Gedatolisib

Gedatolisib is the first total PAM inhibitor approved by the Food and Drug Administration for breast cancer treatment. It works by blocking enzymes through the PAM signaling pathway. Cancers can use this pathway to encourage cells to multiply. By doing so, cancers can become resistant to treatment with hormonal therapy and CDK4/6 inhibitors.

Some other approved medicines target only individual parts of this signal pathway. But gedatolisib blocks multiple targets, completely cutting off this pathway. Completely cutting off the PAM pathway may allow the cancer to respond to treatment again.

Gedatolisib treatment is given with the hormonal therapy fulvestrant (Faslodex) with or without palbociclib (Ibrance). 

How gedatolisib works

People with hormone receptor-positive, HER2-negative metastatic breast cancer typically receive hormonal therapy and CDK4/6 inhibitors as the first line of treatment. Hormone receptor-positive cancer uses hormones — estrogen or progesterone — to signal to its cells to multiply. Hormonal therapy can limit estrogen in the body, block cancer cells from using estrogen, or block cancer cells from using estrogen to grow. Doing so may halt cancer growth. But cancers eventually stop responding to these treatments.  

Signaling pathways play a significant role in treatment resistance. They can give hormone-driven cancers another way to promote cell growth when treatment blocks access to estrogen. PAM is a major signaling pathway that provides cancer one of those other routes to signal growth. The PAM name is an abbreviation of the three enzymes that are part of this pathway: PI3K, AKT, and mTOR.  

Other approved therapies target only individual enzymes in this pathway. These include:  

• PI3K inhibitors 
• Alpelisib (Piqray) 
• Inavolisib (Itovebi) 
• AKT inhibitors 
• Capivasertib (Truqap) 
• mTOR inhibitors 
• Everolimus (Afinitor) 

Gedatolisib is the first inhibitor approved to treat breast cancer that comprehensively blocks all three parts of the PAM pathway. It targets the PI3K and mTOR enzymes at either end of the pathway making it unusable for cancer signaling. Researchers believe blocking multiple PAM enzymes at the same time can prevent cancer from becoming resistant to treatment and make it again sensitive to hormonal therapy. For this reason, the selective estrogen receptor degrader (SERD) fulvestrant is given along with gedatolisib. 

Some of the other targeted therapies in the PAM pathway are approved only for use in people with cancer that has a mutation on the PIK3CA gene. Such mutations cause this pathway to become overactive and promote cancer growth.

Researchers examined gedatolisib use in two different studies. One study looked only at people with PIK3CA-mutated cancer. The other included only people whose cancers had no PIK3CA mutation. In both studies, people receiving gedatolisib treatment went longer without cancer progressing than people treated with fulvestrant alone.

Who gets gedatolisib

Gedatolisib is approved to treat people with locally advanced or metastatic breast cancer. Your doctor may recommend gedatolisib if you have cancer that meets these requirements: 

• The cancer is hormone receptor-positive and HER2-negative 
• The cancer has no PIK3CA mutation. 
• The cancer is metastatic or locally advanced and cannot be removed by surgery. 
• You have been given hormonal therapy with a CDK4/6 inhibitor since being diagnosed with advanced or metastatic breast cancer. 

How gedatolisib is given

Gedatolisib is given through IV infusion on days 1, 8 and 15 over a 28-day cycle. Your treatment center will give a 30-minute infusion of 180 milligrams of gedatolisib through an IV After the infusion on day 15, you have 14 days off before starting a new cycle. 

Gedatolisib can cause mouth and throat sores. Doctors give a steroid-based mouth rinse when prescribing gedatolisib to prevent and manage this side effect. You will swish the rinse around your mouth for 2 minutes, then spit it out. Do not swallow the solution. You can use the rinse up to four times daily, or as your doctor recommends. 

Fulvestrant is part of the gedatolisib treatment regimen. Fulvestrant is an injection to the buttocks. The typical dose comes as two injections given once every 4 weeks. You will receive an extra dose the first month of treatment, after week 2.  

Some people may also receive palbociclib (Ibrance) as part of this treatment regimen. Palbociclib is a cyclin-dependent kinase4/6 (CDK 4/6) inhibitor given as a pill. Take palbociclib once a day for 3 weeks as prescribed by your doctor. Then you will have one week off before starting a new cycle.

You will continue these treatments as long as the cancer continues to respond to the treatment. You and your doctor may also decide to adjust the treatment or change to a different treatment if side effects become too difficult to manage.  

Side effects and things to remember

In research studies, people commonly reported these side effects when taking a treatment regimen that includes gedatolisib: 

• Mouth sores 
• Low white blood cell counts 
• Nausea and vomiting 
• Rash 
• Fatigue  
• Diarrhea 
• Increased blood sugar levels 
• Low platelet count, which may result in bruising or bleeding 
• Inflammation of the lungs 

People taking gedatolisib in clinical trials developed mouth and throat sores, called stomatitis, that can be painful and affect daily living activities. Doctors offer a steroid-based mouth rinse when starting gedatolisib to prevent and manage sores. (Learn more in the How gedatolisib is given section above.) In studies, people found that when using the steroid-based mouth rinse, sores become fewer, smaller, and less painful after the first two weeks of treatment. Let your healthcare team know if you experience mouth or throat sores that persist or get worse after this period.  

Everyone will not have the same side effects from treatment. You may encounter some or few of the side effects discussed on this page. Speak with your doctor about what you can do if you encounter any effects, whether they appear on this page or not.