July 2025: New Trials & Breakthroughs
18 New Breast Cancer Trials + Breakthroughs for Patients with PI3K Mutations
🚀 Welcome to the very first Breast Cancer Briefing.
Each month, we’ll do the heavy lifting for you—scouring new studies to find breakthroughs, while translating the jargon, spelling out who each trial is for, why it might help, and explaining what to do next.
If a friend, family member, or support-group mate could benefit, please hit Forward or share the link. Good intel opens doors, and together we can get life-saving information into more hands.
Thank you for allowing us to be part of your care journey—see you next month for another update.
🌟 TIP: SEARCH FOR ABBREVIATED TERMS TO MATCH YOUR SITUATION:
🔍 HR+, HER2+, ER+, TNBC, exon 20, lobular, etc.IN THIS BRIEFING:
18 NEWLY RECRUITING TRIALS
SPOTLIGHT: 3 BREAKTHROUGHS IN TARGETING PI3K
A Trial for Newly Diagnosed / Before Surgery
New HER2 Antibody vs Perjeta Before Surgery
✅ Newly diagnosed HER2+, HR- early breast cancer needing chemo before surgeryPerjeta with Herceptin (trastuzumab) plus chemo is today’s go-to plan to shrink HER2+ breast cancers that are also hormone (estrogen and progesterone) receptor negative (HR-) ahead of surgery. This study swaps in EG1206A—a bio-similar version of Perjeta—to see if it matches Perjeta’s record for wiping out all visible cancer at surgery (“pathologic complete response”) and keeping it from coming back, all while pairing with the same chemo and Herceptin. Because EG1206A is designed to work like Perjeta, success could mean another effective option that may be easier on costs and supply.
Expect IV infusions every three weeks for 18 weeks before surgery, then another 36 weeks after surgery to finish a full year of HER2-targeted therapy—similar timing and side-effects to current care, but with a newcomer antibody.
🏥 Available in Dallas, Texas | NCT06884254
A Trial for After Surgery to Reduce the Risk of Recurrence
Blood-Test Warning Light: Elacestrant Aims to Block Late ER+ Comeback
✅ ER+ HER2- early-stage patients who finished surgery and the usual 5-15 years of hormone therapy at least 6 months ago, but have ctDNA (tumor DNA) still showing up in bloodTiny traces of tumor DNA in the bloodstream can hint that estrogen receptor-positive (ER+) breast cancer may return years later. This study gives elacestrant—a daily hormone-blocking pill already used when cancer has spread—to see if starting it right after surgery can clear those traces and head off a late relapse. In earlier trials for advanced disease, elacestrant held cancer in check a bit longer than older hormone treatments, with mostly mild side effects like nausea and fatigue.
Expect one pill a day for about a year, plus regular blood tests to watch the tumor DNA signal. It’s a chance to act instead of waiting for a possible relapse.
🏥 Available in New Haven, Connecticut | NCT06923527
16 Trials for Recurrent or Metastatic Breast Cancer
Trodelvy on a Gentler Clock: Trying a Calmer Dose for TNBC
✅ Metastatic or unresectable TNBC, PD-L1-negative, 1st-line treatment
✅ Metastatic or unresectable TNBC after 1+ prior therapiesTrodelvy (sacituzumab govitecan) already keeps this hard-to-treat cancer from growing for about five to six months—roughly triple what older chemo manages—but half of patients struggle with low white-cell counts or diarrhea, which limits dosing. This study tests a slower, every-other-week schedule to see whether it maintains (or even exceeds) those benefits while dialing down side effects. If you are a TNBC patient willing to accept a bit more risk for less side effects, then you might want to consider this trial.
Expect an IV infusion every other week until the drug stops working or side effects become too bothersome—plus extra check-ups to track blood counts and stomach issues. It’s a way to access a proven drug with the hope of fewer rough days between treatments.
