Targeted therapies offer new hope for patients with HER2-mutated non-small cell lung cancers.
Kiley Akers of La Canada, California, is in the best shape of his life. Before the sun came up on a recent morning, he ran 7 miles. The day before, he ran 6.
But Akers, 48, who serves as a running coach for The Leukemia & Lymphoma Society’s Team in Training program, isn’t your typical runner. He also has mucinous adenocarcinoma, a type of non-small cell lung cancer (NSCLC). More specifically, genetic testing of his tumor revealed that Akers has a mutation in the human epidermal growth factor receptor 2 (HER2) gene, which creates an opportunity for cancer cells to grow and spread.
While that might sound like bad news, Akers doesn’t see it that way. Knowing he has this specific mutation has meant his medical oncologist — Dr. Ravi Salgia with City of Hope, a comprehensive cancer center in Duarte, California — could create a medication regimen tailored to his specific genetic mutation. This regimen, known as targeted therapy, attacks the mutation to slow cancer’s growth.
In fact, Akers says his targeted therapy regimen — six daily pills of Nerlynx (neratinib) combined with an infusion of Herceptin (trastuzumab) every three weeks — allows him to keep running while undergoing treatment. “Because of City of Hope and Dr. Salgia, and the research they do, I’m able to continue with one of my passions,” he says. “I’m fortunate and grateful.”
TARGETING THE ENEMY
About 80% to 85% of all lung cancers are NSCLC, on authority of the American Cancer Society. Today, targeted therapies offer new hope to people with HER2-mutated NSCLC. But just how do these therapies work?
According to the National Cancer Institute, targeted therapies block the growth and spread of cancer by interfering with specific molecules, most commonly proteins, that help cancer grow. Researchers have discovered these proteins, known as molecular targets, by taking cells through tissue biopsies or blood tests (liquid biopsies) and comparing the number of certain proteins in cancer cells with the number of those proteins in healthy cells. If cancer cells contain the protein (but healthy cells don’t) or if the cancer cells contain much more of the protein than the healthy cells, the protein may be a substance doctors can “target” with these drugs.
Additional experiments in the laboratory can confirm that specific genetic changes generate these cancer-driving proteins, and this allows for new drugs to be created that can block their activity, resulting in cancer responses.
The HER2 protein is one such target. According to Dr. Kwok-Kin Wong, a medical oncologist at NYU Langone’s Health Perlmutter Cancer Center in New York City, HER2 is one of the most studied proteins in cancer, particularly its role in HER2-positive breast cancer, where cells often make hundreds, if not thousands, of copies of themselves (known as amplification). Studies of HER2’s role in NSCLC have shown that while HER2 can be overexpressed (present in higher amounts than normal cells), it’s not amplified as much as it is in breast cancer, Wong says.
“What we have noted in the last 10 years is that HER2 can be mutated,” he says. “About 2% to 4% of lung adenocarcinomas have HER2 mutations that cause the gene to be oncogenic.”
Oncogenes are gene mutations that cause cancer cells to grow. “Overexpression might be a consequence that might help cancer grow faster, but it’s not the driver,” Wong explains. “These specific mutations in the HER2 gene are drivers.”
Dr. Jennifer Carlisle, a medical oncologist at Winship Cancer Institute of Emory University in Atlanta, explains how targeted therapy works by comparing a cancer cell to a manufacturing plant whose products are the building blocks that help cancer grow and spread. Picture multiple “receiving bays” where the cancer cells receive materials (in this case, growth signals) to help cancer grow, she says. In lung cancers with HER2 mutations — like that of Akers — the lock on the HER2 receiving bay is broken.
“The door stays open, leading to constant growth signals that cause tumors to progress,” Carlisle says. “Targeted therapies work like master keys that can fit in the broken lock and close the door.” Closing the door stops the growth signaling.
THE ‘ULTIMATE PRECISION MEDICINE’
Targeted therapy is a form of precision medicine, a way of saying that doctors use drugs designed to address what’s happening in a person’s unique cells. Oncologists learn about an individual’s cells by studying them and understanding how they differ from healthy cells.
“This is a very complicated field,” Wong adds. “Even though we say HER2 mutated, the type of mutation in HER2 makes a difference. It’s the ultimate precision medicine. The type of mutation of that gene dictates how well it would respond to certain drugs.”
That’s why biomarker testing is so important. “We highly, highly recommend biomarker testing for our lung cancer patients,” Salgia says. “For sure with non-small cell lung cancer and for sure with later-stage disease, it’s a moving needle at this moment in time, but we strongly believe it should be done for early-stage disease as well.”
Targeted therapy isn’t yet the standard of care for people with NSCLC. Carlisle explains that biomarkers currently have limited standard use in early-stage NSCLC, which is best treated by surgery, she says, adding that clinical trials are testing multiple approaches to reduce the risk of recurrence. Immunotherapy and targeted therapy for epidermal growth factor receptor (EGFR) mutations are approved postoperatively for resected stage 2 and 3 NSCLC, and ongoing studies are looking into treating other driver mutations perioperatively (around the time of surgery).
For people with stage 3 disease whose tumors can’t be removed completely with surgery, chemotherapy and radiation followed by immunotherapy is recommended, Carlisle says. In those who have stage 4 HER2-mutated NSCLC, chemotherapy, immunotherapy or a combination of both — depending on the patient’s health and tumor factors — is the typical frontline treatment, she adds.
