This article has been updated to change HR-negative to HR-positive in one instance where it had been misstyped.
NEW YORK – Results from a Phase III trial published in the New England Journal of Medicine last month will be practice-changing for doctors who treat patients with PIK3CA-mutated, hormone receptor (HR)-positive, HER2-negative locally advanced metastatic breast cancer.
The data appear to put Roche's mutant PI3Kα inhibitor Itovebi (inavolisib) in a strongly competitive position against Novartis' Piqray (alpelisib), just as the former garnered marketing authorization in the US last month. In the absence of a head-to-head trial comparing the two PI3Kα inhibitors, physicians are making cross-trial comparisons, and though such comparisons are not ideal, they are encouraged by Itovebi's better efficacy and safety profile.
Based on the data published in NEJM, the US Food and Drug Administration approved Itovebi in combination with Pfizer's CDK4/6 inhibitor Ibrance (palbociclib) and the selective estrogen receptor degrader fulvestrant in October to treat PIK3CA mutation-positive advanced breast cancer after progression on endocrine therapy. In the INAVO120 trial, the Itovebi-based regimen nearly doubled progression-free survival compared to Ibrance and fulvestrant and was also associated with a low rate of grade 3 and higher hyperglycemia, an adverse event that has been a significant hindrance for Piqray and other drugs targeting the PI3K/AKT/mTOR (PAM) pathway.
The PAM pathway has attracted drugmakers' interest in breast cancer because it is a significant resistance mechanism for hormonal therapy. As a result, the competitive landscape for new PI3K-, AKT-, and mTOR- blocking therapies is rapidly evolving as drugmakers try novel strategies to overcome that resistance pathway.
In the INAVO120 trial, Roche randomized more than 300 patients with HR-positive, HER2-negative breast cancer to receive Itovebi-Ibrance-fulvestrant or placebo plus Ibrance-fulvestrant. To be eligible for the trial, patients must have relapsed during or within 12 months after completing adjuvant endocrine therapy and have tested positive for a PIK3CA mutation. Approximately 35 percent to 40 percent of patients with estrogen receptor-positive metastatic breast cancers have PIK3CA mutated-tumors.
Patients on Itovebi-Ibrance-fulvestrant had a median progression-free survival of 15 months, while those in the Ibrance-fulvestrant group lived a median 7.3 months without disease progression or death. The objective response rate in the Itovebi group was 58.4 percent compared to 25 percent in the Ibrance-fulvestrant arm.
Among patients on the Itovebi regimen, 58.6 percent had hyperglycemia compared to 8.6 percent in the Ibrance-fulvestrant cohort. However, the rate of grade 3 or grade 4 hyperglycemia for patients on Itovebi was just 5.6 percent versus none in the placebo group. Overall survival results were not mature at the time of data cutoff but appeared to favor the Itovebi arm.
Five years before Itovebi became an option, the FDA approved Piqray in combination with fulvestrant for patients with PIK3CA-mutated, HR-positive, HER2-negative advanced or metastatic breast cancer following progression on or after an endocrine-based regimen. Current standard first-line treatment for patients with HR-positive, HER2-negative advanced breast cancer who have progressed on endocrine therapy is a combination of a SERD such as fulvestrant and a CDK4/6 inhibitor.
In accordance with the standard of care, Itovebi has been approved in combination with Ibrance and fulvestrant in the first-line setting, while Piqray-fulvestrant is a second-line therapy to be used after endocrine treatment plus CDK4/6 therapy.
Novartis tested Piqray plus fulvestrant versus placebo plus fulvestrant in patients with HR-positive, HER2-negative advanced breast cancer who had previously progressed on or after an endocrine therapy-based regimen in the Phase III SOLAR-1 trial. Results from that study showed that patients with PIK3CA-mutated disease on Piqray-fulvestrant lived 11 months without disease progression or death compared to 5.7 months for those on placebo-fulvestrant. The overall response rate was 26.6 percent for patients in the Piqray group and 12.8 percent in the fulvestrant group. In the overall patient population, with or without PIK3CA-mutated cancer, hyperglycemia occurred in 63.7 percent of those on Piqray and 9.8 percent of those on just fulvestrant. The rate of grade 3 or 4 hyperglycemia was 36.6 percent for patients in the Piqray group compared with 0.7 percent in the comparator arm.
