Targeting the 'Typos' for Lung Cancer Harboring Rare Genetic Mutations

After spending a warm spring day in 2022 pulling weeds and planting perennials, Renata Muller, 66, tucked herself into bed and noticed that she was short of breath. When she woke up the next morning, she felt pressure in her chest.

“I figured I overdid it with the garden work,” she says. But her symptoms didn’t subside. They got worse.

As the day went on, she felt overwhelmingly tired, was unable to go up the stairs without becoming winded and began struggling to breathe. Concerned, her husband, Ralph, took her to the emergency room that evening.

“After 11 hours of waiting and tests, the doctor told me I had a buildup of fluid in the space around my heart and I needed immediate surgery,” Muller recalls.

Four days later, she learned she had stage 4 lung cancer.

Lung cancer is the leading cause of cancer death worldwide, and non-small cell lung cancer (NSCLC) accounts for 85% of those deaths.

In recent years, immunotherapy drugs have dramatically extended the lives of patients with advanced lung cancer, so Muller’s oncologist was optimistic.

He ordered comprehensive genetic testing called next-generation sequencing (NGS). With this kind of sequencing, doctors can detect 4 million variants, some of which can be targeted with treatment.

“My doctor wanted to put me on an immunotherapy drug called Keytruda (pembrolizumab) right away, even before the (next-generation sequencing) results came back, followed by several cycles of two chemotherapy drugs,” she says.

But when Muller realized that starting the treatment regimen would prevent her from participating in a clinical trial, she transferred her care to Stanford. By then, she had the NGS results, which indicated that her cancer was driven by a rare mutation called epidermal growth factor receptor (EGFR) exon 20 insertion, which is often described as an “undruggable” target in the lung cancer world.

For the 1% to 2% of patients with NSCLC who have these mutations, immunotherapy agents offer limited benefit and can even cause additional harm.

Muller’s decision to transfer care opened the door for her to participate in a clinical trial investigating an agent that specifically targets EGFR exon 20 insertion mutations: Exkivity (mobocertinib), a small-molecule kinase inhibitor approved by the Food and Drug Administration (FDA) in November 2021. Six months earlier, the agency had approved another drug targeting the same mutations, a bispecific antibody called Rybrevant (amivantamab).

“For the first time, we have options that target these rare genetic mutations, and that’s a game changer for patients,” says Dr. Estelamari Rodriguez, a thoracic oncologist and clinical research lead of the Thoracic Site Disease Group at Sylvester Comprehensive Cancer Center at the University of Miami.

“In the past, after patients failed chemotherapy, we didn’t have much to offer. ... Now we have these new targeted therapies that are currently used for what doctors call ‘salvage therapy,’ after patients don’t respond to chemotherapy.”

The drugs are the first FDA-approved treatments to specifically target EGFR exon 20 insertion mutations, but several more are in the pipeline, and they may buy patients more time so that science can effectively catch up to them.

EGFR Mutations Explained

EGFR is a protein in cells known as a growth factor receptor, which helps them grow. Some mutations in the EGFR gene can activate the receptor and lead to uncontrolled cell growth, thus leading to or accelerating cancer.

With NGS, doctors can uncover the changes in the DNA that might be fueling (driving) cancer. In NSCLC, EGFR mutations are one of those oncogenic drivers.

Think of DNA as an instruction manual. If there’s a typo in the manual, cells receive incomplete or incorrect instructions and may become cancerous. Doctors look for those typos to determine whether a patient is a candidate for therapies that target them specifically.

Besides misspelled words (point mutations), there may be other mistakes, like missing words (deletions) and added words (insertions). EGFR mutations include all three.

Mutations in exon 19 and exon 21, which are often referred to as “classical” EGFR mutations, account for about 85% of EGFR mutations in NSCLC.

Doctors treat them with drugs called tyrosine kinase inhibitors, which block the action of enzymes that preferentially signal cancer cells to divide and grow.

Up to 80% of patients with classical EGFR mutations respond to tyrosine kinase inhibitors, which can keep the cancer at bay for an average of 19 months — and much longer for a subset of patients.

