Targeted therapies have made a huge impact on the treatment of cancer over the past couple of decades. Making a breakthrough in the 1980s, they work to identify and attack specific types of cancer cells by interfering with specific proteins that drive the growth of cancer cells. Doctors can test for these molecules, also known as molecular targets, by taking cells through tissue or liquid biopsies.

The first Food and Drug Administration (FDA)-approved targeted therapy for lung cancer, specifically, came in 2004 with Avastin (bevacizumab), which inhibits a protein that leads to tumor-associated blood vessels and is currently used to treat advanced colorectal, kidney and lung cancers. Additionally, there has been an explosion of knowledge from sequencing the DNA of many different cancer types to discover the many genes that are mutated, and the proteins encoded by these genes can drive tumor growth.

In this issue of CURE®, we explore targeted therapies further as they pertain to the human epidermal growth factor receptor 2 (HER2) protein in non-small cell lung cancer (NSCLC), which can be mutated or amplified in several tumor types and promotes cancer cell growth. This mutation affects about 2% to 4% of patients with NSCLC.

Of note, there is only one FDA-approved targeted therapy for the patient subset. Called Enhertu (trastuzumab deruxtecan), the drug treats patients with metastatic NSCLC that has progressed on chemotherapy. One expert featured in our issue hopes more targeted therapies for HER2 will be approved to give patients more personalized options. With this said, there are more targeted therapy drugs in clinical trials that could help this patient population. One such drug is a tyrosine kinase inhibitor called poziotinib, which targets the HER2 exon 20 insertion mutation. In our feature, we speak to a patient who enrolled in a phase 2 trial of the drug and has been participating since April 2021. While she has experienced some moderate side effects from the therapy, she is optimistic, as other treatment options led to either severe side effects or disease progression.

Highlighting the importance of participation in clinical trials, it is my hope that this field continues to grow the novel therapy for not only patients with lung cancer, but well beyond. It is critical that the public be aware of how research and clinical trials are catalysts to better the outcomes of patients with cancer.

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Editor's Page

It is my hope that the cancer field continues to grow the novel therapy for not only patients with lung cancer, but well beyond. It is critical that the public be aware of how research and clinical trials are catalysts to better the outcomes of patients with cancer.

Targeting Lung Cancer From a New Direction

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.”

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.

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.”

Feature

Targeted therapies offer new hope for patients with HER2-mutated non-small cell lung cancers.

Staying on Path: Targeted Therapies Are an 'Incredible Win' for HER2-Mutated NSCLC

Tislelizumab plus chemotherapy demonstrated clinically meaningful improvements in progression-free survival (the amount of time that a patient lives with cancer without disease worsening after treatment) versus standard of care chemotherapy as a first-line treatment for patients with stage 3B or 4 advanced squamous non-small cell lung cancer (NSCLC).

Of note, tislelizumab is not approved by the Food and Drug Administration, but there are ongoing trials looking into this monoclonal antibody checkpoint inhibitor.

According to Dr. Jorge J. Nieva, a medical oncologist and section head of solid tumors at USC Norris Comprehensive Cancer Center in Los Angeles, while the data presented don’t necessarily show anything new, these results foreshadow innovations like lower drug prices, which will benefit patients with lung cancer worldwide who may not have been able to afford the treatment otherwise.

“The development of these Chinese drugs is going to drive two things. It’s going to drive lower prices and it’s going to drive innovation,” he explained in an interview with CURE®. “It’s going to be easier for these Chinese firms to replicate Western clinical trial results with new antibodies. From my standpoint, these antibodies are all more alike than they are different. While many of us prefer to drink Coca-Cola or Pepsi, generic colas taste pretty similar. That’s effectively what we have here. This is going to require the drug manufacturers in the U.S. and Europe to begin to develop more innovation. ... These changes are all good for patients.”

In the study, patients received one of the following combinations:

A treatment regimen of tislelizumab plus paclitaxel (group A).

Tislelizumab plus Abraxane (nab-paclitaxel) and carboplatin (group B).

Standard-of-care chemotherapy with paclitaxel plus carboplatin (group C).

Findings showed that progression- free survival was longer in the groups that received tislelizumab. Specifically, for those with stage 3B disease, the median progression-free survival for group A was 9.8 months versus 5.6 months in group C. The median progression-free survival in group B was 11 months.

For patients with stage 4 disease, the median progression-free survival in group A was 7.6 months versus 5.2 months in group C; the median progression-free survival was 7.4 months in group B.

