Inavolisib Plus Palbociclib/Fulvestrant Bolsters PFS in HR+/HER2–, PIK3CA-Mutant Breast Cancer

Treatment with inavolisib plus palbociclib (Ibrance) and fulvestrant (Faslodex) reduced the risk of progression or death vs placebo plus palbociclib and fulvestrant in patients with hormone receptor (HR)–positive, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer which has progressed within 12 months of adjuvant endocrine therapy, according to data from the phase 3 INAVO120 trial (NCT04191499) presented at the 2024 ASCO Annual Meeting.¹

Primary findings from the study for progression-free survival (PFS) were first presented at the 2023 San Antonio Breast Cancer Symposium.² For this end point, the median PFS was 15.0 months with inavolisib compared with 7.3 months for the palbociclib and fulvestrant alone (HR, 0.43; 95% CI, 0.32-0.59; P < .0001). In the ASCO results, the time from randomization to end of next-line treatment (PFS2 proxy) was 24.0 months with the addition of inavolisib compared with 15.1 months for palbociclib and fulvestrant alone (HR, 0.54; 95% CI, 0.38-0.77). The time to first chemotherapy was not yet reached with the addition of inavolisib compared with 15.0 months with placebo (unstratified HR, 0.54; 95% CI, 0.37-0.78).

Based on findings from the phase 3 INAVO120 trial, the FDA granted a priority review to a new drug application for inavolisib as a treatment for patients with hormone receptor-positive, HER2-negative, PIK3CA-mutated, breast cancer. The FDA is scheduled to decide on the application by November 27, 2024.³ The agent has also been awarded a breakthrough therapy designation.⁴

"This triple combination is a promising new treatment option for patients with PIK3CA-mutated [hormone receptor]-positive, HER2-negative metastatic breast cancer," lead investigator Dejan Juric, MD, Medicine-Hematology and Medical Oncology, Massachusetts General Hospital Cancer Center, said during a presentation of the results. "Patient-reported outcomes data suggest patients receiving inavolisib in addition to fulvestrant and palbociclib experienced a longer median time to deterioration in pain severity and maintained day-to-day functioning and HRQOL [health-related quality of life] while on treatment with little increased treatment burden."

In the study, 325 patients were randomized to receive inavolisib at 9 mg daily (n = 161) or a matched placebo (n = 164). Both groups received palbociclib at 125 mg daily on day 1 to 21 of each cycle and fulvestrant at 500 mg on day 1 and 15 in cycle 1 followed by once every 4 weeks. In both arms, about two-thirds of patients had ECOG performance status of 0 and the remainder had 1. Nearly half of patients in each group had 3 or more organ sites involved and nearly half had liver involvement, with approximately 40% having lung involvement. Approximately 82% of patients received prior neoadjuvant or adjuvant chemotherapy and nearly all had received prior neoadjuvant or adjuvant endocrine therapy. A minority of patients had received a prior CDK 4/6 inhibitor (1.9% in the triplet group and 0.6% in the placebo group).

At a median follow-up of 21.3 months, treatment had been discontinued for 57.8% of those in the inavolisib arm compared with 70.1% in the placebo group. There had been 12 deaths in the inavolisib arm (7.5%) compared with 19 in the placebo group (11.6%). Overall survival findings were not yet mature.

The most common post-progression therapy was chemotherapy (61.5% in the triplet arm and 73.2% in the placebo group). The most common chemotherapy administered was capecitabine. A subsequent PI3K inhibitor was received by 25.6% in the placebo group and by 3.1% in the investigational arm, most commonly alpelisib (Vijoice). No patients received a subsequent antibody drug conjugate in the investigational arm vs 1.2% in the placebo group. A subsequent mTOR inhibitor, most commonly everolimus, was received by 12.3% in the investigational arm and by 7.3% of those in the placebo group. A subsequent CDK 4/6 inhibitor was given to 12.3% of those in the triplet group compared with 6.1% in the placebo arm.

Key adverse events (AEs) associated with inavolisib were monitored closely, including hyperglycemia, diarrhea, rash, and stomatitis, which are AEs associated with PI3K inhibitors. All grade hyperglycemia was seen in 59% of patients in the investigational arm compared with 9% of those in the placebo group. These were primarily grade 1 and 2 in severity. Six percent of patients experienced hyperglycemia at a grade 3 severity in the inavolisib group compared with none in the placebo. Forty-eight percent of patients in the inavolisib group experienced diarrhea of any grade compared with 16% in the placebo arm. Overall, 4% of these cases were grade 3 in severity for inavolisib compared with none for placebo. All grade rash occurred in 25% of those in the PI3K arm compared with 17% for the placebo arm, these were all grade 1 and 2 in severity. Stomatitis was present in 51% of patients in the inavolisib group compared with 27% in the placebo arm. Six percent of these were grade 3 in severity for inavolisib compared with none for placebo.

