Participants Discuss PI3K Inhibitors and Endocrine Resistance in Metastatic Breast Cancer

Virginia Kaklamani, MD, DSc

MODERATOR

Professor of Medicine

University of Texas Health Science Center San Antonio

Ruth McLean Bowman Bowers Chair in Breast Cancer Research and Treatment

A.B. Alexander Distinguished Chair in Oncology

Leader, Breast Cancer Program

Codirector, Cancer Genetics Program

UT Health San Antonio MD Anderson Cancer Center

San Antonio, TX

EVENT REGION Texas

PARTICIPANT LIST Rohit Kapoor, MD | Giancarlo Moscol, MD | Tri Vu, MD | Parth Khade, MD | Putao Cen, MD | Syed Raza, MD | Shan Guo, MD | Samir Mazharuddin, MD

CASE SUMMARY

• A postmenopausal woman aged 58 years underwent lumpectomy for a pT2N0M0, grade 2 invasive ductal carcinoma.
• Hormone receptor positive, HER2 immunohistochemistry 0, Ki-67 25%; 21-gene recurrence score: 28
• Adjuvant therapy: docetaxel plus cyclophosphamide, radiotherapy, anastrozole for 5 years (planned)
• Eight months after completion of anastrozole, disease recurrence with symptomatic bone involvement is identified.
• Hormone receptor positive, HER2 immunohistochemistry 0
• T2pN0pM1
• ECOG performance status: 0
• Laboratory results within normal limits

DISCUSSION QUESTION

• Do you have experience using a PI3K/AKT inhibitor, either on or off a clinical trial, in any setting?

KAKLAMANI: Have you used PI3K or AKT inhibitors? What is your perception of these agents?

KAPOOR: I’ve used alpelisib [Piqray] in a couple of patients, but the hyperglycemia made it prohibitive. Both patients had to be taken off because of hyperglycemia—one had diabetes-related ketoacidosis, the other had community‐acquired pressure injury. I’ve used capivasertib [Truqap] once. It has a better adverse event [AE] profile overall, and I think it’s a better drug. I haven’t used the new one, inavolisib [Itovebi].

MOSCOL: Yes, I agree. Alpelisib is a very difficult medication, very challenging. I have mixed feelings because I still believe it’s very effective. The problem is you need to push through the first 3 months, which are the most difficult. There’s a learning curve. After that, it gets a little better. Patients understand what to eat, what not to eat, how to balance, and [they need to take] metformin.

I’ve seen very good responses with alpelisib. I’ve had a couple of patients who exceeded 12 months of durable response. But it’s about how you get there…. I probably had 3 or 4 who didn’t do as well. Capivasertib is significantly easier, but I’m not impressed with the data. I’ve used it, and 2 patients have had progression on it. I still have 1 patient who hasn’t progressed yet, but I believe I’m getting less mileage in terms of efficacy and durability of response compared with alpelisib. I don’t know if it’s because it’s an AKT inhibitor instead of a PI3K inhibitor, but it causes more diarrhea than hyperglycemia.

VU: I also have experience with alpelisib, and I agree, it’s very difficult. My strategy was to start and stop it, using low doses and involving endocrinology. I check laboratory results twice a week. Endocrinology helps manage hypoglycemia with a device that patients wear under their arm that monitors glucose in real time. They can adjust insulin levels based on glucose readings. It’s difficult, but the patient was stable for about 6 months before progression. I haven’t had any experience with capivasertib.

KAKLAMANI: Has anyone tried using metformin prophylactically? I talked to endocrinologists about metformin, but they said because of the unpredictability of glucose levels…metformin can be used as a baseline, but you need something else on top of it.

KAKLAMANI: How do you approach this? What are you looking for at the diagnosis of metastatic disease when you do the testing?

VU: I use FoundationOne, and they do it for free for 2 years. If the disease progresses within 2 years, they can do it for free.

KAKLAMANI: What are you looking for regarding mutations in that first line?

VU: They have a whole panel, around 300 or 200 mutations. We’re always looking for targets like PIK3CA mutations.

KAKLAMANI: For those who said diagnosis and every progression, what are you looking for?

MOSCOL: ESR1 mutations—as patients are exposed to more endocrine therapy, that increases.

KAKLAMANI: That’s what I was thinking as well. We have to make sure the tumor is still endocrine sensitive; otherwise, we’ll move on to cytotoxic therapies. That’s what I typically do as well.

CASE UPDATE

• Next-generation sequencing shows PIK3CA mutation, no other actionable mutations.
• Hemoglobin A1c: 5.7%

DISCUSSION QUESTIONS

• How do you define endocrine resistance?
• Do you consider her to be a high-risk patient?

KAKLAMANI: This patient was on endocrine therapy, and 8 months after completing 5 years of endocrine therapy, she’s now diagnosed with metastatic disease with a PIK3CA mutation.

