Before PI3K/AKT/mTOR Treatment: Trial Access After CDK4/6

If you have been on capivasertib (Truqap), or another PI3K/AKT/mTOR pathway inhibitor, you may have had to stop because the hyperglycemia, diarrhea, rash, or fatigue became unbearable. That is not the same as the drug failing to control your cancer.

This guide is for women with HR-positive, HER2-negative advanced breast cancer after CDK4/6 inhibition stops working. It is designed to be read before starting a PI3K, AKT, or mTOR pathway drug. It is also a worthwhile read for women who do not respond, cannot tolerate one, or are being told to move toward an mTOR inhibitor or HER2-low chemotherapy.

Contents

• Part 1: Choosing treatment and exploring trials

• Part 2: Understanding your PIK3CA mutation while you decide

• A simple way to frame the conversation

• References

• Prepare for a trial conversation

• A template you can send

• Before you write

• Why this matters beyond one email

• Keep the trial record current

Part 1: Choosing treatment and exploring trials

The off-target problem

Capivasertib does not only hit AKT in cancer cells. It hits AKT throughout the body, including the liver, fat tissue, kidneys, and cells that regulate blood sugar.

That is not evidence that your body is fragile. It reflects a non-selective mechanism reaching normal tissue as well as tumour tissue. Some women experience glucose spikes within days, shifting kidney markers, or exhaustion that does not lift on off-days.

Stopping because toxicity becomes unsafe or intolerable differs from progression. Both situations can still affect later trial eligibility.

Newer drugs in this class are being designed to address this problem. Mutant-selective PI3K and AKT inhibitors aim to hit the cancer-relevant mutation while sparing normal tissue. Early data suggest that some may produce less hyperglycemia and fatigue. Access remains the central problem.

"From the outside it can look like 'if I meet the criteria, I can get in'. What I've seen instead is that there might only be one or two actual spots at each site, even on a big global trial. A 400-patient trial sounds huge until you realise that's the entire world's allocation. It makes these studies feel less like options on a menu and more like a lottery with very few winning tickets." — Group member, living with metastatic HR+/HER2-negative breast cancer

The access wall

Some next-generation trials exclude any earlier PI3K, AKT, or mTOR inhibitor. They may exclude prior exposure even when treatment lasted weeks. They may also exclude prior exposure when toxicity caused the stop.

That exclusion is not universal. Current trial records separate into three groups: trials that lock out prior exposure, trials with unclear rules, and trials that remain open to breast-cancer patients with prior pathway treatment.

This is not a moral judgment on trial designers. Comparative trials need defined populations. It does mean that women who already paid the price of older pathway drugs can lose access to some newer trials.

"One thing I wish I'd understood sooner is that eligibility isn't just 'yes or no on paper'. Even when the listing says 'recruiting', my centre might not have any slots allocated to them, or they may already have a long waitlist. I'm number seventy-seven on one trial's list. Realistically, I will never be called. That's not written anywhere in the criteria, but it completely changes what's actually possible." — Group member, living with metastatic HR+/HER2-negative breast cancer

What this means before choosing treatment

• Do I have a PIK3CA mutation? Ask which test established it.

• Which open trials fit my disease and treatment history today? Include trials outside your usual centre.

• Would this treatment make me ineligible for a trial? Ask about prior PI3K, AKT, and mTOR exposure specifically.

• Eligibility on paper does not guarantee a place. Sites can have no local allocation, closed screening, or a waitlist.

What we verified: three trials, three answers

TOS-358 — confirmed open after prior pathway treatment

TOS-358 (NCT05683418) is an oral covalent PI3Kα inhibitor from Totus Medicines. It forms a permanent chemical bond with PI3Kα. The program aims for continuous target suppression at low doses while remaining alpha-selective.

The key posted exclusion language applies prior PI3K, AKT, or mTOR inhibitor treatment to non-breast-cancer participants. Breast-cancer patients are not excluded solely because of earlier PI3K/AKT/mTOR exposure.

This does not guarantee enrollment. Confirm mutation status, organ function, prior treatment lines, measurable disease, and site capacity.

