Roche burnishes breast cancer portfolio with FDA approval for Itovebi, a threat to Novartis and AZ

As Roche comes under competitive pressure on its breast cancer business, the Swiss company hopes a new drug will add a 2 billion-Swiss-francs luster to the once high-flying portfolio.

The drug, inavolisib, has won FDA approval as part of a first-line treatment for HR-positive, HER2-negative breast cancer that has a PIK3CA mutation and is resistant to adjuvant endocrine therapy. The oral med is to be used in combination with Pfizer’s Ibrance and AstraZeneca’s Faslodex.

To be marketed under the brand name Itovebi, inavolisib is a threat to Novartis’ fellow PI3K inhibitor Piqray and AstraZeneca’s AKT inhibitor Truqap. Despite the competition, Roche’s pharma chief Teresa Graham has put Itovebi’s peak sales potential at 2 billion Swiss francs ($2.3 billion).

Graham shared the sales estimate during an April investor call based on an estimate that PIK3CA mutations account for about 40% of HR-positive breast cancers and a belief that inavolisib is simply a better drug than Piqray.

Despite being known for decades, PIK3CA mutations have been surprisingly difficult to treat, as many of the drugs that have been developed had limited efficacy and poor tolerability, Charlie Fuchs, M.D., head of oncology and hematology global product development at Roche’s Genentech, said in an interview with Fierce Pharma.

Itovebi has best-in-class potential from both efficacy and safety perspectives, Fuchs said.

The drug has some strong clinical data to back Fuchs’ claim. In the phase 3 INAVO120 trial, adding Itovebi to Ibrance and Faslodex significantly reduced the risk of progression of death by 57%. Patients in the Itovebi arm went a median 15 months without their disease worsening, versus 7.3 months for those in the control arm. The study enrolled patients with PIK3CA-mutated tumors that were considered endocrine-resistant because they had progressed quickly after receiving postsurgical endocrine therapy.

As to safety, adverse events led to discontinuation of Itovebi in 6.2% of patients versus 0.6% in the control arm for a matching placebo. The rates of serious adverse events were 24.1% and 10.5%, respectively.

One side effect of interest for the PI3K class, high blood sugar levels deemed grade 3 or 4 adverse events were recorded in 5.6% of patients on Itovebi versus 0% in the control group.

Hyperglycemia is a known problem with Novartis’ Piqray. In the phase 3 SOLAR-1 trial that earned Piqray its second-line approval, grade 3 or 4 hyperglycemia happened in 36.6% of patients on the Novartis drug versus 0.6% in the control group.

In that study, discontinuation of Piqray owing to adverse events reached 25%, with hyperglycemia (6.3%) the leading cause.

Fuchs has attributed Itovebi’s seemingly better efficacy and tolerability profile to improved specificity against mutant PI3K alpha subunit and not wild-type PI3K. Hyperglycemia is believed to be a result from the degradation of regular PI3K.

“We’re really committed to delivering a therapy that offers meaningful efficacy, excellent tolerability, and that patients can stay on the drug,” Fuchs said. “And that’s key because if you’re going to really target PI3K, you have to have sustained inhibition.”

Itovebi still faces a couple remaining questions in its current first-line nod. First, data on whether the drug can extend patients’ lives were immature at the interim analysis of INAVO120 after a median follow-up of 21.3 months. At that time, Itovebi showed a positive trend suggesting a preliminary 36% reduction in the risk of death, a number that wasn’t statistically significant. According to the FDA, that overall survival result was gleaned when the trial has accrued 63% of deaths required for a final analysis.

Fuchs described Itovebi’s overall survival showing so far as “a strong trend,” while committing to sharing mature data once available.

Second, treatment of early-stage HR+/HER2- breast cancer is changing. Rather than endocrine therapy alone, Novartis’ Kisqali and Eli Lilly’s Verzenio have both won approvals for use on top of endocrine therapy in the adjuvant setting. This raised the question of whether the Itovebi-Ibrance-Faslodex triplet may still be efficacious in patients who have already used Kisqali or Verzenio in the adjuvant setting, especially given that these two meds are considered more powerful CDK4/6 inhibitors than Pfizer’s Ibrance.

INAVO120 can’t answer that post-CDK4/6 question; the 325-subject trial only had four patients who had prior exposure to adjuvant CDK4/6 inhibitor.

Fuchs pointed to another phase 3 study, dubbed INAVO121. Roche is so confident in Itovebi that it has launched a head-to-head trial against Piqray in the second-line setting in patients with advanced or metastatic breast cancer following CDK4/6-endocrine combination therapy. Launched in June 2023, the study could take a few years to read out.

Other than Piqray, Itovebi could also compete with AZ’s AKT inhibitor Truqap, which about a year ago won an FDA approval to be used alongside Faslodex in HR+/HER2- breast cancer that bears gene alterations in PIK3CA, AKT1 and PTEN.

Once bearing hopes of blockbuster sales, Piqray has already started to see declining sales in its sixth year on the market following Truqap’s entry in late 2023. In the first half of 2024, Piqray’s sales dropped 7% to $229 million.

Roche apparently also believes in the value of an AKT inhibitor. The Swiss pharma previously had an investigational AKT inhibitor, ipatasertib, until repeated phase 3 flops eventually sank the project.

Targeting PI3K either through the mutation or downstream pathways like AKT are all important options for patients, Fuchs said. But the Roche exec stressed that Itovebi is the only one that has evidence to support first-line treatment.

In addition to the current endocrine-resistant approval, Roche is launching a phase 3 trial coded INAVO123 in endocrine-sensitive HR+/HER2- patients. There’s also INAVO122, which is testing Itovebi alongside Roche’s Phesgo in first-line HER2-positive PIK3CA-mutant breast cancer. And Roche is also evaluating the drug’s potential in the adjuvant curative setting of breast cancer as well as in other PI3K-mutated tumor types, Fuchs said.

Itovebi is part of a bigger pipeline that Roche hopes could rejuvenate its breast cancer business. The company’s once flagship HER2 franchise lost some of its luster after Herceptin fell off the patent cliff and Kadcyla comes under pressure from AZ and Daiichi Sankyo’s star antibody-drug conjugate Enhertu.

Besides Itovebi, Roche is advancing the oral SERD drug giredestrant in HR+/HER2- breast cancer, with key phase 3 readouts expected in 2025.

Last week, Roche unveiled a $850 million upfront deal with Regor Pharmaceuticals, adding an early-stage CDK4/2 inhibitor and a phase 1-ready CDK4 drug to its portfolio.