Rare Genetic Changes Can Make a Big Difference in Non-Small Cell Lung Cancer Survival

When Ginger Head was given a diagnosis of stage 4 non-small cell lung cancer (NSCLC) at age 56 in 2017, an oncologist in Birmingham, Alabama, told her she had less than a year to live. The doctor offered her standard chemotherapy to help keep her alive as long as possible and didn’t discuss any other options.

Head, a retired special education teacher, and her husband were stunned. Just days before, she was feeling great, working out five to six times a week. Then, a few days after a biopsy of an unusual lump in her neck, she was given months to live. When the doctor left the room, Head’s husband asked the medical resident, who had stayed, what he would do in this situation. The resident told them that Head’s tumor had high levels of a protein called PD-L1 that would make her a great candidate for immunotherapy. He recommended they go to The University of Texas MD Anderson Cancer Center in Houston.

During the next two years, Head underwent multiple treatments at MD Anderson. She had Gamma Knife radiosurgery for metastases in her brain, followed by chemotherapy plus an immune checkpoint inhibitor that blocked the PD-L1 protein that was helping her cancer spread. Finally, she had 15 rounds of radiation. At that point, Head’s PET scans were clear. But, within a year, the cancer had recurred in her lymph nodes and her brain. Gene sequencing of Head’s tumor tissue showed a rare genetic alteration called a RET fusion that was promoting the cancer’s growth. That made her eligible for a clinical trial of a drug called Gavreto (pralsetinib) that targets the rare genetic alteration.

It’s fairly standard for oncologists to test NSCLC tissue for the gene mutations that most commonly drive the cancer, such as changes in EGFR and ALK genes. But doctors may not always test for less common genetic alterations that could also help the cancer grow and spread. Rare genetic alterations may arise in only 1% to 3% of NSCLC. But drugs on the market or in clinical trials can disable these genes and extend life significantly.

“Some oncologists aren’t testing for these because they are so rare,” says Dr. Jacob Sands, a medical oncologist who specializes in lung cancer at Dana-Farber Cancer Institute in Boston. “But if you’re in that 1%, it makes a huge difference for you. We really need to be doing dramatically better on this.”

Widespread testing for all possible cancer-driving gene alterations would get more people on the best medication for them and help contribute to research of these gene changes. This could help to extend the life of patients with NSCLC.

Genetic Alterations in NSCLC

Up to 85% of lung cancers are non-small cell, which includes adenocarcinoma (also called non-squamous cell carcinoma), squamous cell carcinoma and large-cell carcinoma. Overall, NSCLCs are slower growing and less aggressive than the small-cell form of the disease. While the vast majority of all lung cancers are linked to smoking, when nonsmokers get lung cancer, they are more likely to get the non-small cell type.

NSCLC, particularly adenocarcinoma, often has genetic changes that may help the cancer
progress. The term genetic alteration includes gene mutations as well as other gene-related abnormalities or changes in the cancer cells. Gene mutations are changes in a single, specific gene. But other alterations to longer stretches of DNA can aid and abet cancer growth, too. These changes include rearrangements, deletions, duplications and fusions of segments of DNA. The terms driver mutation, driver gene and driver oncogene also describe these gene alterations that help cancer cells survive. Up to 60% of adenocarcinomas have these genetic alterations.

Genetic alterations are even more common among people who develop this type of cancer before the age of 40. As many as three out of four people who get adenocarcinoma before age 40 have gene changes in their tumors that drugs could target. “Anyone who gets lung cancer before the age of 40, any young people, should get tested for these,” Sands says.

People who have never smoked, such as Head, or who have smoked very little also are more likely to have lung cancers with driver mutations.

“No matter what kind of lung cancer they have, if they have no smoking history or a minimal smoking history, those patients should definitely get comprehensive genetic testing of their tumor,” says Dr. Christina Baik, a medical oncologist who specializes in lung cancer at Seattle Cancer Care Alliance in Washington. These gene alterations matter so much because in metastatic NSCLC, certain medica- tions — some on the market, others currently in clinical trials — can attack and disable the very alterations that help the cancer advance. Most of these medications are pills that patients can take every day at home.