Early Phase 1b results in heavily pre-treated patients reported hyperglycemia that appeared more contained than with older drugs. Those results remain early and need confirmation in larger studies.

Recruiting locations can change. Reported sites have included US locations and Spain. Confirm current locations directly with the study team.

Trial contact: clinicaltrials@totusmedicines.com · Trial record: NCT05683418

"I've begged for expanded access and compassionate use more times than I can count, and I've never had it granted. What I hear back is that any serious side effect or death off-protocol could jeopardise the main trial and the company's whole investment. It's heartbreaking as a patient, but it explains why even promising drugs like this rarely have an easy 'back door' for those of us who can't get into the formal trial." — Group member, living with metastatic HR+/HER2-negative breast cancer

ReDiscover-2 / zovegalisib — confirmed locked out after prior pathway treatment

ReDiscover-2 (NCT06982521) compares zovegalisib (RLY-2608) plus fulvestrant with capivasertib plus fulvestrant. This Phase 3 study tests a mutant-selective PI3Kα inhibitor against capivasertib.

The posted exclusion criteria explicitly exclude prior PI3K, AKT, or mTOR inhibitors, including agents targeting the PI3K/AKT/mTOR pathway. That means prior capivasertib, alpelisib, everolimus, or similar treatment excludes enrollment under the standard protocol. The reason treatment stopped does not change that rule.

For women who have not started a pathway inhibitor, this makes ReDiscover-2 a critical trial to check first. For women with prior exposure, a documented exception request may still raise the access issue. Do not assume a yes — the sponsor and site decide whether flexibility exists.

The study has reported sites in the UK and Australia. Confirm recruiting status and allocated slots locally.

Trial contact: ClinicalTrials@relaytx.com · Trial record: NCT06982521

"On paper this looks like the obvious next step after CDK4/6. In practice, it's brutally competitive. My oncologist technically has the trial 'open' at our centre, but he hasn't been given any patient spots at all. So we list it in my notes as an option that, for now, doesn't actually exist for me." — Group member, living with metastatic HR+/HER2-negative breast cancer

SNV4818 — promising, but still Phase 1/2

SNV4818 (NCT06736704) is a smaller early-phase, mutant-selective PI3Kα program. The program has sites in the US, Canada, and Australia. It aims to target PI3Kα mutations while sparing wild-type PI3Kα. It has generated major industry interest, but it remains an early-phase study.

Ask the recruiting site about prior-treatment rules, mutation requirements, country-specific sites, and current capacity. Do not rely on any summary for an enrollment decision. The posted inclusion criteria include: advanced or metastatic solid tumor with an activating PIK3CA mutation; refractory to or intolerant of available therapies.

Where gedatolisib fits right now

Gedatolisib (Revtorpyk) is a newly approved intravenous drug that also targets the PI3K/AKT/mTOR pathway. It is used with fulvestrant, with or without palbociclib, for HR-positive, HER2-negative metastatic breast cancer without a PIK3CA mutation after progression on endocrine therapy.

Trial data report little clinically significant hyperglycemia compared with older agents in this pathway. Stomatitis, rash, neutropenia, and other side effects remain common. They can still limit dose and treatment duration.

"I know everyone is excited that gedatolisib 'hits multiple targets' and seems to avoid the terrifying glucose spikes we've seen on other PI3K drugs. From the pharmacist breakdown I watched and from what my oncologist told me, it's still a pretty rough ride — less hyperglycemia, but more stomatitis and liver issues to watch closely. It's a step, but not a magic fix." — Group member, living with metastatic HR+/HER2-negative breast cancer

Inavolisib: what the big trial showed and what optINAVO offers

What INAVO120 told us

INAVO120 (NCT04191499) tested inavolisib plus palbociclib and fulvestrant. It compared that triplet with placebo plus palbociclib and fulvestrant. The study enrolled people with first-line, endocrine-resistant, PIK3CA-mutated HR-positive, HER2-negative metastatic or locally advanced breast cancer.

Median progression-free survival was about 15.0 months with inavolisib and 7.3 months with placebo. Later analyses reported an overall-survival benefit of roughly 34 versus 27 months.

