The First of Many Advancements to Come for a Lung Cancer Mutation

Recent drug approvals by the Food and Drug Administration (FDA) are giving patients with non-small cell lung cancer (NSCLC) and EGFR exon 20 insertion mutations the first two treatments that specifically target those mutations.

“EGFR is one of the classic driver mutations,” Dr. Catherine Ann Shu, clinical director of the thoracic medical oncology service at Columbia University Irving Medical Center in New York, explained in an interview with CURE®. “When patients hear about having an EGFR mutation, it’s typically associated with drugs like osimertinib (Tagrisso) or lorlatinib (Lorbrena) ... and those patients tend to do very well on those treatments with a very high response rate. ... But unfortunately, there is another type of EGFR mutation. Most people aren’t really aware of it, but it’s called exon 20 insertion. And patients with those EGFR exon 20 insertions generally do not respond to the classic drugs.”

EGFR mutations exist within 85% of lung cancer cases. Of those, about 10% are exon 20 insertions. “Because it’s more rare, it hasn’t been something that’s been explored as much,” Shu said. “And it is more heterogeneous than the other EGFR mutations. The other EGFR mutations tend to be exon 19 deletions and L858R, which is a pretty standard thing. And exon 20 insertions can be a whole variety of insertions or duplications, so they don’t all look exactly the same. Sometimes it’s a little bit harder for patients and providers to know exactly what’s going on.”

Dr. Pasi A. Jänne, a translational thoracic medical oncologist at Dana-Farber Cancer Institute in Boston and a professor of medicine at Harvard Medical School, noted that it’s easiest to think of exon 20 as a collection of mutations that occur within a particular part of the exon 20 part of the gene. He also said there are data that suggest the mutation is more common in those of Asian descent, likely due to a genetic contribution that hasn’t been thoroughly researched.

A Big Approval

For patients with lung cancer and an EGFR exon 20 mutation, the standard of care has been chemotherapy, according to Jänne. “Until recently, all of the therapies that have been approved for the more common types of EGFR mutations have not been effective in this subset of lung cancer; hence, there’s been a great interest in trying to develop specific therapies that would be effectivein the EGFR exon 20 subset of lung cancer,” he added.

The emphasis being on “until recently,” Jänne noted that the FDA approved Rybrevant (amivantamabvmjw) as the first targeted therapy for the patient subset in May 2021. In the study that led to the approval, 81 patients with NSCLC and an EGFR exon 20 insertion mutation whose disease had progressed after platinum-based chemotherapy participated. After treatment with Rybrevant, patients had an overall response rate (patients who had a complete

or partial response to the therapy) of 40%. There was also a median duration of response (the time that a tumor responds to treatment without growth or spread) of 11.1 months in all patients, while 63% of the patients experienced a response to the therapy for at least six months.

“The response is higher than probably just chemotherapy would be, but remember that these response rates are in patients who have had chemotherapy,” explained Shu, who was the lead author on the study that led to the drug's approval. “This is post- platinum chemotherapy.

Generally, we see a decrease in response rate with every line of therapy. If you think about it, this 40% is already after they’ve progressed on chemo, so it’s really quite good.”

Common side effects from the drug included rash, skin infections around the fingernails or toenails, nausea, fatigue, sores in the mouth, cough, constipation and vomiting. Shu added that there’s also an infusion-related reaction that typically presents on the first dose as shortness of breath, flushing or nausea. It can be managed by lowering the dose and prescribing pre-medications.

One factor to be aware of, according to Shu, is the scheduling around the drug, which is an IV infusion. “The schedule is a little bit more of a pain than being on a pill,” she said. “You have to go in for infusion, (and) the first infusion is split up over two days.

You have to go on day one and on day two because we try to do it slowly to prevent that infusion-related reaction, then you have to come in again on day eight, which is the following week. You have to come in again on day 15.

It’s weekly for the first few weeks, and then it goes out to every other week. It is a little bit more time intensive than even some chemotherapies, but if you can see past that ... the pros definitely outweigh the cons.”

Make It Two

After the FDA’s first targeted therapy approval for this patient subset, the dominoes quickly fell into a second one. In September 2021, Exkivity (mobocertinib) was approved for the treatment of locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations with disease progression after receiving platinum-based chemotherapy.

Within this study, researchers observed an overall response rate of 28% and a median duration of response of 17.5 months. The median overall survival (the time from treatment that a patient with cancer is still alive) was 24 months, while the progression-free survival (amount of time during and after treatment that a patient lives with cancer without it progressing) was 7.3 months.

“For (Exkivity), the side effect profile is a little bit different (compared with Rybrevant). It’s more gastrointestinal (GI) side effects. There’s more of a diarrhea type of side effect, there is some skin rash, but it’s not as predominant as the GI side effect can be. They’re sort of two different classes: skin side effects and GI side effects. And both, with appropriate management and dose reductions, can be manageable,” explained Jänne, who was the lead author on the study that led to the drug's approval.

More specifically, common side effects included diarrhea, rash, nausea, stomatitis (inflamed and sore mouth), vomiting, decreased appetite, paronychia (infection surrounding the fingernail), fatigue, dry skin and musculoskeletal pain.

According to Jänne, next steps for further investigating therapies for this patient subset include looking at the newly approved drugs as monotherapies or combination therapies. “There are clinical trials to see whether — in combination with chemotherapy — (Rybrevant) would be better than chemotherapy as initial therapy. And as a single agent, whether (Exkivity) would be better than chemotherapy as initial therapy for this subset of individuals,” he said. “The paradigm is typically that you get an approval in a following treatment with prior standard of care. And then the next question is: Is this an agent to replace or add to the standard of care? But it’s exciting to have these options for individuals. We didn’t have these several months ago, and we hope that (these two approvals are the first of) many to come.”

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