According to the PIKASSO-01 trial, the potent, highly mutant-selective PI3Ka H1047R inhibitor LOXO-783 demonstrated proof of concept of mutant selectivity. However, due to high rates of diarrhea, the determination of an optimal preclinical dose was limited.

These results will be presented by Komal Jhaveri, MD, Memorial Sloan Kettering Cancer Center, New York, New York, at the San Antonio Breast Cancer Symposium.

According to study authors, approved treatments for PI3K mutant-driven breast cancer that include inhibitors of the PI3K/AKT pathway also inhibit wild-type PI3K, “leading to dose-limiting toxicities that include hyperglycemia, rash, and GI side effects.”

There were 43 patients enrolled in phase 1a of the PIKASSO trial (35 patients with advanced breast cancer [30 with HR-positive/HER2-negative disease; 5 with TNBC], and 8 with other solid tumors) and 106 patients with advanced breast cancer (90 with HR-positive/HER2-negative; 16 with TNBC) enrolled in phase 1b. All patients had tumors that were PIK3CA H1047R-mutant. In phase 1a, patients received LOXO-783 as a monotherapy in doses from 200 mg to 600 mg twice daily or 500 to 600 mg once daily. There were 4 patients who experienced dose-limiting toxicities: 1 each at 500 mg once daily, 600 mg once daily, 400 mg twice daily, and 600 mg twice daily. In phase 1b, patients received LOXO-783 (at 400 to 600 mg twice daily or 300 to 600 mg once daily) in combination with either endocrine therapy (fulvestrant or aromatase inhibitor) or paclitaxel. Key objectives included safety, tolerability, pharmacokinetics, and antitumor activity. 

Across all cohorts in both phase 1a and phase 1b, a high incidence of diarrhea was observed. Overall, there were 84% of patients who experienced diarrhea at any grade, and 37% of patients who experienced diarrhea required a dose modification. Other frequent treatment-emergent adverse events with LOXO-783 with or without endocrine therapy included fatigue and nausea. Other frequent treatment-emergent adverse events with LOXO-783 and paclitaxel included neutrophil decreased, anemia, fatigue, and white blood cell decreased. Treatment-related adverse events led to discontinuation of any study treatment among 4% of patients who received LOXO-783 with or without endocrine therapy and 10% of patients who received LOXO-783 plus paclitaxel. There were no incidents of treatment-related hyperglycemia observed.

Among evaluable patients who received LOXO-783 as a monotherapy, the objective response rate (ORR) was 3% and the clinical benefit rate (CBR) was 17%. Among patients receiving doublet therapy, the ORR and CBR were 5% and 19% respectively with endocrine therapy, and 19% and 25% respectively with paclitaxel. 

Study authors concluded that while “LOXO-783 demonstrated proof of concept of mutant selectivity by entirely sparing hyperglycemia in the clinic,” the high rates of diarrhea limited the ability to “achieve the optimal preclinical dose of LOXO-783.”

Source:

Jhaveri K. A first-in-human 1 a/b trial of LOXO-783, a potent, highly mutant-selective, brain-penetrant, allosteric PI3Ka H1047R inhibitor in PIK3CA H1047R-mutant advanced breast cancer and other solid tumors: Results from the PIKASSO-01 study. Presented at San Antonio Breast Cancer Symposium. Dec 10-13, 2024; San Antonio, TX. Abstract: SESS-2420