🏥 Available in Los Angeles, California | NCT06926920
Rebooting After Initial Immunotherapy: Axatilimab + Keytruda with a Short Burst of Radiation for TNBC
✅ Metastatic or recurrent TNBC that kept growing after prior immunotherapyThis study tries a three-way plan to wake the immune system back up: a brief course of focused radiation to expose tumor signals, Keytruda (pembrolizumab) to lift the immune “brakes,” and axatilimab to block CSF1R—thought to quiet down tumor-friendly cells that smother immune attacks. After immunotherapy stops working, choices are usually more chemotherapy or drugs like Trodelvy; this combo aims to give immune therapy a second chance and, in early lab work, has shown promise at shrinking tumors when used together.
DIFFICULT TREATMENT SCHEDULE
Expect one week of treatment layers: Keytruda IV starting on day 1 every three weeks for up to 2 years, radiation on days 8-10, then axatilimab IV every two weeks until the cancer grows or side effects become too bothersome, with scans and blood tests to track response and side-effects. The 2 and 3 week schedule will make this trial a demanding one for schedules.
It’s a chance to see if a targeted immune reset can slow the cancer without jumping straight to more chemo.
🏥 Available in Los Angeles, California | NCT07015853
A New DNA-Repair Blocker Tackled With or Without PARP Pills
✅ Metastatic, HER2-, BRCA1/2-mutated breast cancer that has come back after earlier treatmentXL309 is a first-in-human pill designed to jam a DNA-repair switch called USP1. Cancers with BRCA mutations already struggle to fix DNA, which is why PARP drugs like olaparib can help—until the cancer figures out a workaround. By adding a USP1 blocker alone or together with olaparib, doctors hope to hit the tumor’s backup repair system and keep it from growing again. Lab studies on XL309 suggest the combo could make tumor cells break down, but this is the first test for XL309 in people, mainly to find a safe dose and see if tumors stop or shrink. While some USP1 inhibitors have faced setbacks, like TNG348 with anemia, fatigue, and liver toxicity, other inhibitors in this class, such as SIM0501, XL309, RO7623066, and HSK39775, are still in early clinical development. Standard choices at this stage are more chemo or PARP pills alone, which often lose punch over time.
Expect to take daily capsules and visit the clinic often at first for blood tests and scans. Doses of XL309 start low and rise only if side-effects stay mild. Some participants will be given Olaparib as well.
This trial gives patients a chance at a fresh DNA-targeted option.
🏥 Available at 16 locations throughout the United States, including multiple sites in Florida, Tennessee, and Texas | NCT05932862
New Dual HER2/EGFR Pill Takes Aim at Tough Mutations
✅ Metastatic or unresectable breast cancer with HER2+ (mutation, amplification, or over-expression)
✅ Metastatic breast cancer carrying rare EGFR exon 20 insertion mutationsYH42946 is an oral drug built to block both HER2 and the hard-to-treat but targetable EGFR exon 20 alteration—changes that let tumors dodge today’s HER2 pills and classic EGFR drugs. In lab tests the pill slowed growth of cells driven by these mutations, which usually resist standard chemo and older targeted therapies. This first-in-human study starts at very low doses, then steps up to find a safe daily amount while checking how many tumors stop growing or shrink.
You’ll take a tablet every day and have more frequent blood tests and scans at first; doses rise only if side-effects stay mild—offering a chance at a precisely aimed treatment when other options are running short.
🏥 Available at many Korean locations and in Fairfax, Virginia | NCT06616766
New EGFR Antibody Being Tried After Chemo Stops Working
✅ Metastatic EGFR-positive breast cancer after other treatmentsZZ06 is an antibody that locks onto EGFR—a growth signal many breast tumors overuse—then flags the cancer for destruction. While EGFR-blocking drugs such as cetuximab help colorectal and head-and-neck cancers, none are approved for breast cancer yet, and chemo, hormonal, and/or checkpoint drugs remain the usual fallback. This first-in-human study starts at low IV doses twice a week to find a safe level and watch whether tumors stay stable or shrink.
DIFFICULT TREATMENT SCHEDULE
Expect 30-minute infusions twice weekly for a month-long cycle, with extra blood tests and scans; doses rise only if side-effects like rash or fatigue stay mild—giving you a shot at a fresh, targeted option when standard care has run out.