“Unfortunately, the treatments we use for classical EGFR mutations aren’t effective in patients with EGFR exon 20 insertions,” says Dr. John V. Heymach, chair of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center in Houston.

The additional insertions in these mutations cause defects in the drug-binding pocket, reducing sensitivity to tyrosine kinase inhibitors.

That’s why it’s important for patients with lung cancer to characterize their disease before beginning treatment. For NGS, doctors place tumor tissue in a machine that can rapidly sequence the tumor’s DNA and identify a large number of biomarkers all at once.

If patients can’t undergo a traditional biopsy for NGS, doctors may use a liquid biopsy to search for the biomarkers by analyzing tumor DNA in the bloodstream.

“PCR (polymerase chain reaction) testing is not sufficient to pick up certain mutations, including EGFR exon 20 insertion mutations,” Rodriguez says. “So it’s extremely important for patients to get NGS or a liquid biopsy upfront, so they can take advantage of new treatments that can extend their lives.”

Experts say that NGS should be standard of care following a diagnosis for all patients with lung cancer because treatments vary depending on the mutations they have. According to some estimates, however, only half of patients know this critical information when they begin treatment.

Novel Treatment Options

Many patients with EGFR exon 20 insertion mutations have never smoked, so they’re not flagged for lung cancer screening. By the time they develop symptoms, they have advanced disease and surgery is no longer an option. And radiation won’t work because the cancer has spread throughout the body and there are too many targets to treat.

That leaves two options: cutting off the fuel that is driving the cancer and/or killing the cancer cells.

Doctors typically start with traditional platinum-based chemotherapy, but in patients with EGFR exon 20 insertion mutations, chemotherapy shrinks tumors by only 20% to 25%, which may provide patients six months on average, according to Heymach.

Now, however, doctors have two additional treatments.

Rybrevant

Delivered by infusion every two weeks, Rybrevant targets both
EGFR and an oncogene called MET. Instead of disabling the ATP-binding kinase activity of EGFR, as tyrosine kinase inhibitors do, the antibodies in Rybrevant go after the EGFR protein on the cell surface to disable the receptor and allow the body’s natural killer cells to attack the cancer.

Studies show a response rate of up to 40% with Rybrevant, and a median progression-free survival (the length of time during and after treatment when a patient with cancer lives without disease worsening) of seven months.

Approximately 65% of patients have an infusion reaction, which may include becoming flushed, feverish and short of breath, so the first infusion is often delivered very slowly, says Dr. Jyoti D. Patel, medical director of thoracic oncology and assistant director for clinical research at the Lurie Cancer Center of Northwestern University in Chicago.

Most patients have a reaction only to the first or second infusion. Other side effects include rash (86%), paronychia, an infection of the nail bed (45%), and diarrhea (12%).

Exkivity

Exkivity is active against both EGFR and human epidermal growth
factor receptor 2 (HER2). A capsule taken orally, Exkivity is specially designed to accommodate the narrow binding pocket of the EGFR exon 20 insertion mutation.

“It attaches to the internal part of the EGFR receptor, interrupting signaling from the receptor downstream,” says Dr. Lyudmila A. Bazhenova, a medical oncologist at Moores Cancer Center, University of California, San Diego.

The response rate with Exkivity hovers around 28%, and the median progression-free survival is seven months.

Its side effects are similar to Rybrevant’s but more pervasive, with up to 82% of patients experiencing diarrhea, 46% rash and 39% nausea and vomiting.

There hasn’t been a head-to-head study comparing the safety and efficacy of these drugs, so doctors aren’t sure which works best.

But they know that both eventually stop working.

“Patients can develop secondary mutations that prevent the medications from binding appropriately, or the cancer becomes more resistant and learns to bypass EGFR,” Heymach says.

Without a clear advantage, patients typically decide whether they want to start with an oral medication or an infusion. Because they have different mechanisms of action, doctors usually sequence the drugs, starting with one and then turning to the other when the disease progresses.

“Unfortunately, neither of these drugs show(s) significant activity in the brain or spinal cord, and most patients with EGFR mutations suffer from metastases to the brain,” says Patel. “So there’s a huge need for new drugs that can penetrate the central nervous system, and some of the drugs under development are being designed specifically for that purpose.”