The toxicities in the triplet include metabolic and mucosal effects: hyperglycemia, stomatitis or mucosal inflammation, diarrhea, other gastrointestinal events, and ocular side effects. Grade 3 hyperglycemia occurred in about 5–6% of participants. Grade 3 stomatitis occurred at a similar rate. A small minority discontinued study treatment because of adverse events.

The bottom line is clear. INAVO120 showed strong progression-free and overall-survival gains in the right population. It also showed significant hyperglycemia and stomatitis despite a mutant-selective design.

What optINAVO is doing differently

optINAVO (NCT07368998) is a Phase 2, randomized, open-label study. It drops palbociclib. It tests inavolisib plus fulvestrant at two different inavolisib doses. It is for PIK3CA-mutated, HR-positive, HER2-negative locally advanced or metastatic breast cancer.

Its primary endpoint is objective response rate. Progression-free survival and safety are key secondary outcomes. It is not designed to give the definitive overall-survival answer that INAVO120 could provide.

It can answer a different question: can inavolisib with fulvestrant alone retain activity at a lower dose with fewer side effects?

The safety context still comes from Phase I/Ib work and INAVO120. Hyperglycemia and stomatitis are frequent. Diarrhea, other gastrointestinal effects, and ocular adverse events also matter. What remains unknown is whether removing palbociclib or adjusting the dose meaningfully reduces hyperglycemia and stomatitis.

What this means if you are offered inavolisib

The average trial participant does not experience an extreme course. But normal baseline glucose does not guarantee safety.

"Reading about someone going from 'normal sugars' to a hyperglycemic crisis in three days on inavolisib changed how I think about 'baseline labs are fine'. It made me insist on a real monitoring plan and a clear stop-threshold before I would even consider a trial place." — Group member

What this means practically

• US or Spain, with prior PI3K/AKT/mTOR intolerance: TOS-358 is the clearest currently identified option. Confirm all other requirements and capacity before assuming enrollment.

• UK or Australia, before pathway treatment: ReDiscover-2 may be a strong option to check before capivasertib, alpelisib, or everolimus. Prior exposure closes standard enrolment, but a letter using the template below is warranted.

• Interested in SNV4818: Treat it as "ask before assuming." It is promising but early phase.

"When you add up all the slots across these next-generation PI3K trials, it's shockingly small compared to how many of us are out here needing them. The good ones are especially competitive. It really is a zero-sum game: if someone else gets a place, it means another person doesn't — and often there's no second-best option in the same class." — Group member, living with metastatic HR+/HER2-negative breast cancer

Part 2: Understanding your PIK3CA mutation while you decide

Where you are right now

Having a PIK3CA mutation identified, but not yet starting a targeted drug or trial, can be a useful window. It gives you time to understand what the mutation does, what is realistically available, and which supportive questions make sense while you and your oncologist decide between standard care and a trial. For background on how resistance and dormancy develop after endocrine therapy, it may help to read alongside this section.

What the PIK3CA mutation does

This mutation does not only make cancer cells grow faster. It can also alter the environment around the tumour.

It can shift macrophages and T cells toward a more tolerant, less cancer-fighting state. One documented route involves 5-lipoxygenase (5-LOX) within the tumour. This produces leukotriene B4 (LTB4), which recruits immune-suppressing myeloid-derived suppressor cells (MDSCs) and reduces T-cell activity.

Another related route involves COX-2 and prostaglandin E2 (PGE2). This pathway can also suppress T cells and alter macrophage activity.

These are separate but related downstream consequences of the same mutation. They do not replace the direct tumour-cell role of PIK3CA. They add an immune-environment dimension to it.

Supportive questions while you decide

None of the following replaces standard treatment or a trial decision. They are supportive topics to raise with your care team while you map out next steps.

Low-dose aspirin

Low-dose aspirin has the most real-world human evidence of the options discussed here. Large observational studies have linked regular aspirin use with lower breast-cancer recurrence. Newer research describes a mechanism in which aspirin blocks a platelet signal that otherwise suppresses T-cell activity.