In terms of overall response rate (the number of patients who see a partial or complete response to therapy), patients with stage 3B disease demonstrated an overall response rate of 84.2%, compared with 82.5% in group B and 59.1% in group C. For patients with stage 4 disease, group A showed an overall response rate of 67.1%, compared with 70.9% in group B and 44.2% in group C.

Nieva said the outcomes associated with tislelizumab are similar to those of a common checkpoint inhibitor.

“This is generic Keytruda, and (patients) don’t need to think about it as anything more than that,” he said. “It’s a similar strategy in terms of drug selection (and) effect size. It’s another study of chemotherapy in combination with a PD-1 checkpoint inhibitor. It shows that adding a checkpoint inhibitor to chemotherapy makes it work better, so there’s nothing new to learn here. ... All we learned is that it doesn’t matter who manufactures the antibody; you’ll get a similar effect. And so to that sense, the only thing the study told us is that maybe someday prices will come down.”

The most common side effects across all groups included anemia, hair loss, decreased white blood cell count and low neutrophil count.

“There (are) a lot for patients who have high PD-L1 scores. They can be treated with a checkpoint inhibitor alone, ... with a checkpoint inhibitor plus chemotherapy (or) ... two checkpoint inhibitors and chemotherapy. All of these are options. And they all represent overwhelming advance over how we treated lung cancer patients 10 years ago that no matter which particular strategy is selected by a patient and their doctor, they know that anything that involves these — I could say almost miraculous class of drugs — is going to be giving them an opportunity for cure,” Nieva said.

He also added that he hopes that studies like this will push researchers in the U.S. to discover more innovative treatments, including subcutaneous formulations (drugs given as an injection) instead of intravenous ones (drugs given through the veins). He also said that this could lead to newer checkpoint inhibitors that may generate similar responses.

“There are a number of exciting new checkpoints that are going to come out and understanding how to use those checkpoints in an additive fashion with the current standards of care is going to be important,” Nieva said. “We’re going to have additional science around delivering these drugs and new delivery methods. Are these drugs safe enough to administer at home and self-administer? That’s going to be something that could potentially become a wave of the future for the checkpoint inhibitors, because I do see the drugs as actually being quite safe. Other innovations are going to come from understanding why some people don’t respond and trying to fix that so that they do.”

Research News and Updates

Recent results may lead to more checkpoint inhibitor options and lower treatment prices, giving accessibility to more patients with lung cancer worldwide.

A ‘Miraculous Class of Drugs’ to Increase Accessibility in Lung Cancer

Jerry Sanford retired to Naples, Florida, after a 29-year career as a New York City firefighter, but the city managed to call him back to help his brothers right before one of the most critical times in the history of the United States: 9/11. Although Sanford later developed cancer potentially associated with the fumes and toxins surrounding Ground Zero, he felt it was important to recount his experiences from the weeks leading up to and following 9/11 in his book, “It Started With a Helmet: A Retired Firefighter’s Return to New York City the Day Before 9/11.”

Within the pages of the book, which was published soon before the 20th anniversary of the attacks, readers will also find stories about Sanford’s time as a New York City police officer before starting with the city’s fire department, as well as his own diagnosis of adenocarcinoma, a type of lung cancer found in the glandular cells in the organ’s tissues, which likely developed from his exposure to the toxic air.

“It’s an appropriate title because it all started in Naples, Florida. How did a helmet from New York City get from the Bronx to Naples, and from Naples back to the Bronx? The book is all about that,” Sanford said in an interview with CURE®. “It’s a very slim novel, but it categorizes a little bit of my life when I was a police officer,
my story about 9/11 and then what happened, what (I did) after 9/11.”

After what he describes as “driving his wife crazy” for five months, Sanford found himself at the North Naples Fire District station for an interview with the chief for a public information officer position.

About a month into the job, Sanford was presented with an old New York City firefighter helmet that had been dropped off at the station in Florida. “(The chief) said to me, ‘We have an old New York City fire helmet here that a man brought in. It was his father’s, and he didn’t want it anymore,’” Sanford explained. He called Ladder 42, the company the helmet came from. The station was undergoing a renovation, so it was decided that Sanford would return it when the work was done in 2001.