In the meantime, patients like Muller whose have brain metastases are affected turn to Gamma Knife radiation treatments that deliver multiple radiation beams simultaneously to kill cancer cells while sparing healthy tissue.

“To ensure the rays are focused on the tumors, they stretch a mask over your head and face, making you look like a superhero,” says Muller, who has had two Gamma Knife procedures, each in under an hour.

Once her brain lesions were addressed, she started on Exkivity and has been taking the drug ever since. “As long as I’m able to tolerate the medication, and it’s keeping the cancer at bay, I’ll stay on it,” she says.

Sequencing Treatment

On Feb. 15, 2021, Jeff Battles, 53, felt odd chest pains. They became so intense that he went to the emergency room at 2 a.m., during a blizzard.

A computed tomography scan revealed large tumors in his chest and throughout his rib cage. Battles had stage 4 lung cancer.

A local oncologist ordered NGS genetic testing on his tumor, and while Battles awaited the results, he did two cycles of chemotherapy.

“A few weeks later, when testing showed I had the EGFR exon 20 insertion mutation, we started looking into clinical trials,” says Battles, who owns a medical device manufacturing company in Meadville, Pennsylvania.

The trial, ZENITH20, at Cleveland Clinic was designed to assess the efficacy and safety of poziotinib.

“I took an 8-milligram pill daily, and it stalled disease progression for about seven months,” says Battles. “But when the cancer began growing and spreading again, my doctors put me on (Rybrevant) infusions.”

As he had with poziotinib, Battles experienced a noticeable reduction in tumor size during the first month, but after seven months on Rybrevant, the effects leveled off. When his disease began progressing again, Battles did two more rounds of chemotherapy.

“We’ve used most of the tools in the toolbox at Cleveland Clinic, so now we’re investigating other trials and treatments,” he says.

Unfortunately, Battles’ experience is common among patients with EGFR exon 20 insertion mutations.

Targeted treatments like Rybrevant and Exkivity can control the cancer for months or even years, depending on the patient and the drug, but they will not cure it.

New Horizons

The hallmark of cancers driven by EGFR exon 20 insertion mutations is “acquired resistance,” meaning that they learn to outsmart treatments.

When resistance is acquired, doctors often repeat biopsies and order biomarker testing to identify new mutations they can target with different therapies — and for the first time, patients with these rare mutations have options.

“This is the beginning of the story,” Rodriguez says. “It’s our first attempt at getting at this mutation for patients who had previously been bundled into the EGFR category. But since we’re getting a response from targeted treatment after patients (progress on) chemotherapy, we know these are effective agents.”

Now that scientists have established EGFR exon 20 insertion mutations as a targetable mutation, the next step is learning how to improve response rates with currently approved drugs. That starts with understanding the different drug responses within EGFR exon 20 insertion mutations. For instance, emerging research suggests that the insertion location within EGFR mutations affects how patients respond to treatment.

The more scientists learn about these responses, the better equipped they’ll be to target them.

The good news is that the pace of research is rapid. Several drugs that target EGFR exon 20 insertion mutations are under development, and a few are already available. And, unlike other drugs, these treatments can work quickly, with patients responding systemically within six weeks in some cases.

Previously, overall survival of only two to three years was probable. But patients on Exkivity and Rybrevant are living much longer.

“And there’s a host of other new drugs coming down the pipeline,” Heymach says. “The exciting thing is, it’s very likely there’s going to be multiple options for these patients in the future.”

In the meantime, the goal for these patients is to stay one step ahead of the cancer by using Rybrevant and Exkivity as a bridge to the next best therapy.

“When I was diagnosed ... I didn’t anticipate I’d be doing this well several months later,” Renata says. “My blond hair is more gray these days, and I don’t have the high energy I used to, but I’m able to do most of my usual activities, including gardening.” Next up: a trip to Indonesia with her husband. “I’d like to go scuba diving,” she says.

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To learn more about Jeff Battles' experience with lung cancer, listen to the "Cancer Horizons" podcast where he tells his story.