“Identifying a driver oncogene in a cancer and getting treatment for that particular genetic change can improve people’s survival,” Baik says.

How Doctors Find Genetic Alterations

Doctors may test for genetic alterations in a couple of ways.

A polymerase chain reaction (PCR) test is a fast and inexpensive way to look for specific alterations by analyzing certain segments of tumor DNA. Doctors might order this type of test for specific common mutations, such as EGFR and ALK. However, a separate test is required for each mutation. Testing for numerous mutations through this method could require multiple biopsies.

Next-generation sequencing, a more expensive test that may not be covered by all insurance plans, decodes the entire genetic code of the tumor. This type of test will uncover any genetic alteration that may be of interest in determining the care plan, which can make a significant difference in prognosis.

“Every lung cancer patient has to have genetic screening,” says Dr. Anne S. Tsao, a medical oncologist who specializes in lung cancer at MD Anderson. “Those mutations are out there, but if we don’t screen you, you may not get optimal care and we may never know what we might’ve been able to do for you.”

Some people will need a second round of genetic testing after treatment has begun. “Tumors evolve over time,” Tsao says. “They can be sensitive to a particular drug for a while and then develop secondary mutations that make them resistant to the drug.” When a person progresses on a targeted drug, a new genetic test can help doctors determine which drug to use next.

Rare Genetic Alterations in NSCLC

Some of the less common genetic alterations that can drive NSCLCs include RET fusions, which Head has; EGFR T790M mutations and EGFR exon 20 insertion mutations; ROS1 rearrangements; MET amplifications and PIK3CA mutations. This is not an exhaustive list. Each of these alterations respectively may arise in 1% to 3%, maybe more, of NSCLCs. That may seem small, but combined, these alterations represent a substantial proportion of patients with lung cancer.

RET Fusions

RET fusions are very rare genetic alterations. The Food and Drug Administration (FDA) has approved two drugs to target the alteration: Retevmo (selpercatinib) and Gavreto. The latter received approval in September 2020 based on results from the ARROW trial, where 57% of patients previously treated with platinum-based chemotherapy responded to the drug, and just under 6% had a complete response. Among individuals who hadn’t yet received any treatment, 70% responded and 11% had a complete response. Many trial participants, including Head, were still responding to the drug after the trial ended.

Head takes four pills every morning at 3 a.m. “They want you to be good and empty when you take it, so I’ve just gotten accustomed to waking up in the middle of the night, taking my four pills and going right back to sleep,” she says.

The most common side effects of the drug, which occur in about 20% to 35% of patients, include liver damage, anemia, constipation, high blood pressure and low white blood cell counts. Head didn’t experience any of these, only extreme fatigue during the first month on the medication.

“Just getting a coffee cup out of the cabinet every morning made me feel like I was seeing stars,” she says. “Now I’m back to walking four miles a day with a girlfriend, and I can tell that my lung capacity is getting so much better.”

EFGR T790M and Other Modes of Resistance

EGFR T790M mutations are usually responsible when people progress on inhibitors such as Iressa (gefitinib) or Tarceva (erlotinib). “About 60% of patients who have progression on those drugs have T790M as that resistance mutation. Then Tagrisso (osimertinib) is the standard of care,” Sands says.

J.D. Walk of Ravensdale, Washington, received Tarceva when he first started treatment for stage 4 EGFR-positive NSCLC at age 39 in 2016. He had shown signs of lung cancer for at least a year prior to his diagnosis, but his doctor insisted for many months that it was pneumonia. For a man his age who had never smoked and was in excellent physical health, pneumonia was the more likely interpretation of the chest X-rays than lung cancer.