On September 11, 2001, Sanford was flying from New York City back home to Naples with his wife, Maria. A few days before, he had come to return the old helmet to Ladder 42, and participated in a rededication ceremony for it. But two hours before he flew out of LaGuardia Airport, the world changed. The two planes had crashed into the World Trade Center, releasing about 24,000 gallons of jet fuel, at least 100,000 tons of organic debris and 230,000 gallons of transformer, heating and diesel oils. It wasn’t until he was changing planes in Pittsburgh that he learned what was happening.

“And at first, I didn’t comprehend. I thought it was a sightseeing plane or something. But then we got thrown off the plane and it was pandemonium in the airport. We then quickly tried to get a car and get out of Pittsburgh. And then we found out by listening to the radio that, in fact, the second plane had hit the second tower, (then) Shanksville and the Pentagon. So it (was) a very heavy day,” Sanford remembered.

Two weeks later, Sanford returned to Brooklyn to help. “And the job was just torn apart. We had lost so many men from so many different ranks,” he said.

Sanford was assigned to the press office, where he would handle the media and attend funerals of those rescue workers who had died in the chaos. He recalled: “I could go into the firehouse and cry and grieve, which I did with my brother firefighters, but the media ... you had to kind of keep them at bay because they were from all over the world. This was a worldwide story. It wasn’t just a New York City story.”

Sanford said he knew about half of the rescue workers who lost their lives that day.

“I thought, wait a minute, this can’t be New York City, this can’t be where I served for 30 years,” Sanford recalled. “And it was just a horrible experience seeing that, but you know what, you have to do it, you got to pull up your pants, you got to get out there and you have to do it. Because you know what? They would have done it for me. And that’s why I was there. Because the brothers, we don’t leave anybody behind. We get in there and as the thousands of people are exiting the World Trade Towers — we’re going in. I’m very proud of the role, my small role. Everybody played a role that day. Everybody has a story. But I’m very proud that I was able to come back to New York and help.”

After the towers fell, a giant, toxic cloud loomed over Ground Zero. For hours, days and weeks after, rescue workers — including Sanford — inhaled the fumes. Twenty years later, the impact of those fumes is still being felt. According to Cancer Treatment Centers of America, an estimated 2,000 responders and Ground Zero workers have died from diseases including prostate cancer, leukemia, thyroid cancer and lung cancer, possibly attributed to the fumes they inhaled on the site.

In addition, rescue workers who helped during the aftermath of 9/11 may have a 9% increased risk of receiving a cancer diagnosis.

In December 2007, Sanford was diagnosed with adenocarcinoma in his upper right lung. His oncologist at the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Florida, recommended a surgical approach. A recurrence in February 2008 of the same cancer in the lower left lung led to another successful surgery. “I went every year after that to my oncologist, and I had my CAT scan every year and everything was fine,” he explained.

But in 2012, the cancer returned. This time, his oncologist recommended extensive chemotherapy and radiation. “But God is good. I never got sick,” Sanford said.

Sanford has been cancer free since that year.

Twenty years ago, “we all came together as one neighborhood. Everybody was a New Yorker 20 years ago, helping everybody,” Sanford said. “But on the sad side, we keep losing firefighters and police officers every day from something that happened 20 years ago — from that cloud, that terrible cloud that we ingested, including myself. It took six years for (doctors) to detect it in me.”

to Jerry Sanford's full podcast episode here. 

Bookshelf

Twenty years after 9/11, a retired firefighter reflects on the weeks following the attacks, as well as his own diagnosis of lung cancer six years later, in a newly published book.

9/11 Firefighters and Unending Tragedy: 'Together as One Neighborhood'

Despite a decrease in lung cancer rates across the country, significant differences in disease rates and outcomes remain at the state level because of a variety of disparities, according to study results presented at the annual meeting.

In the presentation, Dr. Raymond U. Osarogiagbon, a medical oncologist at the Baptist Cancer Center in Memphis, Tennessee, discussed the geographic disparities in lung cancer mortality rates across the United States.

“We know that (lung cancer) is the oncologic challenge of our age. If one takes the perspective of the sheer cost in terms of human life, (it is) the No. 1 killer of men and women in the United States and in a lot of countries around the world. ... In the United States, the good news is it has been going down sequentially over time,” Osarogiagbon explained in an interview with CURE®. “The bad news, though, is in the United States, if you dug in a little bit deeper, you will find a very different picture. At the state level, if we disaggregated lung cancer as a cause of death, you will find a huge difference between the states ... with the cluster of highest per capita death risk in the Southern and Midwestern United States.”