🏥 Available in Los Angeles, New York, Fairway (Kansas), and China | NCT04412616
New Pill Tries to Help Palbociclib Work Again
✅ Metastatic or recurrent HR+ breast cancer that kept growing after CDK4/6 drugsThis early-phase study is the first to test a brand-new medicine (BMS-986500) both alone and teamed with palbociclib plus fulvestrant. The goal is to see whether adding the pill can slow or shrink tumors even after CDK4/6 drugs have stopped working. Palbociclib with fulvestrant is a standard fallback, giving many women a few extra months before the cancer grows again, but its effect fades in most cases. By blocking a different, still-undisclosed target, BMS-986500 could restore control or extend the benefit. The first part of the trial simply finds a safe dose while watching for early signs that tumors pause or shrink.
Expect daily pills—and for some participants with monthly fulvestrant shots and palbociclib tablets—and more frequent blood tests and scans at the start. Doses rise only if side-effects stay mild, giving you a chance at a new option when choices are running short.
🏥 Available at 13 locations throughout the United States | NCT06997029
Personalized “NeoVax” Shot Tries to Teach the Immune System Each Tumor’s Fingerprints
✅ Metastatic HR+ HER2- breast cancer that has stopped responding after at least two rounds of treatmentNeoVax is a custom-made vaccine: doctors sequence your tumor, pick a handful of unique mutations (“neo-antigens”), and mix them into a shot meant to train your T-cells to hunt those exact targets. In early melanoma studies, similar vaccines sparked strong immune reactions and helped some tumors shrink. Here, the vaccine is paired with nivolumab (a checkpoint blocker) and a booster called poly ICLC to keep immune cells active. Standard options at this stage are more chemo or hormone pills with fading impact; this trial explores whether a tailor-made immune attack can hold the cancer back longer.
EASIER TREATMENT SCHEDULE
Plan on one booster shot every four weeks (plus nivolumab infusions) for six months, with blood draws and scans to track your immune response. It’s a chance to try a vaccine built from your own tumor when other treatments have run out of steam.
🏥 Available in Seattle, Washington | NCT05098210
Smart Chemo Aims at 5T4: Early Test for Metastatic Breast Cancer
✅ Metastatic or unresectable HR+ breast cancer after other treatments
✅ Metastatic or unresectable TNBC after other treatmentsThis first-in-human study is trying XB010, an “antibody-drug conjugate.” The antibody hunts for 5T4—a protein seen in most (85-90%) of breast cancers —while its attached chemo payload (a tubulin blocker) is released only after docking, aiming to kill cancer with less spillover to healthy cells. Doctors will start at low doses, alone or paired with the immune drug pembrolizumab, to see what’s safe and whether any tumors shrink or stay stable. A similar drug, Naptumomab, has already been in clinical trials for several years, and is showing decent tolerability. Standard care at this point is more chemo or single-agent immunotherapy, which often lose punch; XB010 offers a fresh, targeted option that could hit tumors from two angles.
Expect an IV infusion every three weeks and close monitoring of blood counts, nerve tingling, and fatigue. Dosing continues only as long as side-effects stay mild, giving patients a chance to stay on treatment longer if it helps
🏥 Available at 8 locations in North Carolina, Missouri, Oklahoma, California, Texas, and Virginia | NCT06545331
Proton Beam Trial Aims to Protect the Brain and Spinal Fluid When Breast Cancer Spreads
✅ Breast cancer that has spread to the fluid around the brain and spinal cord (leptomeningeal metastasis) and no prior radiation to the spinal cordWhen cancer cells reach this delicate fluid space, doctors usually give involved-field x-ray radiation that targets only the problem spots to ease symptoms. This study instead tests proton craniospinal irradiation (pCSI), which bathes the entire brain-and-spine fluid space with pinpoint proton beams that stop once they hit their target, sparing nearby tissue. Researchers will compare the two approaches to see which better delays nerve problems and keeps cancer in check. Earlier, smaller studies hinted that proton treatment held the disease steady about three times longer than standard x-rays.
