Inavolisib Regimen Approval Opens the Door for Triplet Therapies in HR+, HER2– Breast Cancer

Hope Rugo, MD, FASCO

The October 10, 2024, FDA approval of inavolisib (Itovebi) plus palbociclib (Ibrance) and fulvestrant (Faslodex) has offered patients with endocrine-resistant, PIK3CA-mutated, hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer a tolerable and efficacious treatment option following recurrence on or after completion of adjuvant endocrine therapy, according to Hope Rugo, MD, FASCO.¹

Findings from the phase 3 INAVO120 trial (NCT04191499), which supported the approval, showed that patients who received the inavolisib regimen (n = 161) achieved an objective response rate of 58% (95% CI, 50%-66%) vs 25% (95% CI, 19%-32%) among those treated with placebo plus palbociclib and fulvestrant (n = 164). Additionally, the median duration of response was 18.4 months (95% CI, 10.4-22.2) vs 9.6 months (95% CI, 7.4-16.6), respectively.²

“Thankfully these patients have a number of treatment options, so we need to be evaluating their survival over time. It’s exciting when you [consider] the fact that the first data from this phase 3 trial were made public in December 2023 and presented 3 days later at the San Antonio Breast Cancer Conference—I was honored to discuss that data—and it’s been approved in October 2024,” Rugo said in an interview with OncLive®. “That’s a very great speed of getting a new approach into the clinic. It’ll take us a bit to see what happens with survival, but it’s going to offer us a lot of insights into how to treat patients in this situation.”

In the interview, Rugo detailed the significance of the approval, how the agent will be incorporated into clinical practice, and the patient population evaluated in INAVO120. Rugo is the director of Breast Oncology and Clinical Trials Education, medical director of Cancer Infusion Services, the Winterhof Family Endowed Professorship in Breast Cancer, and a professor in the Department of Medicine at UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco.

OncLive: What patient population was enrolled in INAVO120?

Rugo: This is an exciting step. The naysayers will say that we don’t understand sequencing and how this all fits together in terms of triplet vs sequential doublet therapy, but the key here is that our standard of care is CDK4/6 inhibitors in the first-line setting. This trial focused on a patient population who [responded] poorly to therapy in the first-line metastatic setting [and had progressed on adjuvant] endocrine therapy. Correlative studies of the successful studies with CDK4/6 inhibitors [in the] first- and second-line settings [found] that, although CDK4/6 inhibitors improve the progression-free survival [PFS] with a similar HR, the PFS curves are shifted down so there is a shorter PFS because [of] that PIK3CA mutation.

In [INAVO120], they selected patients who not only had a PIK3CA mutation, but who were essentially in the second-line setting. These were patients who had relapsed within a year of their adjuvant endocrine therapy with an aromatase inhibitor or tamoxifen, or they relapsed when they were receiving adjuvant endocrine therapy. The trial was based on very robust preclinical data that had been studied in a number of different settings, but because of the toxicity of the triplet combinations, hadn’t moved forward [before].

The preclinical data suggested that in cancers that have a PIK3CA mutation, if you combined a CDK4/6 inhibitor, endocrine therapy, and a drug targeting the PI3K pathway, the response and the response duration [are] improved; in some of these studies in mice the development of resistance [was] delayed.

In the INAVO120 trial that led to the FDA approval, patients were selected who had disease that we would predict would have a short PFS with first-line endocrine therapy and a CDK4/6 inhibitor. The hormone therapy chosen [in the triplet] was fulvestrant.

Interestingly, in this trial, and one of the caveats in the analysis, is a fair number of patients had received tamoxifen as their adjuvant therapy and not an aromatase inhibitor. We don’t know how that plays into this. The choice of the CDK4/6 inhibitor was based on the most commonly used CDK4/6 inhibitor at the time that the trial was designed, palbociclib. Also, palbociclib plays well in the sandbox; it mixes well with other drugs and doesn’t have the same drug-drug interactions as the other 2 CDK4/6 inhibitors. Although there are ongoing studies testing the combination of inavolisib and fulvestrant with ribociclib [Kisqali] now.

What key efficacy and safety data were seen in INAVO120?

It was interesting that the control arm had a [median] PFS that was very similar to the correlative studies that have been done on subgroup analyses of the patients who were receiving fulvestrant and other CDK4/6 inhibitors generally [in the] second-line [setting] or in this same setting who relapsed early on adjuvant endocrine therapy. [The median PFS] was more than doubled in patients who received the triplet [vs combination with a] HR of 0.43. This is very exciting [with] a 57% relative improvement and a very high response rate was seen with the triplet compared with the doublet therapy.