States with the worst lung cancer mortality rates include Kentucky, Mississippi, Arkansas, Tennessee, West Virginia, Alabama, North and South Carolina and Louisiana, according to Osarogiagbon.

“At the county level, the difference is even worse,” he said, noting that there are some that have rising numbers of death due to lung cancer such as the Appalachian Regional Authority and Delta Regional Authority, while others have plateaued with no decrease.

Disparities that come into play include women and racial minorities being at a higher risk for lung cancer despite lower levels of tobacco exposure.

Dr. Kim Lori Sandler, an associate professor of radiology and radiological sciences and co-director of the Vanderbilt Lung Screening Program at Vanderbilt University School of Medicine in Nashville, Tennessee, emphasized that there are exposures other than smoking that can contribute to disparities. “We know that smoking is the No. 1 cause of lung cancer, but there’s also other causes. We know radon exposure and other types of exposures can be a cause of lung cancer. Certain populations are continuing to have those exposures like smoking and other high-risk exposures,” she told CURE®.

This is where the importance of lung screenings comes in, said Sandler, who was not associated with the study presented at the meeting. “The populations that were highlighted in the presentation, a lot of it looks at this Southeast region where we continue to have very high rates of smoking,” she said. “And unfortunately, our rates of lung cancer screening (in that region) have remained lower than other areas of the country, like in the Northeast. If you look at maps of the availability of lung cancer screening programs, you see them very highly localized in these Northeast centers where there are a lot of different programs available, and then when you get to the Southeast, they’re more spread out and patients need to travel further in order to be able to enroll in those programs.”

According to Osarogiagbon’s presentation, keeping up with yearly lung cancer screenings, which are usually covered by insurance, would reduce the risk of dying from the disease by 20%.

“It is from the point of onset on, whether it is finding (lung cancer) early, whether it is receiving optimal treatment for it, whether it is receiving the proper surveillance for it after diagnosis and treatment ... there are highly preventable differences,” he said. “It is people who live in parts of the world, or parts of the country that have resources that are organized in a certain way, who do well and not others. It is White people who do well, better than racial minorities. It is oftentimes when we’re talking about interventions themselves and access to them, it is men who do better
than women. And these are all things that are all necessary — things that significantly inhibit the full benefits of discovered innovations.”

The lack of screenings taking place in those states with higher cases of death from the disease may also lead to later-stage diagnoses. In this circumstance, that means that not as many patients with lung cancer will be able to be cured with surgery. For example, 50% of patients with lung cancer in Wyoming can be cured by surgery versus 90% in states like New Jersey, Massachusetts and Utah.

“If you drill further down and go to the county level, it’s even uglier than that. There are counties at the low end as low as 12% of patients with early-stage lung cancer that can be cured by surgery,” Osarogiagbon added.

Of note, the five-year survival rate of an early-stage lung cancer diagnosis is 90%. But once the disease enters late-stage, the five-year survival rate drops to 10% or lower. “Ideally, when we detect lung cancer, we’d love to find it at its earliest stage where we could cure a patient with a minimally invasive surgery, not requiring chemo- therapy or radiation therapy,” Sandler explained. “In our screening program, it’s unusual to say finding cancer is a win. But if you can find it that early, and truly offer a curative option for the patient, that’s an enormous victory for us.”

These disparities must be confronted with a multipronged approach, according to Osarogiagbon.

“We (need to) begin to focus on preventing, narrowing (and) eliminating disparities. We have to understand that the solutions come from multiple levels. The least effective is the level of directly hectoring, nagging (and) blaming the victims of disparities. (Patients) don’t go in with the idea that they will do something to hurt themselves. A (patient with) lung cancer who is poor does not stand up in the morning and decide, ‘Yippee, I am going to make sure I get the wrong treatment today. I don’t care if I die.’” he said. “When we talk about disparities, it is very important for (providers) to get away from the traditional, narrow lens of who are these people or why do they have such terrible outcomes, and recognize that we have seen the enemy. It is us.”

Sandler agreed with the outlook, emphasizing the need to banish the stigma around smoking and lung cancer, especially when other factors could be at play.

Because of this, Sandler believes that further investigation on eligibility for screenings and expanding eligibility to at-risk populations would make an impact, along with engaging further with communities to enhance outreach and education.