EASIER TREATMENT SCHEDULE
You’d receive one 30-minute radiation session each weekday for two weeks, along with MRIs and spinal-fluid checks. It’s a chance to try a full-coverage proton plan that could give more months of clear thinking and mobility.
🏥 Available in New York, Missouri, California, and Arkansas | NCT06500481
Early Test of a Dual Immune Antibody for Advanced Breast Cancer
✅ Metastatic or recurrent breast cancer after standard treatments (any HR/HER2 status: HR+, HR-, HER2+, HER2-)This first-in-human study is trying out an experimental antibody called XB628 that aims to wake up two parts of the immune system at once: it blocks PD-L1 (a shield tumors use to hide) and NKG2A (a brake on natural killer cells). Researchers will start with low doses and step them up to see how safe the drug is and whether any tumors shrink or stop growing. Standard options at this point are mostly more chemotherapy or single-target immunotherapy, which often lose steam; XB628 hopes a two-pronged approach can bring fresh immune firepower.
Expect IV infusions every few weeks and close monitoring of your immune cells and side-effects. It’s an opportunity to try a first-in-class immune booster when other treatments have run out of steam.
🏥 Available in Hickory, NC, and San Antonio, TX | NCT06952010
Two-Target Immune Antibody Aims to Re-Engage Attack After Chemo Stops
✅ Metastatic or unresectable breast cancer after at least three prior treatments (any HR/HER2 status: HR+, HR-, HER2+, HER2-)This early-phase study is testing DR-0202, an antibody built to latch onto two different signals—one on tumor cells and one on nearby immune cells—to draw fresh immune firepower against stubborn tumors. When standard chemo, hormone pills, targeted drugs, or checkpoint blockers no longer hold the cancer back, options grow thin; this drug hopes to slow growth or shrink tumors by jump-starting a new type of immune response. Doctors will start at low doses and continue dosing only if side-effects remain mild, watching for signs that tumors stop growing or ease up.
DIFFICULT TREATMENT SCHEDULE
Expect an IV infusion every two weeks, plus blood tests and scans. If tolerated, treatment continues as long as it helps—offering a shot at a novel immune approach after other choices are exhausted.
🏥 Available at 10 locations across the United States | NCT06999187
Tissue-Factor “Smart Bomb” Tries to Hit Breast Tumors After Chemo Fails
✅ Metastatic or unresectable breast cancer that has kept growing after at least two prior treatments (any HR/HER2 status: HR+, HR-, HER2+, HER2-)ADCE-T02 is an antibody-drug conjugate that seeks out tissue factor—a protein many aggressive breast tumors display—and delivers a potent chemo payload right inside the cancer cell. When options run thin, standard care is usually another round of broad-shot chemotherapy that may offer only brief control. By homing in on tissue factor, ADCE-T02 aims to curb tumor growth with fewer off-target effects, but this first-in-human study’s main goal is simply to find a safe dose and watch for early signs of tumor shrinkage or stability.
Expect an IV infusion every three weeks at a starting low dose, with frequent lab tests and scans; doses climb only if side-effects stay manageable—offering a chance at a targeted option when routine chemo has run out of steam.
🏥 Available in Houston, Texas, and several sites in Australia (Randwick, Bedford Park, Frankston, Malvern) | NCT06597721
New Daily Pill Being Tested After Breast Cancer Spreads
✅ Metastatic, progressive breast cancer after at least one prior treatment (any HR/HER2 status: HR+, HR-, HER2+, HER2-)This first-in-human study is checking the safety of a brand-new pill called SLV-154 in people whose cancer has kept growing despite other treatments. Scientists don’t yet know its exact target, but early lab work hints it may slow tumor growth in several cancers. When breast cancer reaches this point, choices often boil down to more chemotherapy with limited payoff; SLV-154 offers a fresh option and a chance to see whether a different approach can hold the cancer back.
Expect to start on a low dose once a day, with regular clinic visits so doctors can watch for side effects and adjust the amount. If the drug is well-tolerated, you may stay on it as long as it helps.