An approved HER2 targeted therapy for NSCLC would give patients a more personalized treatment option, Carlisle says. “We have found with other driver mutations, such as EGFR and ALK (anaplastic lymphoma kinase), that going after the driver first and saving chemotherapy and/or immunotherapy for later helps patients live longer,” she explains.
In May 2020, the Food and Drug Administration granted a breakthrough therapy designation to Enhertu (trastuzumab deruxtecan) in treating people with metastatic NSCLC that has progressed on chemotherapy. This drug is an antibody-drug conjugate that links the HER2-binding antibody trastuzumab to a very potent chemotherapy drug called deruxtecan, which inhibits cell division. When this drug binds to the cell, it is drawn inside, where deruxtecan is released, killing the cancer cells more specifically with less injury to normal cells. Carlisle mentions that additional trials of Enhertu are being conducted for people with stage 4 HER2- mutated NSCLC that continues to grow after standard therapy options.
Salgia says the floodgates have really opened for people with lung cancer thanks to genetic testing, known as next-generation sequencing.
“Next-generation sequencing identifies a set of molecular abnormalities,” he says, adding that researchers can look at the gene’s amplification as well as its translocation — meaning whether it moved from one chromosome to another chromosome. “This is how the code is being broken for lung cancer. Lung cancer is no longer lung cancer. It’s a cancer that arises in the lung that has certain characteristics under the microscope, at the protein level and at the gene level.”
Mary Modica, 76, of Queens, New York, has been participating in a phase 2 study of a targeted therapy drug called poziotinib (a tyrosine kinase inhibitor) since April 2021. The drug targets HER2 exon 20 insertion mutations — a specific type of HER2 mutation known to be an oncogenic driver in NSCLC.
“I wasn’t feeling well and they thought maybe I had pneumonia,” says Modica, a never-smoker. “That’s when I went for a chest X-ray and my primary care doctor told me I had lung cancer.”
Her doctor referred her to a thoracic surgeon who delivered the awful news: Modica had a stage 4 inoperable lung tumor. Biopsies soon showed that the cancer had spread to her tailbone and clavicle.
She was first treated with immunotherapy and radiation, but she developed a terrible rash that led doctors to stop the therapy. She then received chemotherapy followed by chemo maintenance, but the cancer continued to grow and spread.
Her oncologist referred her to another doctor for potential access to a targeted therapy clinical trial. Modica says she sought several opinions before deciding on the Perlmutter Cancer Center at NYU Langone Health. There, her medical oncologist, Dr. Joshua Sabari, recommended that she join a clinical trial of poziotinib based on the results of her tumor biomarker testing.
Modica admits she doesn’t know much about the molecular profile of her tumor — or about how targeted therapy works. What she does know is that she has complete faith in Sabari, who mapped out several different treatment options for her to consider.
She learned that poziotinib would be administered as a pill, not infused through an IV. “That was better for me because my veins were kind of shot,” she says. Today, she takes 12 milligrams of the drug each day.
“Once I went on it, it really picked up my spirits,” Modica says, adding that being in the trial involves many follow-up visits. “They monitor you extremely closely.”
Modica says she sees her care team once a month for blood draws, consultations with her doctor and sometimes, a nutritionist. Every other month, she has CT scans of her abdomen, lungs and pelvis; she also has an MRI of her brain every six months.
While she feels optimistic, Modica says targeted therapy has some side effects she’s had to manage. These have included extremely dry skin, hair loss and diarrhea. But they haven’t deterred her from the drug. “You have to learn how to make it work for you,” she says. “I’m not going to be cured, but this is my life. So I’m going to live it to the fullest. I’m out every day. Yesterday, I volunteered at a golf outing and I was outside all day.”
Many people on targeted therapies experience side effects like diarrhea, liver problems, skin issues and high blood pressure. Akers says diarrhea has been the most challenging side effect of his targeted therapy regimen because he works and is active, he says.
He uses some over-the-counter medications to manage it, but also uses other strategies. “It’s about learning the right foods to eat and what I can tolerate,” he explains. “I also think stress can add to it. I really try to stay on top of hydration, too.”
Ultimately, Akers says, something his doctor told him has helped him understand the value of targeted therapy.
After his scans showed that he was having a good response to treatment, his doctor told him, “This is like managing high blood pressure.”
“That blew my mind,” Akers says. “I was like, ‘What? This is cancer.’ I liken it to running one of my long races where they mark the courses with trail ribbon. I tell myself to just follow the ribbon. I feel like I’m going to overcome this and it’ll be something in the rearview mirror. With this therapy, I get the benefits of the cancer-killing property of chemotherapy, but without it destroying all the healthy cells. I ran before treatment yesterday.”
That kind of optimism is what keeps doctors and researchers going in the quest to identify novel targeted therapies to treat NSCLC. Salgia encourages people with HER2-mutated NSCLC and their families to seek out expertise in treating the disease and to consider clinical trials.
“Every time a new drug gets approved, it’s an incredible win for patients,” Salgia says. “These novel therapies can actually impact survival and quality of life. We’re definitely not done until we cure lung cancer. That’s why I’m here. That’s why our team is here. We need to support lung cancer research.”
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