There currently are no consensus treatment guidelines for patients with a PIK3CA mutation, but therapy options for this subset of breast cancer patients now include the PI3Kα inhibitors Itovebi and Piqray, and AstraZeneca's Truqap (capivasertib), which targets AKT, another member of the PI3K/AKT/mTOR pathway.
Komal Jhaveri, a breast oncologist at Memorial Sloan Kettering Cancer Center and the lead investigator of the INAVO120 study, observed that with Itovebi's approval, PIK3CA-mutated advanced breast cancer patients who have recurred within a year of adjuvant therapy have not only a first-line precision medicine option but also a compelling reason now to be tested for PIK3CA mutations earlier in their treatment trajectory. "Up until now, the standard of care was to offer the CDK4/6 inhibitor along with endocrine therapy, and we used to think about identifying PIK3CA mutations as early as progression after a CDK4/6 inhibitor," Jhaveri said. "But with these data where we've been able to show near doubling of progression-free survival in the first-line metastatic setting, it's become imperative for us to remind ourselves that for this particular patient population … you want to look out for these alterations prior to initiating first-line therapy or at the time of metastatic diagnosis."
She noted that INAVO120 represents an unusual success story for a triplet therapy comprising a PI3Kα inhibitor, since when combined with a CDK4/6 inhibitor, such regimens tend to carry the risk of cumulative toxicities. "It was very nice to see that [based on] good [preclinical] data that shows the triplet is synergistic and effective that we were able to then translate that into the clinic," Jhaveri said. "And it became a reality in the Phase III setting in the INAVO120 study, which has led to the approval of this combination for patients with PIK3CA mutations."
Jhaveri emphasized that this patient population typically has a very poor prognosis, as demonstrated by interim overall survival results showing that at the six-month landmark analysis, 90 percent of patients were still alive in the control arm, compared to 97 percent in the Itovebi arm, meaning 10 percent of patients in the control arm had already died. "It was an eye-opener and a realization of how poorly prognostic this group is if we treat them only with fulvestrant and a CDK4/6 inhibitor," she said.
She further noted that when compared to Piqray's toxicity profile in SOLAR-1, the lower rates of grade 3 and grade 4 hyperglycemia seen with the Itovebi regimen in INAVO120 promise to be far more manageable for doctors and patients. That means a larger proportion of patients on Itovebi who have hyperglycemia can expect a milder, more manageable manifestation that can be monitored and treated successfully without the need to discontinue therapy.
"Grade 3 hyperglycemia rates and overall discontinuation rates were low. Grade 1 and 2 hyperglycemia can be managed. With medications, we are able to keep patients on the same drug with potentially maybe one dose reduction," she said. Jhaveri and her colleagues plan to present additional long-term safety data on Itovebi, including hyperglycemia rates, at the upcoming San Antonio Breast Cancer Symposium in December.
George Sledge, Caris Life Sciences chief medical officer and adjunct clinical professor at Stanford Medicine, agreed that the combination of efficacy and the reduced risk for high-grade hyperglycemia makes Itovebi an appealing choice. "I don't see any reason to go with Piqray," Sledge said. "[Piqray] is a heavy lift in that you're having to continuously monitor blood sugar and frequently adjust diabetes medications. It's an extra burden on the clinic compared to a lot of other drugs that we use."
Sledge, who wasn't involved in the INAVO120 trial, highlighted the promising overall survival trends in that study as another differentiator between Itovebi and competitors. "Of all the drugs that have targeted [the PAM] pathway, none have shown an improvement in overall survival. All [these drugs] were approved based on progression-free survival [data]," Sledge said. " Even though the [overall survival] data are not quite mature, [Itovebi] appears to have an advantage."