🏥 Available in Missouri, California, and Texas | NCT06771219
First-In-Human Virus Therapy Tries to Kick-Start the Immune System in Metastatic Breast Cancer
✅ Metastatic or unresectable breast cancer that keeps growing after standard treatments (any HR/HER2 status: HR+, HR-, HER2+, HER2-)IDOV-Immune is a lab-engineered vaccinia virus designed to slip into cancer cells, burst them from the inside, and rally the immune system for a follow-on attack. Oncolytic viruses have helped some melanoma patients, and researchers now want to see if this one can slow or shrink breast tumors when other options run out. The first goal is safety—doctors will start at very low doses and watch closely for fever, chills, or other side effects—while also looking for early hints that tumors stop growing. Standard choices at this stage are typically more chemo or single-drug immunotherapy, which often lose steam; a virus could offer a fresh route.
You would receive a single IV infusion at the start of a 28-day cycle, then frequent check-ups; doses only rise if side-effects stay mild, giving you a chance to stay on treatment longer if it helps.
🏥 Available in Texas and Missouri, as well as in Melbourne & Westmead (Australia) | NCT06910657
New PET Tracer Could Light Up Lobular Breast Cancer Spread
✅ Advanced or metastatic invasive lobular breast cancer (ILC), nearly all (93%) of which is HR+ and HER2-Standard FDG PET scans often miss lobular tumors because these cancers take up less sugar, making them look faint or invisible on the images. This study tests [68Ga]Ga DOTA-5G, a tracer that latches onto somatostatin receptors—a protein present on about half of lobular breast cancers—to see if it shows hidden disease more clearly. Researchers will give one low-dose injection and compare how well the new scan spots tumors that other imaging might overlook.
EASIER TREATMENT SCHEDULE
You’ll get an IV injection with a small amount of radioactivity (safely tolerated), wait about an hour, then lie still for a PET/CT scan—no extra treatments, just pictures that could give you and your doctors a sharper map of where the cancer is.
🏥 Available in Sacramento, California | NCT07020806
Is One Year Enough? Testing a Planned Break from Immunotherapy in Metastatic Breast Cancer
✅ Metastatic breast cancer on PD-1/PD-L1 immunotherapy with the cancer still stable after 12 monthsMany patients stay on immunotherapy until the cancer grows again—often up to two years or longer. But some studies hint that taking a break after a solid response may keep the cancer quiet while sparing side-effects and cost. This study randomly compares two paths: stopping a standard PD-L1 drugat the one-year mark versus sticking with it. Researchers will track how long the cancer stays controlled and how people feel either way.
If you’ve been on immunotherapy for under a year with no tumor growth, this trial offers a chance to see whether you can press pause—meaning fewer infusions and clinic days—without giving up control.
🏥 Available in Pittsburgh, Pennsylvania | NCT04157985
👉 HOW TO ACCESS A TRIAL
If you’re interested in pursuing a clinical trial, the quickest way to move forward is to book a second-opinion visit with one of the doctors leading the trial. Because they are running the trial and treat people like you every day, they can tell you whether you qualify and what to expect. You’ll need to bring recent scan reports, your pathology report, and a clinic not, including a list of past treatments—these let the research nurse pre-screen you before you arrive.Do you need help finding the right trial or getting connected?
Sagely Health offers a premium, physician-led consultation service that pairs a deep dive into your records with direct introductions to world-class specialists and trial investigators. Our team translates the latest science into clear options, compares every promising treatment (standard or experimental), and makes warm hand-offs so you’re not left cold-calling clinics.
THIS MONTH’S BREAKTHROUGH SPOTLIGHT
TARGETING PI3K:
🔬What’s New for People with Breast Cancer
If you're living with hormone receptor–positive, HER2-negative or HER2-positive metastatic breast cancer, especially after your initial treatments have stopped working, there's a chance your tumor carries a PIK3CA mutation — a change in the tumor’s growth machinery that can help cancer resist hormone therapy. About four out of every ten patients with HR+/HER2– breast cancer have this mutation, and it’s also found in about three out of every ten HER2-positive cancers.
