.4 months (95% CI: 4.0–7.7), and the median DoR was 4.2 months (95% CI: 1.9–9.7).
Among 14 PIK3CA-mutant breast cancer patients, the DCR reached 92.9%, with a median PFS of 6.3 months.
In the combination therapy study, the final RP2D regimen was JS105 250 mg + dalpiciclib 125 mg + fulvestrant 500 mg. Among 26 HR+/HER2– breast cancer patients with PIK3CA mutations, the ORR was 50.0% (95% CI: 29.9–70.1%), the DCR was 88.5% (95% CI: 69.8–97.6%), and the median PFS was not reached (95% CI: 7.4–NE).
Safety and Tolerability
Overall, JS105 showed a manageable safety profile, and most treatment-related adverse events (TRAEs) could be controlled through standard clinical interventions.
In the monotherapy and combination studies, 5.8% and 3.0% of patients, respectively, discontinued JS105 due to TRAEs.
The most common TRAEs were consistent with the drug’s mechanism and target profile, including hyperglycemia, rash, and gastrointestinal events.
Pharmacokinetics
Pharmacokinetic analyses showed that JS105 exhibited dose-dependent exposure across the 50–350 mg range, with no significant accumulation after multiple doses. The half-life was approximately 5–7 hours.
No pharmacokinetic interactions were observed between JS105 and dalpiciclib in the combination study.
Study Conclusions
JS105 demonstrated good tolerability, manageable safety, and clear antitumor activity as both monotherapy and in combination therapy in patients with advanced cancers.
In particular, the combination of JS105 with endocrine therapy and CDK4/6 inhibitors showed higher response and disease control rates, supporting further clinical investigation.
Investigator’s Remarks
“As a highly selective PI3K-α inhibitor, the release of JS105’s first clinical data marks a solid step forward in precision therapy for patients with PIK3CA-mutant advanced cancers,” said Prof. Min Yan of Henan Cancer Hospital.
“At this year’s ESMO Congress, JS105 demonstrated encouraging efficacy and controllable safety both as monotherapy and in combination with endocrine therapy and CDK4/6 inhibition.”
“In HR+/HER2– advanced breast cancer, the combination of JS105 with dalpiciclib and fulvestrant achieved an ORR of 50% and a DCR of nearly 90%, suggesting the potential for durable clinical benefit. For patients with limited treatment options—especially those harboring PIK3CA mutations—this represents a meaningful new therapeutic opportunity.”
“Furthermore, JS105 displayed favorable pharmacokinetic characteristics, with a moderate half-life, no accumulation, and no interaction with dalpiciclib. These findings provide a strong foundation for its future clinical application and combination development.”
“We look forward to validating its efficacy and safety in larger Phase III studies, and to bringing JS105 to PIK3CA-mutant cancer patients in China and beyond.”
Prof. Min Yan
Department of Breast Oncology, Henan Cancer Hospital Deputy Director, Henan Provincial Breast Disease Diagnosis and Treatment Center