Inavolisib was discontinued due to any AE for 6.2% of patients. Additionally, the PI3K was discontinued due to key AEs in just 2 patients: 1 for hyperglycemia and 1 for stomatitis. Dose reductions for the key AEs were low at 2.5% related to hyperglycemia, 1.2% for diarrhea, 0.6% for rash, and 3.7% for stomatitis. Dose interruption due to these key AEs occurred in 27.2% of patients for hyperglycemia, 6.8% for diarrhea, 1.2% for rash, and 9.9% for stomatitis. The median time to onset of these events was 7 days for hyperglycemia, 15 days for diarrhea, 29 days for rash, and 13 days for stomatitis.

"Inavolisib discontinuation is only 6.2% for patients, which is a stark contrast to discontinuation of 25% or more for earlier PI3K inhibitors," said Juric. "Management of these events was straightforward when needed. This emphasizes the importance of careful monitoring during the first cycle of therapy and adherence to management guidelines."

In the investigational arms, concomitant medication was given to 40.7% of patients for hyperglycemia. This consisted primarily of metformin (93.9%). For diarrhea, 28.4% of patients received a concomitant therapy, primarily loperamide (82.6%). Sixteen percent of patients received a therapy for rash, primarily a topical hydrocortisone (19.2%). Concomitant therapy was given to 42.6% of those experiencing stomatitis, which consisted of a steroid mouth wash for 60.9%. Additionally, 20% were given steroid mouthwash prophylactically.

The median time to confirmed deterioration in worst pain severity was 30.9 months with the inavolisib triplet compared with 18.1 months for the placebo group (HR, 0.74; 95% CI, 0.48-1.13). Most patients reported that diarrhea, mouth sores, and rash were worse post treatment with inavolisib. In a simple question on how "bothered" patients felt by the treatment, results were similar between groups, with more feeling bothered by treatment in the first 10 weeks of treatment. Baseline levels of health-related quality of life were maintained, including physical functioning and role functioning.

"Inavolisib significantly improves PFS1 and PFS2 and lengthens time to chemotherapy and deterioration of worst bone pain, but is associated with toxicity, including patient report," summarized discussant Ruth M. O'Regan, MD, Chair of Medicine and Charles A. Dewey Professor at the University of Rochester. "We need biomarkers to ermine which patients will experience early disease progression justifying the addition of a third agent."

Inavolisib is currently being examined in several phase 3 studies for patients with PIK3CA-mutated breast cancer, including the INAVO120 (NCT04191499), INAVO121 (NCT05646862), and INAVO122 (NCT05894239). Each of these studies is exploring different combinations and settings, including locally advanced and HER2-positive disease.

References

1. Juric D, Kalinsky K, Turner N, et al. First-line inavolisib/placebo + palbociclib + fulvestrant (Inavo/Pbo+Palbo+Fulv) in patients (pts) with PIK3CA-mutated, hormone receptor-positive, HER2‑negative locally advanced/metastatic breast cancer who relapsed during/within 12 months (mo) of adjuvant endocrine therapy completion: INAVO120 Phase III randomized trial additional analyses. J Clin Oncol. 2024;42 (suppl 16):1003. Doi: 10.1200/JCO.2024.42.16_suppl.1003.
2. Jhaveri KL, Im S-A, Saura C, et al. Inavolisib or placebo in combination with palbociclib and fulvestrant in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer: Phase III INAVO120 primary analysis. Presented at San Antonio Breast Cancer Symposium®; December 5–9, 2023; San Antonio, TX. Abstract GS03-13.
3. FDA grants priority review to Genentech’s inavolisib for advanced hormone receptor-positive, HER2-negative breast cancer with a PIK3CA mutation. News release. Genentech. May 28, 2024. Accessed May 29, 2024. https://www.gene.com/media/press-releases/15026/2024-05-28/fda-grants-priority-review-to-genentechs
4. FDA grants breakthrough therapy designation to Genentech’s inavolisib for advanced hormone receptor-positive, HER2-negative breast cancer with a PIK3CA mutation. News release. Genentech. May 20, 2024. Accessed May 29, 2024. https://www.gene.com/media/press-releases/15025/2024-05-20/fda-grants-breakthrough-therapy-designat