Lisa A. Carey, MD, and Dejan Juric, MD, on Breast Cancer: Updates From the INAVO120 Trial

Lisa: Welcome to ASCO Post, Dan. Dejan: Hello. Lisa: So, the INAVO120 trial, super important trial, had some great updates, really important data come out here at ASCO 2024. For everybody, just quickly highlight the eligibility and the design of this important trial. Dejan: Indeed, it's a quite important trial. It studies in a randomized double-blind fashion inavolisib or placebo when combined with fulvestrant palbociclib in PIK3CA-mutated ER-positive, HER2-negative breast cancer. Eligibility criteria are quite important. We often say that precision oncology depends on giving the right treatment to the right patient the right time. And for this reason we have specific criteria. This had to be a first-line disease. PIK3CA-mutated. Most of the patient that was detected by ctDNA. It was critical that the disease recurred on or shortly after completion of adjuvant therapy and the patient had to have a measurable disease. Finally, since we are giving PI3K alpha inhibitor, it was important to have fasting plasma glucose that was nicely controlled in A1C under six. Lisa: Now, previously the primary endpoint of progression-free survival has been reported with a more than doubling of it. It's really nice data, but frame it in terms of the new information that's important about patient experience and some of the other endpoints that were presented at ASCO 2024. Dejan: Indeed the doubling of PFS that we saw, so 7.3 months to 15 months was quite impressive. However, additional analysis presented here, shed a lot more light on that patient experience. Specifically, it looks at what happens with the patient after discontinuation of this therapy. We wanted to know is there a carryover effect. And indeed the benefit that's in the trial is seen when you look at post-progression therapy and when you look at PFS-2, we have prolongation that's more than 8.9 months. Actually, the benefit widened as the patient continue the treatment with second-line therapy. Lisa: Right. And just for people who don't spend time with this terminology, PFS-2 is from randomization until the next line of therapy following the treatment. The protocol-directed treatment. Dejan: Correct. Correct. Additional endpoints that we looked at is time to initiation of chemotherapy and that was considerably longer in the experimental arm. When you look at actual patient experience, what we were primarily interested, what was sort of the first thing that I looked at is what happens with pain. It's such a dominant feature of metastatic breast cancer, particularly when it involves bone and we saw the time to deterioration, clinically meaningful deterioration in pain scores was considerably longer with inavolisib, the Delta was approximately 12.8 months, so more than a year. Lisa: Right, before their pain got significantly worse. Dejan: Exactly, exactly. Lisa: It is a really important study. It's worth noting, these are bad actors, right? They had to be in the trial, they had to relapse early. They obviously had to have the biomarker definition. And the control arm didn't do very well. So as you think about where you're taking several of our, you're taking a PI3 kinase targeted, you're taking the CDK4/6 inhibitor and you're giving it all in the first line. Where do you think this is going in terms of how we treat patients in the future? Dejan: I think these are the critical points. We often think about ER-positive, HER2-negative breast cancer as somehow having, quote, good prognosis. However, a subset of patients with that lastly heterogeneous group of patients will have particularly poor outcomes. And PIK3CA mutant sometimes is exactly that. What this trial also shows and what's really critically important, we often think of targeting disease in terms of single target, at most two targets. Here we are going after three highly interconnected targets. If you go after one, the other one reacts. So only by targeting all three of these central hubs, we can actually get these impressive outcomes in high-risk disease. As far as I'm concerned, this should be the preferred approach for treatment of these patients with these high-risk features. What's additional studies now need to show, can we expand the patient population that has similar benefit? Can we go after endocrine-sensitive patient population? Is this triplet somehow uniquely active in endocrine-resistant disease? Or could we preempt and delay emergent resistant even in endocrine therapy? Additional studies that are obviously needed is to understand how the inavolisib performs in second-line setting, perhaps in combination with fulvestrant. Lisa: Well, that is terrific. Congratulations and thank you. Dejan: Thank you.