For years, researchers have tried to develop drugs that block this mutation’s effect. And while early attempts showed promise, they often came with tough side effects like high blood sugar and skin issues, making it hard for many patients to stay on treatment.
But that may be starting to change. New research on inavolisib, RLY-2608, and a combination of tucatinib and alpelisib is offering new hope for patients with PIK3CA-mutated breast cancer, combining effectiveness with better tolerability and more personalized treatment options.
A MAJOR STEP FORWARD
Inavolisib May Improve Survival in HR+ Breast Cancer
One of the most important new developments in PI3K treatment comes from a large clinical trial testing a drug called inavolisib in people with hormone-positive, HER2-negative metastatic breast cancer who had already tried hormone therapy. In this study, patients received inavolisib along with two other standard medicines, fulvestrant and palbociclib.
The results showed that patients on the inavolisib combination lived about 7 months longer on average than those on the standard treatment alone, and they were also more likely to see their tumors significantly shrink (63% of them did). Importantly, fewer patients had to stop treatment due to side effects compared to older PI3K drugs like alpelisib. One reason may be because inavolisib is both an inhibitor of PI3K but also a degrader of the protein, meaning it triggers PI3K to be recycled. While some people did experience high blood sugar or mouth sores, most of these were manageable and occurred less frequently than with earlier medications.
If your tumor has a PIK3CA mutation, this treatment is worth watching, especially as it moves toward wider approval. If you’re interested in pursuing it now, there is a trial available offering Inavolisib with and without the drug Atezolizumab. It is available in California and Tennessee, as well as locations in Canada and Korea.
NEWER OPTIONS MAY BE GENTLER
RLY-2608 Targets Only the PI3K Mutation
Another drug researchers are excited about is RLY-2608, which is designed to be even more precise — it only attacks the specific mutated form of PI3K, while leaving the rest of the body’s normal PI3K processes alone. In a recent study, patients with advanced HR+/HER2– breast cancer who had already received hormone therapy and CDK4/6 inhibitors tried RLY-2608 in combination with fulvestrant.
About a third of the patients saw meaningful shrinkage of their tumors, and many more had some degree of improvement. Just as importantly, serious side effects were rare — only 2% had high blood sugar levels that were considered severe, and fewer than 1% had severe rashes. For people who might not tolerate drugs like alpelisib, this new medication could offer a more comfortable option in the future.
If you’ve already tried hormone therapy and CDK4/6 inhibitors, and your tumor has a PIK3CA mutation on a genetic analysis (like Next-Gen Sequencing), this trial could open the door to a better-tolerated alternative. Available at multiple centers in Virginia, Texas, New York, Tennessee and other states, with a total of 36 locations.
AN INNOVATIVE COMBO
Tucatinib + Alpelisib in HER2+ Breast Cancer
While PI3K-targeted treatments are often discussed in HR+ disease, they may also help people with HER2-positive breast cancer, especially those whose cancer keeps growing after standard treatments like Enhertu (T-DXd) or tucatinib. In a recent trial, researchers tested a new combination of tucatinib (a HER2-targeted pill) and alpelisib in patients with HER2+ tumors that had PIK3CA mutations. These were people who had already tried multiple lines of treatment
Among those who received a lower, more tolerable dose of the combination, 60% had their tumors shrink, and most patients were able to stay on treatment for several months. By adjusting the dose, doctors were able to limit side effects like diarrhea and rash, which were common in earlier studies of alpelisib.
If you have HER2-positive, PIK3CA-mutant breast cancer and have already tried therapies like T-DXd or tucatinib, this chemo-free trial may be an option to ask about in clinical trial discussions. Available in Colorado, Louisiana, and Wisconsin.
🎯 At Sagely Health, we're tracking 46 different PI3K Treatments as they are tested in clinical trials (with some already approved). We'll share more in future editions (subscribe below). Reach out if you'd like more information.✍🏻 Do you have feedback? We’re listening at info@sagelyhealth.com or leave a comment!