Efficacy vs Feasibility: Weighing Timing, Selectivity, and Logistics in PIK3CA Wild-Type HR+/HER2- Locally Advanced or Metastatic Breast Cancer Treatment Sequencing​

Breast oncology experts debate real-world treatment decisions for patients with PIK3CA wild-type HR+/HER2− locally advanced or metastatic breast cancer who have progressed on a CDK4/6 inhibitor—weighing whether an actionable mutation should dictate the next therapy, how broadly and intensely to target the PI3K/AKT/mTOR pathway, and how route of administration and patient preference factor into treatment selection.

Round 1

After progression on a CDK4/6 inhibitor, should an actionable mutation determine treatment selection in PIK3CA wild-type disease?​

The debate opens with a patient with PIK3CA wild-type disease progressing on an aromatase inhibitor plus a CDK4/6 inhibitor. The panelists debate whether a newly identified actionable mutation should direct the next treatment or instead inform an individualized sequencing decision that also considers the overall evidence, clinical context, and patient factors. They then examine whether randomized evidence in PIK3CA wild-type disease supports considering a broader PAM-pathway–targeted approach at this post-progression decision point.

Round 2

How should the breadth of pathway inhibition and regimen intensity influence treatment selection after CDK4/6 inhibitor progression?​

The discussion turns to how broadly and intensely to inhibit the PI3K/AKT/mTOR pathway after CDK4/6 inhibitor progression. Panelists debate whether broad, multi-node PAM inhibition should be prioritized regardless of PIK3CA status, weighing potential gains in disease control against added toxicity and monitoring needs, and discuss when selective pathway targeting or a less-intensive regimen may be preferred.

Round 3

How does route of administration ​and patient preference impact ​treatment selection?​

In the final round, panelists consider how route of administration and patient preference affect treatment selection. They weigh the potential benefits of IV therapy—including more frequent clinical contact, closer toxicity monitoring, and assured adherence to clinic-administered doses—against the autonomy, convenience, and reduced disruption associated with oral therapy, which many patients may prefer.

Seth Wander, MD, PhD: Thank you all for joining us. I think we have some folks online as well. We appreciate the opportunity. Thanks to the team at Great Debates and Oncology Learning Network. We're going to talk today about efficacy versus feasibility, weighing timing, selectivity, and logistics in PIK3CA wild-type, hormone receptor-positive/HER2-negative, locally advanced or metastatic breast cancer treatment sequencing. With an asterisk, we're going to talk about the mutant as well. We'll cover some data for PIK3CA mutant also. So I'm joining you from Mass General in Boston. It's my pleasure to be joined by my friends and colleagues, Dr VK Gadi and Dr Paolo Tarantino from University of Illinois and Dana-Farber, respectively. And they're going to get into a vicious debate on some of the emerging data in PIK3CA wild-type and mutant. I should probably separate them a little more at this table. They probably need something in between. 

So the objectives for this afternoon, by the end of the program, we want you to be able to define the post CDK4/6 clinical decision point for patients with PIK3CA wild-type, ER-positive/HER2-negative disease; evaluate efficacy, maturity of evidence, and combination intensity when selecting post-progression therapy; integrate toxicity, route of administration, access, and patient preference into that shared decision-making. So let me just make a few comments. I don't have to tell anybody in this room how dynamic this particular area has been just over recent hours and days. We have had an unprecedented number of FDA approvals in the last few weeks, more than I can remember at any point in my career training or in practice. So this is really getting extremely complicated, and this is one way to visualize what we're doing right now. There's several different ways to lay this out, but, just briefly right now, what I think is the standard of care as of Friday; it could change on Monday with more FDA approvals, but on Friday, patients with frontline therapy are getting AI in a CDK, mostly ribo [ribociclib] for survival benefit. 

If they're PIK3CA mutant and endocrine refractory, they would be eligible for inavolisib and INAVO120 regimen. In the second-line setting, this is where personalization is increasingly important. So if they're BRCA mutant, they're eligible for a PARP inhibitor. If they're ESR1 mutant, we had 3 single-agent approvals: elacestrant, imlunestrant, vepdegestrant, PROTAC. Now we have imlunestrant─abema [abemaciclib] doublet approved in that setting as of last week. And we have the camizestrant data, which, if you're following the study, you would be testing for ESR1 on frontline therapy without radiographic progression. So that's sort of a new line that actually is somewhere in between the top and the bottom here. If they're PIK3CA mutant or AKT/PTEN mutant, they can get capivasertib with fulvestrant. They can get alpelisib if they're PIK3CA mutant. And if they have none of the above, this is really an area of unmet clinical need. This used to be fulvestrant, fulvestrant-abema, which is the post-MONARCH regimen, everolimus with endocrine therapy. 

But a couple of weeks ago we had an FDA approval that we'll focus on today with gedatolisib, which is the first PAM pathway inhibitor. Now we have data for that in the mutant and wild-type PIK3CA setting, but the label as of right now is just in the PIK3CA wild-type because the mutant data is more recent. And we'll talk about that today. Once you've exhausted all of the above, now we're thinking about ADC therapy, T-DXd for HER2-low or -ultralow, conventional chemotherapy, of which there are obviously many choices, and other ADCs, sacituzumab and dato-DXd. But we're really going to zoom in on that second-line setting and we're going to focus on some of the newer data related to gedatolisib. Now, mechanisms of endocrine and CDK4/6 inhibitor resistance are diverse. Our team and many others have looked at this through next-generation sequencing and laboratory models. 

And what you see is that there's no clear single driver of CDK4/6 resistance in particular. We see activation of AKT/mTOR downstream of PI3 kinase. We see activation of RAS, MAP kinase, MEK. We see alterations in FGFR, enhertu. We see cell cycle regulatory changes: Cyclin E, CDK2, loss of RB, up regulation of Cyclin E. We see loss of ER itself. So lots of different roads. And what's even more complicated is that some of these alterations provoke unilateral resistance to CDK, but not the antiestrogen. Some of them provoke resistance to both the antiestrogen and the CDK, while other mutations like ESR1 only really impact the endocrine component. The CDK inhibitors are okay regardless of ESR1 status, at least in the lab when you use this in in vitro models. And so this is very complex to model and to understand, but one of the things we're going to focus in on is that PI3K/AKT/mTOR pathway is a key element driving response to both endocrine-based therapies in the second-line setting and beyond, as well as to CDK4/6 inhibitors. 

And so what about biomarker testing? Now, we're going to hear a little bit from our colleagues on the panel about how they test and what they think you should or should not do. But for now, what we typically do at diagnosis, we obviously need IHC to understand ER, PR, HER2. We should understand the germline BRCA status. And really at diagnosis, increasingly we need to understand the PIK3CA status, particularly if they're endocrine refractory because that would be on label for inavolisib. Now you can explore other things like AKT, P10, ESR1, MSI status, TMB, et cetera, but it's probably not going to change your therapeutic decision-making in that frontline setting. During or after progression on the frontline, that's where we start to see the emergence of ESR1. We might see acquired changes in AKT and P10. We see the emergence of some of these other things that drive CDK resistance, like HER2, FGFR, RAS, NF1, et cetera. 

And then again, we can see that develop later on. So we're doing increasingly broad genomic and molecular profiling in the first line with SERENA-6 and now beyond, of course, the first line in the setting of second- and third-line progression.