Sledge cautioned, however, that as is often the case with newly approved cancer therapies, Itovebi will likely not perform as well in the real world as it has in the INAVO120 trial because clinical trial participants tend to be younger and healthier. Sledge noted that in the respective pivotal trials of Piqray and Itovebi, all patients with type 1 diabetes and certain patients with type 2 diabetes were excluded. "If you have an older group where there's a higher component of prediabetes or diabetes, who would have been excluded from the trial, the moment you go into [a real-world population], you get worse results," Sledge said.
Although comparisons between INAVO120 and SOLAR-1 appear to favor Itovebi-Ibrance-fulvestrant over Piqray-fulvestrant, Sledge cautioned that cross-trial comparisons can be misleading because differences in study design, patients' tumor characteristics, and the treatments patients received prior to entering the trial can impact the findings. Case in point, INAVO120 involves treating patients in the first-line setting, whereas SOLAR-1 focuses on the second-line setting.
Novartis did not respond to questions about oncologists' views about Itovebi's activity compared to Piqray's ahead of press time.
Roche, however, is conducting a head-to-head comparison of Itovebi and fulvestrant. In the Phase III INAVO121 trial, the biotech is comparing Itovebi-fulvestrant to Piqray-fulvestrant in patients with HR-positive, HER2-negative, PIK3CA-mutated locally advanced or metastatic breast cancer who have progressed during or after CDK4/6 inhibitor therapy. The trial's primary endpoint is blinded independent central review-assessed progression-free survival. Secondary endpoints include overall survival, overall response rate, and measures of safety and quality of life. As in INAVO120, patients with type 1 diabetes or type 2 diabetes requiring systemic therapy are excluded from enrolling in the trial.
One potential concern for Sledge as Itovebi enters the market is that the CDK4/6 inhibitor in the triplet regimen is Ibrance. "[Ibrance] has become less popular in recent years compared to other CDK4/6 inhibitors," Sledge said.
Novartis' Kisqali (ribociclib) and Eli Lilly's Verzenio (abemaciclib) are the two other CDK4/6 inhibitors approved for first-line treatment in HR-positive, HER2-negative advanced breast cancer. "If doctors wanted to use this in a frontline setting, we don't really have the data on combining it with the other two CDK 4/6 inhibitors."
Ibrance was the first CDK4/6 inhibitor approved in this treatment setting. And although Ibrance, Kisqali, and Verzenio have shown to similarly impact progression-free survival across various trials, maturing overall survival results have shown that Kisqali and Verzenio, when combined with fulvestrant, allow patients to live longer than with fulvestrant alone. In comparison, Ibrance-fulvestrant has not demonstrated a statistically significant improvement in median overall survival versus just fulvestrant.
Further muddying the waters, the Phase III SONIA trial, a head-to-head comparison of patients who received CDK4/6 inhibitors in the first line versus those who got it as a second-line option, showed no statistically significant difference in progression-free survival or overall survival.
Another important question for the future, according to Sledge, is whether these drug combinations can be safely moved into the adjuvant setting. At that point, "toxicity becomes particularly important," Sledge said, noting that toxicities that would be acceptable for patients with advanced cancer are often not acceptable to patients undergoing adjuvant therapy who can expect good outcomes with current standard treatments.
Despite these lingering questions and the need for further trials to resolve them, Roche has high expectations for Itovebi's ongoing launch in the fourth quarter of 2025. In a call last month to discuss the company's third quarter financial results, Roche Pharmaceuticals CEO Teresa Graham said that "the Itovebi approval in the US not only came earlier than expected, but we were also granted a very strong US label. All endocrine-resistant patients are included, not only those developing endocrine resistance within 12 months of endocrine therapy."
Graham said Roche hopes to expand the addressable patient pool for Itovebi by pushing it into earlier lines of therapy in PIK3CA-mutated HR-positive, HER2-negative breast cancer based on data from INOVO121 and other new trials. Roche is seeking approval for Itovebi-Ibrance-fulvestrant in Europe and is hoping to hear from regulators there in the first half of 2025. The drug has also received breakthrough therapy designation and been granted priority review in China.
"We are convinced that Itovebi has a peak sales potential of more than $2 billion in HR-positive breast cancer alone," Graham told investors on the call. "Beyond these trials, we are also actively looking at other tumor types where PI3 kinase mutation plays a significant role."