KHADE: Typically, I would say [they are high risk] if they’ve been on endocrine therapy previously and relapsed within a couple of years of adjuvant endocrine therapy treatment or had disease progression while on endocrine therapy in the metastatic setting.

KAKLAMANI: That makes perfect sense. These patients have at least some degree of endocrine resistance. Even if someone has a PIK3CA mutation or an ESR1 mutation, they have some degree of resistance, but it doesn’t mean they’re completely endocrine resistant. As far as high risk, someone with an ESR1 mutation or a PIK3CA mutation tends to have more aggressive tumors, so that would be high risk as well.

DISCUSSION QUESTIONS

• What are your reactions to the phase 3 INAVO120 trial (NCT04191499) efficacy data?¹
• In your opinion, do the end points demonstrate a clear benefit with the addition of inavolisib to fulvestrant plus palbociclib for this high-risk, endocrine-resistant population?
  

KAKLAMANI: What are your thoughts on the INAVO120 trial results? Would you use inavolisib for your patients? What end points resonate with you, and what do you discuss with your patients?

CEN: It doubled survival in the trial, and I would recommend it to patients.

KAKLAMANI: What end point do you find impressive in this trial? Would it be progression-free survival [PFS] or something else?

CEN: The additional 7.7 months of PFS [stood out to me].

RAZA: For me, the response rate is more impressive, especially in progressive visceral disease. These patients were at high risk for visceral disease, and I was more impressed with the response rate.

KAKLAMANI: I was also impressed with that. The PFS is something we’ve seen with other PI3K inhibitors, but not to that extent. The response rate almost tripled, which I didn’t expect. As for the control arm, the CDK4/6 inhibitor had a median PFS of around 7 months. Any thoughts on that?

RAZA: I think there were 2 factors: They were resistant to hormone therapy and had PI3K mutations. They were expected to do worse. The CDK4/6 inhibitor alone didn’t perform as well as we expected in hormone-sensitive disease.

KAKLAMANI: I agree. This is an endocrine-resistant patient population, so I wouldn’t expect much better outcomes.

DISCUSSION QUESTIONS

• How familiar are you with the on-target toxicities of PI3K/AKT inhibitors?
• How comfortable are you with management of these AEs? What is your general approach?

KAKLAMANI: Do you usually send patients to endocrinology? Do you feel you can manage hyperglycemia? Do you have your nurses call the patients? How does that work?

GUO: I’m reasonably comfortable. I’ve seen some AEs, but nothing too bad. Most of the time, I start patients on metformin and warn them about hypoglycemia and diarrhea. I often don’t start the full dose and [then] see how things go. Surprisingly, some patients never have hyperglycemia. I’ve had patients who became slightly hypoglycemic, so I had to stop metformin. I think it’s manageable. I haven’t needed to consult endocrinology. Most patients in the community aren’t eager to see additional doctors.

KAKLAMANI: I agree. Endocrinologist appointments can be hard to get, at least in our part of the country. After seeing all this, how comfortable are you managing the toxicities, and how comfortable are you with the safety data of the INAVO120 trial?

MAZHARUDDIN: I feel it reflects what we’re used to with PI3K inhibitors overall. I take it as a serious medicine and prepare my patients for it, but it’s not so bad that it turns me away, especially seeing the efficacy data.

KAKLAMANI: With alpelisib and capivasertib, if we were doing genomic testing in the first line, we had several months to prepare our patients, knowing they might get a PI3K inhibitor. We could do a hemoglobin A1c, start them on an antidiabetic diet, or even give them metformin. With inavolisib, we’re giving it in the first line, so we don’t have time to prepare. This might be a little tricky.

Does anyone not want to give inavolisib in the first line? Maybe give a CDK4/6 inhibitor first and then give endocrine therapy with a PI3K inhibitor in the second line? How do you see that data?

VU: It’s a balance. In the metastatic setting, we want patients to live longer, but they’re also frail. The more pills they take, the more AEs they may have. Sometimes we start with one and add a second if they tolerate it well, and then maybe add a third. It’s a balance between overall survival and quality of life.

KAKLAMANI: That makes sense. We need to see the patient in front of us, make sure they meet the criteria for inavolisib, and see what the burden of disease is. I always tell my patients this is a marathon, not a sprint. If we give them a lot of toxicities upfront, it might make it hard to move on to the second and third lines. We lose around 20% of patients between lines of therapy, so it’s important that our patients can go on to receive second-, third-, and fourth-line therapies.

_{DISCLOSURES: Kaklamani previously reported a consultant/adviser/speaker role for AstraZeneca, Gilead, Menarini, and Novartis; all other participants have no known disclosures.}

REFERENCE:

1. Turner NC, Im SA, Saura C, et al. Inavolisib-based therapy in PIK3CA-mutated advanced breast cancer. N Engl J Med. 2024;391(17):1584-1596. doi:10.1056/NEJMoa2404625