Inavolisib Plus Palbociclib and Fulvestrant for Patients With Relapsed PIK3CA-Mutated Advanced Breast Cancer

Demetria Smith-Graziani, MD, MPH, Winship Cancer Institute at Emory University, Nashville, Tennessee, discusses results from the INAVO120 study. This phase 3 trial evaluated the addition of inavolisib, a PI3-kinase inhibitor, to palbociclib and fulvestrant among patients with PIK3CA-mutant, HR-positive, HER2-negative locally advanced or metastatic breast cancer, who relapsed during or within 12 months of completing adjuvant endocrine therapy.

When compared with placebo plus palbociclib and fulvestrant, the inavolisib combination was associated with an improved progression-free survival that was durable. According to patient-reported outcomes, the addition of inavolisib did not increase the treatment burden. Dr Smith-Graziani highlighted this as, “we've had difficulty with PI3-kinase inhibitors causing a fair amount of toxicity in patients that can be sometimes hard to manage.”

Overall, Dr Smith-Graziani concluded “there's a lot of great potential for [inavolisib] to be an additional treatment for a patient population that really needs additional options.”

Transcript:

Hi, I'm Demetri Smith Graziani, and I am an assistant professor and breast medical oncologist at Winship Cancer Institute of Emory University.

Today, I'm going to be talking about the results of the INAVO-120 trial. This is a phase 3, randomized trial looking at the use of a novel alpha-selective PI3 kinase inhibitor called inavolisib.

In this trial, they looked at patients who had metastatic hormone receptor-positive and HER2-negative breast cancer that had recurred within 12 months of completing their adjuvant endocrine therapy. Patients who met that criteria received first-line treatment in the metastatic setting with either inavolisib or placebo combined with palbociclib and fulvestrant. And this is specifically for patients who had a PI3-kinase mutation, this is a PI3-K inhibitor.

Initially, results were reported at San Antonio Breast Cancer Symposium in 2023, showing the addition of an inavolisib actually increased the median progression-free survival compared to placebo, really doubled it from about 7 and ½ months to 15 months. And initial overall survival data showed that there was improvement there as well. Additionally, they saw that there were similar rates of neutropenia between patients who received inavolisib versus placebo. The potential side effects were similar to what was already known about these these drugs separately, with the most common things specific to inavolisib being hyperglycemia, which did occur in a majority of patients, although grades 3 and higher hyperglycemia only occurred in about 5.5% of patients. Additionally, there was stomatitis, rash, and diarrhea was also pretty common in about half of patients, though again, grade 3 was about 4% of patients.

At ASCO this year, they presented some updated results looking at additional progression-free survival, specifically time from randomization to the end of progression on second-line therapy after this initial treatment, which served as a proxy for PFS-2. They also looked at some patient-reported outcomes to get a better sense of how these potential side effects were actually affecting patients.

They found that the PFS2, again, was significantly increased for patients who were on inavolisib compared to placebo, about 24 months compared to about 15 months for those in placebo. And then they also looked at the time to first chemotherapy, which the median time was not reached for those in the inavolisib arm. For those on placebo, was 15 months.

They did find overall that there were no grade 4 or 5 adverse events. And most of the adverse events actually did resolve during the time that patients were monitored on the study. It looks like from the adverse events that did occur, the average time of onset was usually within those first 30 days of being on treatment. And similarly, it was hyperglycemia, stomatitis, rash, diarrhea. Most of those were managed with supportive care or dose interruptions or reductions. When looking at the patient-reported outcomes, or PROs, they found that patients who were on the inavolisib had a longer duration without an increase in their pain severity, had maintained their functional capacity for longer, as well as their quality of life.

Really in both arms, any side effects and impact to their overall quality of life were considered to be moderate or less, which means that inavolisib did not add additional treatment burden for patients. Now, this is really important because we've had difficulty with PI3-kinase inhibitors causing a fair amount of toxicity in patients that can be sometimes hard to manage. And so finding something that is, one, more effective than an already very effective combination of CDK4/6 inhibitor plus endocrine therapy, and something that does not add toxicity, really provides an important option for patients. Especially a group of patients that might be a little bit more high-risk and have more aggressive disease, with PIK3-kinase mutated tumors and also having recurred within a year of completing their adjuvant endocrine therapy.

I think it's important as we look toward how this might be used in the future, that we think about making sure that patients have appropriate ways to manage any potential symptoms. I think one of those things is appropriately selecting the right patients to get on treatment.

On this study, patients had fasting glucose of less than 126 and a hemoglobin A1C of less than 6%. These were patients that either did not have diabetes or were very well-controlled in their diabetes. For things like stomatitis we have steroid mouthwash that can be very helpful. Sometimes we do give metformin actively to help with controlling blood sugar. And then making sure that we are giving appropriate anti-diarrheal medications as needed. Managing things like rash with antihistamines or other topical treatments.

Overall, I think there's a lot of great potential for this to be an additional treatment for a patient population that really needs additional options.

Source:

Jhaveri K. 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, Texas.

Juric D, Kalinsky K, Turner NC, 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(16_suppl). doi: 10.1200/JCO.2024.42.16_suppl.1003