Beatriz Sawaya came to MSK from Brazil to receive a new treatment for resistant breast cancer as part of a clinical trial. The therapy, now FDA approved, has kept her cancer under control for five years. “It was a scary time, but MSK made it possible for me to move back home and stay on the drugs that have saved my life,” she says.
Most breast cancers are estrogen receptor (ER) positive, meaning they depend on estrogen to survive and grow. Doctors treat these cancers with drugs that cut off their fuel supply, an approach called endocrine therapy. Unfortunately, ER-positive breast cancers often become resistant to this treatment.
The outlook has been especially poor when the resistant ER-positive tumor is negative for a protein called HER2 — another important drug target — and also carries a PIK3CA gene mutation.
Approval for Inavolisib Triplet Therapy Breast Cancer Based on Clinical Trial Results
But now the U.S. Food and Drug Administration (FDA) has approved a new three-drug combination treatment that appears to be very effective for these breast cancer patients. In a phase 3 clinical trial, the “triplet” therapy more than doubled progression-free survival time — the period in which the disease didn’t worsen — compared with standard therapy.
The treatment combines a new drug, inavolisib, with two older breast cancer drugs, fulvestrant (Faslodex®) and palbociclib (Ibrance®). Inavolisib, which targets PIK3CA mutations, appears to be a vital addition to making the triplet therapy more effective.
Improving Outcomes for ER+ HER2- Breast Cancer Patients
MSK medical oncologist Dr. Komal Jhaveri
“This patient group has traditionally done poorly, and adding the third drug, inavolisib, really made a big difference,” says medical oncologist and breast cancer specialist Komal Jhaveri, MD, who helped lead the trial. “In addition to the increased effectiveness of the triplet therapy, not many patients discontinued therapy due to increased side effects.”
Clinical Trial Details
The phase 3 trial involved 325 patients with ER-positive, HER2-negative breast cancers that carried PIK3CA mutations. In all cases, the cancer had returned during or within 12 months of completing endocrine therapy. There were additional disease features that gave patients a poor prognosis.
The trial participants were divided into two groups: One group received only fulvestrant and palbociclib; the other received the triplet therapy that included inavolisib.
In follow-ups at a median time frame of 21 months:
- People who received the triplet combination survived for a median time of 15 months without the disease getting worse, compared with a median of 7.3 months in the group receiving only two drugs.
- There was no significant difference in side effects in the two groups. In the triplet protocol, toxicity profiles were similar to what is expected of the individual drugs. Only 6.8% of patients in the inavolisib arm decided to discontinue the study.
Targeting the PIK3CA Mutation To Treat Metastatic Breast Cancer
Up to 40% of ER-positive, HER2-negative breast cancers have a PIK3CA mutation.
“PI3K inhibitors have shown promise for treating breast cancer — and some are already FDA approved — but these drugs have faced the challenge of serious side effects,” Dr. Jhaveri says. “Currently they are offered to patients after their tumors progress on more conventional drug combinations, such as endocrine therapy and palbociclib. However, for patients with a PIK3C mutation who have recurrence while on endocrine therapy, or within 12 months of completing it, the triplet therapy adding inavolisib to fulvestrant and palbociclib is proving to be beneficial.”
She added that clinicians still must closely monitor potential side effects — such as high blood sugar, diarrhea, rash, and mouth sores — and step in quickly if support is needed.
MSK Leads Clinical Trials From the Beginning
Dr. Jhaveri has been closely involved in the clinical testing of inavolisib from the earliest stages of research. MSK played a leading role in the phase 1 trial, caring for most participants. The MSK team learned to manage side effects so that testing could keep moving forward.
Results from the phase 1 trial were recently published in the Journal of Clinical Oncology confirming the triplet therapy is safe and supporting the ongoing phase 3 trial.
“We have patients who started this therapy in the phase 1 trial who are still doing well five years later,” Dr. Jhaveri says.
Patient Travels From Another Country To Join Inavolisib Clinical Trial
One of the patients who has benefited from the triplet therapy is Beatriz Sawaya, who came to MSK from Brazil to participate in the study. In 2016, Beatriz, a renowned author living outside Sao Paolo, had an ER-positive, HER2-negative breast tumor surgically removed. All seemed well until early 2019, when the cancer reappeared in her liver, lymph nodes, and spine.
Her doctor in Sao Paolo, Artur Katz, MD, had trained at MSK, and Beatriz was confident in his ability. But the outlook for controlling the metastasized cancer was not good.
“I was in his office with my three children, and my son Matias was asking Dr. Katz for a clear picture of my prognosis,” Beatriz says. “I decided I did not want to know and left the office. I later learned he told them I probably had about a year to live.”
Matias urged Beatriz to get a second opinion about the best treatment plan. Dr. Katz endorsed the idea and recommended she connect with MSK medical oncologist Andrew D. Seidman, MD. At that time, Dr. Seidman was the medical director of the Bobst International Center, which helps international patients arrange appointments and second opinions, either in person or through telemedicine.
MSK medical oncologist Dr. Andrew Seidman
Beatriz flew to New York. Dr. Seidman agreed with Dr. Katz’s plan, and Beatriz flew back to Brazil and began chemotherapy, knowing her prospects remained dim.
But two months later, Dr. Seidman called Dr. Katz and proposed Beatriz join the phase 1 clinical trial that had just launched to test the triplet therapy. Beatriz says the opportunity gave her hope at just the right time.
“It was a difficult period — my father had just died, and then I got cancer, and I was feeling very sad,” she says. “Then Dr. Seidman appeared like a light with the new treatment.”
Beatriz moved to New York for a short time, accompanied by her daughter, Julia, and began the triplet therapy. Soon after starting treatment, the cancer went into remission and the lesions in her liver shrank. Then the COVID-19 pandemic started, so Drs. Seidman and Jhaveri worked with the trial’s sponsor, Genentech, to arrange for Beatriz to receive her treatment in Brazil.
“It was a scary time, but MSK made it possible for me to move back home and stay on the drugs that have saved my life,” she says.
Breast Cancer Combination Therapy Continues To Be Effective
Five years later, Beatriz is still on the triplet therapy as part of the phase 1 trial. She has tolerated the drugs well, and her cancer has remained stable, which Dr. Seidman calls “remarkable.” She likes to go for walks and spend time with her three children and four grandchildren. Beatriz continues to write historical fiction and is nearing completion of the first book in a trilogy set during the Paraguayan War of 1864-1870.
Back home in Brazil, Beatriz enjoys spending time with her granddaughter, Emilia, her three other grandchildren, and her three grown children.
“It was very, very hard when I thought I had a year to live, thinking about not seeing my granddaughter be born,” she says. “I am very happy and thankful because of the clinical trial, and I have a debt to Dr. Seidman for his care. He has always made me feel like a person who matters a great deal to him, and when I come to New York for follow-up exams, it’s like visiting a dear friend.”
Dr. Seidman said patients like Beatriz have played a crucial role in demonstrating that the triplet therapy had great promise. “Her participation in Dr. Jhaveri’s phase 1 trial helped set the stage for the larger phase 3 trial,” he says.
It has been gratifying, Dr. Jhaveri says, to see the new treatment move from initial testing to FDA approval, which will make the therapy accessible to patients around the world. “From the beginning, MSK has been closely involved in testing how people respond to this drug,” she says. “It’s a phenomenal story.”