This sits within the broader arachidonic-acid context of PIK3CA-related immune suppression, though it acts through a different route. The evidence is mixed. One large study in older adults found no cancer-prevention benefit and signalled possible harm in that population. Aspirin also carries a real bleeding risk. This is a specific conversation with your oncologist, not a self-start decision.

Celecoxib

Celecoxib is a prescription anti-inflammatory drug. It blocks the COX-2/PGE2 branch specifically. Laboratory and animal studies show reduced immune-suppressive cells and improved T-cell activity. These studies also suggest it can work alongside immunotherapy. It does not target the 5-LOX/LTB4 branch, so it addresses a related but different part of the pathway.

Celecoxib carries boxed warnings for cardiovascular and gastrointestinal risks. Discuss it individually with your clinician. Do not use it as self-directed cancer treatment.

Boswellia serrata

Boswellia serrata, also known as frankincense extract, contains AKBA. AKBA has the strongest and most specific laboratory evidence among natural compounds for directly inhibiting 5-LOX.

It may also reduce Akt/STAT3 signalling that helps activate 5-LOX. That gives it a two-angle mechanistic rationale. The evidence for this specific PIK3CA-related immune pathway comes from laboratory and animal work. It is not evidence from human cancer trials.

Consider it a mechanistically interesting supportive topic, not a proven cancer treatment. Read the dedicated Boswellia in Oncology Overview for evidence, bioavailable formulation, safety, and interaction context.

A simple way to frame the conversation

You have a PIK3CA mutation that may affect tumour cells directly and the immune environment around them. Standard drugs and emerging trials aim at the tumour-cell side.

Aspirin and celecoxib are established medicines with real, but mixed, evidence related to the immune-environment side. They are reasonable add-on questions, not substitutes for the main treatment path you choose. Boswellia is a lower-evidence supportive option. Some patients discuss it alongside the above. It still needs review for interactions and treatment timing.

References

• Li X, et al. Oncogenic PIK3CA recruits myeloid-derived suppressor cells to shape the immunosuppressive tumour microenvironment in luminal breast cancer through the 5-lipoxygenase-dependent arachidonic acid pathway. Clinical and Translational Medicine. 2023.

• Kuang B, et al. Celecoxib in oncology: targeting the COX-2/PGE2 axis. 2025.

• Li K, et al. Myeloid-derived suppressor cells as immunosuppressive regulators of the tumour microenvironment. Signal Transduction and Targeted Therapy. 2021.

• Chen EP, Smyth EM. COX-2 and PGE2-dependent immunomodulation in breast cancer. 2011.

• Jin K, et al. Cyclooxygenase-2-Prostaglandin E2 pathway: a key regulator of anti-tumour immune escape. Frontiers in Oncology. 2023.

• Yang J, et al. Aspirin prevents metastasis by limiting platelet TXA2 suppression of T cell immunity. Nature. 2025.

• Add-Aspirin Trial, Cancer Research UK / MRC Clinical Trials Unit, University College London.

• ASPREE Trial secondary analysis, JAMA Oncology, Monash University. 2025.

• Trivedi VL, et al. Anti-cancer properties of boswellic acids. 2023.

• Ren F, et al. Interferon-γ and celecoxib inhibit lung-tumor growth through modulating the M2/M1 macrophage ratio. 2014.

Prepare for a trial conversation

Bring a one-page treatment history. Include start and stop dates, doses, best response, progression dates, and toxicities. Include the reason each drug stopped.

Also bring your biomarker reports. PIK3CA, ESR1, AKT1, PTEN, and HER2 results can affect both standard options and trials.

“Before I start another PI3K, AKT, or mTOR inhibitor, can we check which trials I may lose access to? Please include mutant-selective PI3Kα studies and confirm actual site capacity.”
— Suggested wording

A template you can send

If you were intolerant of, rather than non-responsive to, a PI3K/AKT/mTOR pathway inhibitor, you can send this to a trial’s medical-information contact. You can also bring it to your oncologist or nurse. They may be able to send it between visits.

