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SAN ANTONIO -- The addition of inavolisib to palbociclib (Ibrance) plus fulvestrant (Faslodex) boosted progression-free survival (PFS) in patients with recurrent PIK3CA-mutated HR-positive, HER2-negative advanced breast cancer, according to the INAVO120 trial.

In patients who recurred within 12 months of adjuvant endocrine therapy, treatment with the investigational selective PI3Kα inhibitor demonstrated more than a doubling of median PFS from 7.3 to 15 months (stratified HR 0.43, P<0.0001), reported Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York City.

There also was a trend toward improved overall survival (OS) at the first interim analysis (median follow-up of 21.3 months) with inavolisib compared with placebo as add-on therapy, she said at a (SABCS) press briefing.

Jhaveri stated that the triplet therapy "may represent a new standard of care for patients with PIK3CA-mutated HR-positive, HER2-negative advanced breast cancer. What we have learned so far is that we have not been able to combine alpelisib with a CDK4/6 inhibitor, due to the challenges with the safety profile. This is the very first time we've been able to use a triplet combination of inavolisib with a CDK4/6 inhibitor and endocrine therapy, guided by preclinical data showing synergistic activity."

"What is reassuring is not only the favorable impact on efficacy, but we're seeing low discontinuation rates with such a triplet regimen," she noted. The discontinuation rate was 6.8% with inavolisib treatment group versus 0.6% for palbociclib and fulvestrant alone, according to a Genentech/Roche .

Inavolisib is an oral highly potent and selective inhibitor of the PI3K catalytic subunit α isoform protein that also promotes the degradation of p110α, which may improve the therapeutic window. Currently available α isoform PI3K inhibitors have faced challenges with safety and tolerability, she said.

Palbociclib received in combination with letrozole for the treatment of postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. The agent's indication was as a treatment for men with with HR+, HER2- metastatic breast cancer.

Trial Details

is a phase III, randomized, double-blind placebo-controlled study that assessed inavolisib combined with palbociclib plus fulvestrant or placebo and the latter two agents (control arm) in patients with PIK3CA-mutated HR-positive HER2-negative advanced breast cancer.

Eligible patients had measurable disease and had progression during or within 12 months of completion of adjuvant endocrine therapy. No prior therapy for advanced breast cancer was allowed. Eligibility criteria included a fasting glucose <126 mg/dL and the hemoglobin A1c <6%.

A total of 325 patients were randomized 1:1 to the triplet regimen of inavolisib (9 mg orally daily) with standard of care doses of palbociclib with fulvestrant or placebo with standard of care doses of palbociclib and fulvestrant until progression or toxicity.

At the landmark analysis of 18 months, 46% of the patients were progression free in the inavolisib arm compared with 21% in the control arm.

Median OS in the placebo arm was 31.1 months and was not reached in the inavolisib arm (stratified HR 0.64, P=0.0338 in favor of inavolisib). The prespecified boundary for OS was not crossed at the interim analysis. At the 6-month landmark analysis, 89.9% of the patients in the placebo arm and 97.3% in the inavolisib arm were still alive, and at the 18-month mark, these percentages were 67.5% and 73.7%, respectively.

SABCS press briefing moderator Virginia Kaklamani, MD, of UT Health San Antonio, noted that "most of my colleagues and I were not eager to be looking at triple combinations. I think we were initially shocked [that] we had to look at combinations in the first place."

"I was impressed with the [INAVO120] results," she stated. "We have a pretty active doublet with a CDK4/6 inhibitor and endocrine therapy that many of us thought it would be hard to surpass, and we are surpassing [it] now."

Inavolisib plus palbociclib and fulvestrant had a manageable safety profile consistent with the safety profiles of the individual agents, with no new safety signals. The proportion of patients that developed neutropenia was comparable between the inavolisib and placebo arms 88.9% vs 90.7%, respectively.

The rate of grade 3/4 stomatitis was 5.6% in the inavolisib arm and 0% in the placebo arm.

In the inavolisib arm, the rate of all-grade hyperglycemia was 58.6%, with grade 3/4 hyperglycemia in 5.6%, compared with 8.6% and 0%, respectively, in the control arm. Almost half (48%) of the patients randomized to inavolisib had diarrhea, with 3.7% having grade 3/4 diarrhea, whereas 16% in the control arm had all-grade diarrhea, and no grade 3/4 diarrhea.

Also, 25% experienced rash in the inavolisib arm, with no cases of grade 3/4, compared with rates of all-grade and grade 3/4 rash of 17.3% and 0%, respectively, in the control arm.

Some 22.2% had low-grade ocular toxicity in the inavolisib group versus 13% in the control arm. Longitudinal eye examinations were incorporated into the study design as a result of preclinical findings of ocular toxicity with inavolisib. "Because we had longitudinal eye exams, we picked up asymptomatic ocular toxicities of dry eyes. These were clinically not very significant," said Jhaveri.

No primary prophylaxis for hyperglycemia, diarrhea, rash, or stomatitis was provided in INAVO120, she reported. Primary prophylaxis with antihistamines to prevent severe or even low-grade rash may be considered if inavolisib gains approval, she said, and dexamethasone mouthwash may be offered to prevent stomatitis, as with the use of alpelisib (Piqray).

Kaklamani cautioned that "sometimes we've seen that when we take these drugs into our clinic, the toxicity profile changes," adding that it's important to learn in advance "how to deal with these toxicities."

Genentech stated in the release that data from INAVO120 study "will be submitted to health authorities with the view of bringing this potential treatment option to patients as soon as possible." Other ongoing trials of inavolisib are and .

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