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.

To hear arguments related to treating patients with an actionable mutation, see Round 1.

To hear arguments related to pathway inhibition and regimen intensity, see Round 2.

To view the full series, click here.

Seth Wander, MD, PhD: Okay. So we're coming in for a landing here in the next 15 minutes or so. How does the route of administration and patient preference impact treatment selection? So what we haven't mentioned in a lot of detail is the kind of tox profile and the way we give this drug. So there's a long history of attempts to target PI3K and mTOR together. And the story that I like to tell is about, oh my gosh, 15 to 20 years ago, I was a graduate student, and we were working on PI3K/mTOR signaling in breast cancer. 

And we wrote a review that I think is still one of our highest cited papers, but it hasn't been cited in many years. And the reason is around that time, there was huge interest in developing dual mTOR and dual PI3K/mTOR inhibitors, and every company had these drugs in their pipeline. So we wrote this review about how this was going to cure every kind of cancer and this was going to change the world because this is the backbone of many different cancer types, PI3K/AKT/mTOR signaling. 

We were dead wrong on everything we said in that review. That paper has 2 or 3 big tables of drugs, preclinical, early clinical, late clinical, which is a graveyard. Every single one of those drugs failed. Because when you give them orally hitting both upstream and downstream, the toxicity was way too high. The therapeutic index was too narrow. Except in the middle of one of those tables is a drug that became gedatolisib after several transitions from different companies. 

So we weren't totally wrong, we were 98 or 99% wrong. And the reason is because this drug is given IV. So the pharmacokinetics, the processing in the liver, you're bypassing that, you're getting far less hyperglycemia and GI toxicity and rash than you would see with single node PI3K inhibitors and way, way less than you would see with a dual PI3K/mTOR inhibitor, which we don't even have to compare it to because those drugs are 15 years old and gone from our mind. 

But those drugs really were really hard to tolerate for all the reasons you would expect. So now the question for this end of the debate becomes how much of a challenge or a problem is the IV administration of geda? As we think about moving this drug into earlier lines of therapy, there's a phase 3 trial right now in the frontline setting using geda. Is the IV treatment a pro, a con, both? And how much practical impact will it have on what you guys are doing in clinic? So VK is going to tell us that it is preferred. 

VK Gadi, MD, PhD: So before I do that, I just want to give props to your foresight and just say that we tend to think about overcoming resistance by going over a completely second pathway, but there's actually lots of evidence showing that the cancer cells are resilient in a way that if you block somewhere along the same node, there will be another entry path into that pathway and you just basically turn it on. 

So this idea of hitting the top and the bottom of the node actually makes a lot of sense because you will see other drugs who've been able to do that have also been successful even if they've not made it to clinic. So intellectually, the rationale for that is abundantly clear that you get comprehensive shutdown of a pathway in that way. 

Anyway, so some of the reasons why we may want to do this, and it's interesting, I've had conversations now with community providers about this particular drug and kind of what their thinking is because at the end of the day, we're going to give this 95% of the time not in academic centers, if at all. And one is that there are patients who really don't like being on oral therapies and being seen once a month. 

And that's not always the case, obviously. Many patients are just fine not seeing us, but there's an element of I feel cared for when I see you. I feel cared for when I get into clinic. I meet the nurses. I sit down. I have a schedule and a regimen. And for those patients... And keep in mind once a patient is in the clinic and getting this infusion, the time for infusion is not like a 5½-hour infusion with an antibody drug conjugate or whatnot. 

It's actually a very quick in and out scenario akin to what we might do with a bisphosphonate, for example. So it's not a huge commitment for each episode, but it is a commitment to come in, but you're building trust all that time. It's funny, I see patients infrequently. If I'm giving trastuzumab, I might see a patient every 4 months and I have community colleagues that are seeing those patients every 3 weeks. And I used to think it was just because they made more money. 

It's not, it's because those patients expect it. So there's this element of patient─provider trust there. And then you do have drugs that are oral agents that have plenty of side effects and toxicities. So this idea of being in the clinic to see those, assess those either by myself or with our nurse practitioners and others involved in the care of these patients, being able to monitor those adverse events and get ahead of them, it also is another way that we build trust with those patients as well. 

So those are some unique features of trust that you get with IV therapies. It's not on here, but let's face it; the next line of therapy for most of these patients is a big gun. It's probably an ADC, probably T-DXd, probably sacituzumab, something like that, and those drugs have legit toxicities. You have a transition opportunity to build that trust before you just jump into the deep end with those other drugs that makes things really hard so people have a better expectation of what's going on as their care evolves to more toxic agents. 

So what are some of these toxicities? These are sort of what I would say of special interest with this class of drugs. First and foremost, hyperglycemia. And as you pointed out, when you purely target the PIK3CA pathway and heavily so, you see a lot of all-grade toxicity, but more troublesome, you see grade 3 toxicity. I've actually put patients in the hospital with alpelisib with blood glucoses in the 800s, for example. Seen it plenty. 