By the time Walk received a definitive diagnosis, he had 39 brain metastases and the cancer
had destroyed one of his ribs. Ten rounds of radiation eliminated the brain metastases. He then started the targeted drug Tarceva. Walk did well on the drug for about a year. He was back to weight training at the gym, but during a workout in 2017 he passed out.

Walk had developed leptomeningeal disease, a condition in which cancer cells migrate from the lungs and get into the cerebrospinal fluid. From there, the cells can grow in the spinal cord or the brain. “The doctors told me when most people get leptomeningeal disease it’s three weeks to three months before they pass away, and it looked like I’d already had it for a month or so.”

By that calculation, Walk may have only had a number of days or weeks left. But he still had treatment options ahead of him. He received an Ommaya reservoir, a port that delivers chemotherapy directly to the ventricles in the brain where cerebrospinal fluid is made. The treatment left him in such a fog that he doesn’t remember much from the time the treatment started until about six months after it was finished. He was on disability and couldn’t do his job as an account manager at Siemens. He couldn’t drive; he could barely walk. What was worse was that, although he had outlived his previous prognosis, his doctor told him that he wasn’t getting any better.

Tagrisso also received approval for people whose metastatic EGFR T790M-positive NSCLC had progressed on another EGFR inhibitor.

“Within a couple weeks after I started Tagrisso, the leptomeningeal disease was almost gone,” he says. By the time Walk’s short-term disability had run out, he was able to go back to work.

Three years later, Walk still takes Tagrisso. Though it was rare to survive a single bout of leptomeningeal disease, Walk survived it a second time last summer. Now the cancer is concentrated in his lungs, where it remains stable. He has no other metastases in his ribs, lymph nodes or brain. Walk, a husband and father of four daughters, says, “I just try my best to live like this cancer never happened.”

In recent studies, Tagrisso has slashed recurrence rates and risk of later brain metastases in early stage EGFR-positive disease as well.

EGFR-positive lung cancers may also become resistant to EGFR inhibitors through another alteration called an exon 20 insertion. These mutations may be harder to target with a drug because the exact mutation can vary greatly from one person to the next. These differences can affect a person’s response to treatment. Some drugs in development may be helpful in the future.

Other Targetable Mutations

About 1% to 2% of NSCLC have a ROS1 rearrangement. The FDA has approved four drugs that target ROS1: Xalkori (crizotinib), Zykadia (ceritinib), Lorbrena (lorlatinib) and Rozlytrek (entrectinib). The former two target the more common ALK alterations as well.

MET amplifications are a type of alteration in the MET gene. Nearly 4% of people with non-small cell lung cancer have some change in this gene. For just more than 1% of them, it’s an amplification, which means there are additional copies of a portion of this gene. Some targeted drugs, including Gilotrif (afatinib), Xalkori, Vizimpro (dacomitinib), Tarceva, gefitinib and Tagrisso, which are already approved for lung cancers with other genetic profiles, have also shown promise in tumors with this particular alteration.

The phase 2 ORCHARD trial looks at gefitinib, among numerous other drugs, as a treatment for non-small cell lung cancer that has progressed on Tagrisso. One of the common ways these EGFR-positive lung cancers seem to develop resistance to Tagrisso is through a MET amplification. Another phase 2 trial in progress examines the benefits of Xalkori in people with MET amplifications who have had previous treatment with another drug.

PIK3CA, a more common alteration, is altered in just under 7% of non-small cell carcinomas. These alterations often come along with one of the more common EGFR, BRAF, ALK or KRAS mutations. Clinical trials are in progress to identify drugs that may target PIK3CA and extend survival.

Looking Ahead in the Non-Small Cell Lung Cancer Landscape

Medical oncologists envision a day when metastatic lung cancer can be treated as a chronic disease with a pill a day throughout life. But far more genetic testing of lung tumors is necessary to get these tailor-made treatments to everyone and to learn about other gene alterations that may respond to targeted drugs.

“Having what is essentially a designer treatment for you, an optimized treatment for you,” Tsao says, “is going to reduce the risk of unnecessary side effects, improve your outcome and improve your survival.”

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