This was validating because we had seen these exciting preclinical data but had a hard time giving the treatment in clinical practice because of the toxicities of the agents. However, in this trial in part due to the toxicity profile of inavolisib and the selection of patients, the toxicity was quite manageable. Investigators selected patients who didn’t have diabetes or glucose intolerance. Essentially, all the patients had a normal hemoglobin A1c [level] or close to normal and didn’t have a big problem [with treatment]. [Inavolisib] also doesn’t seem to cause the diarrhea that we sometimes see with other agents that block this pathway, and [instances of] rash were easy to manage. You do see toxicity [and can observe] stomatitis and other common toxicities of blocking the PI3K pathway. Hyperglycemia [also occurs] in patients who are at risk, but the patients at risk were not studied in INAVO120.

To manage the other toxicities, we have to monitor glucose very carefully. Monitoring for stomatitis, diarrhea, and rash, are the main things to be looking carefully for in drugs that target this pathway.

What happens when we take this agent into the real-world population of patients? First, we’re able to target a group of patients who have a poor prognosis, hormone receptor-positive breast cancer, and treat them with a triplet [hormone therapy]-based combination that resulted in a median PFS of over a year. We just don’t see that with a doublet treatment.

How will inavolisib be incorporated into care in this patient population?

I don’t think that sequential therapy is a better option for these patients because after fulvestrant, unless we have an oral SERD that’s very effective in that setting, what are we going to give as the endocrine partner? [Therefore], the triplet in this setting makes a lot of sense to me and because it’s based on multiple preclinical studies, it has more validity for benefit in our patients. Tomorrow, if we [were to] have a patient who’s relapsing on adjuvant endocrine therapy or within a year of their adjuvant endocrine therapy, we would first test for alterations in PI3K. They didn’t look at AKT or PTEN alterations in this population, it was [solely] activating mutations in PI3K. It’s a reasonable approach to take.

The concerns are that you want to be very careful in patients who have high hemoglobin A1c [levels] because we do not have data with inavolisib in that setting, and you don’t want to be surprised with a patient who has severe hyperglycemia 2 weeks [after receiving therapy]. You need to make sure the glucose is well controlled and that you monitor these patients very carefully. We’ve seen elevations in fasting glucose [levels], nothing serious, and it was managed with metformin in patients taking inavolisib in other combination studies who started out with a normal hemoglobin A1c level; it’s a pathway toxicity that occurs in patients, and patients at higher risk need to be monitored much more closely.

There are also cytopenias seen with palbociclib, and I don’t have a concern about using palbociclib in this setting vs ribociclib. Ribociclib has come out as the drug with the survival benefit, but palbociclib looks very good in repeated real-world studies and in the patients who have this poor prognosis disease, we want a triplet therapy that’s very effective. The ribociclib combination is being studied, and that will be another option for us I hope in the not-too-distant future.

What are the next steps following this approval?

Incremental steps [to] benefit patients, understand the mutations, [and understand] the pathway alterations that occur that drive these cancers and drive resistance is very important in our quest to improve outcomes for patients with breast cancer. Hopefully we’ll be able to continue evaluating triplets now that we have 1 successful one. Substituting oral SERDs [as] they may be even more effective, substituting CDK4/6 inhibitors, [and] better understanding the toxicity in patients who have diabetes or glucose intolerance [are] all next steps. Targeting patients who [will experience] early relapse in the early stage setting perhaps will lead to improved treatment in the future. This [approval] is a very exciting advance for our patients.

What questions remain regarding survival and sequencing?

One of the end points that’s become increasingly important to us—it was always important, but it seemed elusive in hormone receptor-positive, HER2-negative disease—has been overall survival [OS]. It’s been thrilling to be able to see OS benefits with combination therapy, both with endocrine therapy and CDK4/6 inhibitors, but also with antibody-drug conjugates [ADCs]. What about OS in this group of patients? They will have access to drugs that target the PI3K pathway as well as AKT alterations—capivasertib [Truqap] is now approved with fulvestrant for tumors that have PIK3CA, AKT1, and PTEN alterations. Does the sequencing matter and if you use an oral SERD does it matter?

Looking at survival will be an interesting end point in this population. We’re now in a tough situation in terms of looking at OS. We’re back to the beginning because we saw these survival benefits [and] now we have drugs [such as] ADCs and other agents that improve survival. Now it’s all about access. For example, depending on where the trial is done and how many patients are treated, you may not have access to all of the ADCs that improve survival, so that could impact assessments and will have to be looked at very carefully.

[Additionally], there are many drugs that are targeting this pathway where there’s now great interest in triplet combinations. Capivasertib, the AKT inhibitor, is being studied in a triplet combination [with fulvestrant and either] palbociclib or ribociclib in the phase 3 CAPItello-292 trial [NCT04862663] in the first-line setting in a high-risk population as well. We’re going to see more data using this approach in the future.

References

1. FDA approves inavolisib with palbociclib and fulvestrant for endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, advanced breast cancer. FDA. October 10, 2024. Accessed October 30, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-inavolisib-palbociclib-and-fulvestrant-endocrine-resistant-pik3ca-mutated-hr-positive
2. Itovebi. Prescribing information. Genentech Inc; 2024. Accessed October 30, 2024. https://www.gene.com/download/pdf/itovebi_prescribing.pdf