Subject: Inquiry Regarding Expanded Access / Compassionate Use — [Trial Name/NCT Number]

Dear [Trial Medical Information Team / Principal Investigator],

My name is [Name], and I am a patient with [HR+/HER2-negative metastatic breast cancer, PIK3CA-mutant / relevant details]. I was treated with [capivasertib / other pathway inhibitor] from [dates], but was required to discontinue due to [severe hyperglycemia / specific intolerance — be specific, for example, “fasting glucose exceeding 20 mmol/L requiring hospitalization” or “Grade 3 rash”]. I did not discontinue because of disease progression on the drug.

I understand that [Trial Name, NCT number] currently excludes patients with prior exposure to PI3K, AKT, or mTOR inhibitors. I am writing to ask:

1. Is there any expanded access, compassionate use, or parallel single-arm cohort available for patients who were intolerant of, rather than non-responsive to, a prior agent in this class?

2. If not currently, is this a population your clinical team is considering for future trial design or amendment?

3. Are there other trials in your portfolio, or ones you are aware of, that specifically welcome patients with prior AKT/PI3K inhibitor intolerance?

I am asking not only for myself but on behalf of a wider community of patients who share this exact situation. We would be very grateful for any guidance you can offer. My treating oncologist, [Oncologist name, contact], can provide further clinical detail if helpful.

Thank you for your time and for the work your team is doing in this space.

With hope and respect,
[Your name]
[City, Country]
[Contact details]

Before you write

• Confirm current recruiting status. Site information changes. Check the listed trial record before assuming a location still enrolls.

• Confirm your nearest open site. A study can recruit overall while individual sites have closed.

• Document your specific intolerance. Include glucose readings, hospital records, or formal Grade 3/4 toxicity notes. These are stronger than a general description of being unable to tolerate treatment.

• Confirm your PIK3CA mutation status. All three trials discussed here require it as a baseline entry criterion.

• Confirm the exact prior-treatment exclusion wording. Ask the trial team directly before assuming eligibility. Protocols can change. This guide can also become outdated.

• Review the full eligibility criteria. Organ function, prior treatment lines, and other requirements apply separately to each trial.

“I’ve written to multiple trial teams over the years, with letters from oncologists attached, clear documentation of severe toxicity, and still been told “no”. It’s demoralising, but I keep going because every “no” is also data — it shows exactly where the system is failing patients who were intolerant, not non-responsive. If enough of us keep asking the same question, someone eventually has to redesign the trial to answer it.”
— Group member, living with metastatic HR+/HER2-negative breast cancer

Why this matters beyond one email

One email might not change a trial’s eligibility criteria. A pattern of emails can matter. Patients, advocacy groups, and oncologists can raise the same issue in tumor boards and conferences. This is how eligibility criteria can eventually shift. Trials can be amended. Expanded-access programs can be created when enough voices ask the same question.

TOS-358 already has eligibility that can include this population. That shows the field can design around prior pathway-drug intolerance. The problem is not solved everywhere, but it is solvable.

If this is your story, do not sit with it quietly. Send the email. Ask your oncologist to ask. Share any answer, good or bad, with the group so the community can build a shared map of what is actually possible.

“It’s hard not to feel like all this writing and asking goes into a void. I honestly don’t expect a single email from me to change anything — but I keep doing it because if nobody pushes back, the same exclusion rules just roll on to the next generation of trials untouched.”
— Group member, living with metastatic HR+/HER2-negative breast cancer

Trial sponsors respond to demand signals. Those signals can come from oncologists, patient-advocacy groups, and patients asking the question out loud.

Keep the trial record current

Use the official registry as the starting point. It lists the protocol, eligibility, locations, and contacts. The listed study team gives the final enrollment decision.

• ClinicalTrials.gov: TOS-358

• ClinicalTrials.gov: ReDiscover-2

• ClinicalTrials.gov: SNV4818

• ClinicalTrials.gov: INAVO120

• ClinicalTrials.gov: optINAVO

This information is for education only. It is not medical advice, diagnosis, or treatment. Please speak with a qualified clinician before making changes to care, medication, or supplement use.

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