In AVO, you have better selection of patients going in into that study. So you see a number that's actually kind of low, 5.6%, but I think in the wild that's going to be higher. And you had this very strict inclusion criteria of an A1C less than 6. I've yet to find that patient in my practice. CAPI is at 8, and I think the reason why they got away with that is because it is discontinuous dosing. 

They're not able to continuously hit this pathway. So it's 4 days out of 7, as you pointed out as well, Seth. And then lastly, VIKTORIA-1, there's an inclusion A1C of less than 6.4, but you can see the grades of all-grade toxicity and grade 3 (9 and 2%, respectively). And frankly, this number does not go up much if you liberalize that A1C. Again, it was a function of having alpelisib in the comparator arm. 

Diarrhea is there, but again, less of this toxicity across the board compared to the other agents. Mucositis, more of this toxicity, and more grade 3. This is something that we've all learned to manage better. Breast cancer doctors are behind on this compared to general practitioners or those that may have been giving EGFR inhibitors this whole time. But here again, this toxicity does extinguish itself over time as patients are on the drug. 

You just see less of it. It can happen in a mercurial way here and there, but patients generally are not unable to eat or keep up with nutrition and drink fluids, et cetera. We just have to support them in the early days, and rash follows a similar pattern. But again, that's not that different than what you're seeing with these other agents. 

Paolo Tarantino, MD, PhD: All right. So for this final round, let me take again the time machine and go farther back in time when I was born. I was born... 

Gadi: That was the year I started practicing. 

Tarantino: When I was born, my parents were looking for a second house. They managed to put some money on the side and they wanted to buy a home house. I used to live in Napoli in the South of Italy and they decided to look around the corner that there is the Amalfi Coast, this beautiful place. They found a house in this tiny village there called Atrani. And since then, I spent every summer of my life in Atrani and it's beautiful place. 

I recommend it to all of you. But besides recommending it to you, I often recommend it to patients. Patients have heard about the Amalfi Coast, not all of them have been there. I tell them, "You want to go to Positano? Don't. Go to Atrani instead." Everybody knows about Positano, but Atrani is a hidden gem. It's beautiful. It's authentic. You're going to love it. And the challenge is that it's so much easier to go to make a trip to the Amalfi Coast and spend a couple of weeks there if you're taking an oral pill because you can just take the box with you. 

And of course, you can link to a hospital down there if you have some troubles. If you need infusions every week, it's a little harder. And I think it comes to that when we think of, of course, the challenges of this drug. I don't think that IV injections on their own are a huge issue, but the simple fact to be needing them every week, at least every 3 weeks and then 2 weeks off, it does kind of impact the schedule. 

It does impact your ability to access to a hospital that is far away. It does come with logistic challenges. I do think that that's one important part of it. Now, there's other parts of it. There are some patients that don't love to have an IV access. They are scared about infections. Patients that just don't love needles. I don't love needles. But the truth is that I think it's more about read the schedule. 

One thing that I believe will help in the future is that there is a subcutaneous schedule of gedatolisib that is already in development. And we've seen it, for instance, with trastuzumab and pertuzumab, the switch towards subcutaneous made it easier. I think it's going to happen also with gedatolisib. 

At the same time, as I was mentioning before, overall survival and quality of life are both extremely important, but when we're thinking about optimizing outcomes, one patient may want to optimize more quality of life, the trip to the Amalfi Coast, but other patients instead may want to either want to or need to, because of the abundance of disease, want to optimize outcomes, oncologic outcomes. 

And so I do think having a regimen that will involve a bit more infusions, a bit more, let's say, involvement, but that comes with high response rate, long PFS, optimal outcomes. It is a pro. We do want options. We do want to tailor according to the disease profile, according to the patient profile. And I still think even if you make it short in those 2 weeks window that gedatolisib allows, still a trip to the Amalfi Coast is worth it. So I recommend it to anybody. 

Wander: All right. Sounds like a nice vacation. All right. Thanks to both of our panelists here today. I think we covered a lot of really important and interesting things. And these are not abstract concepts. These are real questions that are going to be confronted in clinic with our patients right now in the immediate future. So I think we should all be thinking very hard about how we're going to sequence, when we're going to sequence, who needs PAM blockade, wild type or mutant, how do we prioritize oral versus IV administration? 

So a couple of concluding comments. Actionable alterations can inform treatment selection, but don't necessarily determine the optimal sequence. The VIKTORIA-1 data establishes gedatolisib-based therapy as an evidence supported option after CDK progression in PIK3CA wild type. And I would argue in mutant disease. Right now the label is in wild type disease, but we expect other opportunities in the future. 

Pathway breadth and regimen intensity has to be weighed against toxicity monitoring, evidence maturity, patient goals, functional status, glycemic control, all of these other things. Doublet and triplet regimens have not been directly compared. And so we have to individualize selection based on the mutational profile, the prior therapy, the extent of disease, and obviously the tox profile. Route of administration, access, adherence, and patient preference is obviously going to impact all of the above.