She noted that there have been some steps forward. “In terms of the disparities, the guidelines were just updated earlier this year, and they did decrease the age to 50 (and the pack-year smoking history) to 20, from 55 and 30, respectively,” she said. “And if you look at the recommendations from the (United States Preventive Services Task Force), they specifically say that this is to address disparities in the African American community and for women, because those are the populations that we’re really going to see an increase in eligibility. It’s not perfect. It’s a first step. But I think having that conversation and seeing the readiness of different organizations to accept new guidelines and continue to work on new guidelines is a really, really positive step forward.”

Looking deeper into mortality rates highlights the importance of eliminating disparities in lung cancer and expanding screening eligibility for at-risk populations.

Facing Disparities in Lung Cancer Mortality Rates

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.

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.”

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.”

Rapid Reporter

Two new FDA approvals for patients with lung cancer and EGFR exon 20 insertion mutations have given the subset its first targeted therapies.

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

Kris Munday was 10 years old when she smoked her first cigarette. Her friend’s mom had packs stashed in her purse and the girls smuggled them. By age 12, Munday was smoking regularly, and in her 20s, she was up to a pack and a half a day. When she moved to Sutherlin, Oregon, with her fiance and retired at age 35, her daily cigarette count doubled to fill the time.

“I no longer had to work in an office environment, which meant I had more time to smoke,” says Munday, a dog rescuer and breeder. “It had gotten so bad that I was waking up in the middle of the night to smoke.” To curb midnight cravings, Munday started wearing a nicotine patch overnight. But in 2014, when she was 45, she developed a horrific cough. Despite multiple rounds of antibiotics and half a dozen X-rays, doctors couldn’t get to the bottom of her coughing fits.

Within months, Munday developed debilitating fatigue and her cough became so aggressive her lungs partially collapsed. Doctors ordered two bronchoscopies at separate facilities to determine the cause of her symptoms, which showed that Munday had a pea-sized spot on her lungs. “I was hospitalized for unrelated gallbladder surgery and the pulmonologist came to my room and said, ‘Kristine, you have lung cancer,’” she remembers.

Lung cancer will affect an estimated 236,000 Americans this year, and cigarette smoking is the No. 1 risk factor for the disease, according to the Centers for Disease Control and Prevention. In the United States alone, smoking accounts for 80% to 90% of lung cancer deaths, with smokers up to 30 times more likely to die from lung cancer than those who are smoke free. The more years a person smokes and the more cigarettes they puff daily, the higher the odds of negative effects. But cigarettes aren’t the only culprit. Tobacco products, including e-cigarettes and cigars, also increase a person’s risk of lung cancer.

“Tobacco harms every organ and system in the body,” says Judith (Jodi) Prochaska, an addiction specialist with the Stanford Prevention Research Center in California. “It can affect wound healing, post-surgical outcomes and the metabolism of medications, including chemotherapy.” In fact, there’s evidence to suggest that nicotine spurs the growth of new blood vessels that feed cancerous tumors. So patients with lung cancer who continue to smoke after receiving a diagnosis are not only more vulnerable to a second lung cancer, but they’re also at higher risk of developing other cancers, such as head and neck, bladder, cervical, stomach and pancreatic.

To make matters more complex, nicotine is highly addictive. “Even patients who have quit smoking for years may crack under the pressure of a lung cancer diagnosis and return to cigarettes,” Prochaska says. To address these challenges, the National Cancer Institute (NCI) developed the Cancer Center Cessation Initiative in 2017 as part of then-Vice President Joe Biden’s Cancer Moonshot initiative. Since then, more than 50 NCI-designated cancer centers have implemented smoking cessation treatment programs.

Major cancer organizations, including the American Society of Clinical Oncology, the American Association of Cancer Research and the Association for the Study of Lung Cancer, say smoking cessation should be standard of care for patients with cancer — and for good reason. The benefit of quitting on survival rates is on par with emerging therapeutics for lung cancer. Unlike smoking cessation, these therapies could cost thousands of dollars and may not be accessible for the lion’s share of patients. But quitting smoking is possible for every smoker, and many smoking cessation resources are completely free for patients.

Charlie Thurlow was 57 when doctors told him he had stage 3B lung cancer. After months of coughing, weight loss, night sweats and eventually the collapse of his right lung, Thurlow’s doctor ordered a CT scan. “There was an 11-centimeter tumor across the top of my right lung,” says Thurlow, now 70 years old and retired from a publishing career in New York City. “And there was pain there, too. At times, I’d tried to wrap my chest with a knee bandage so I wouldn’t cough so deeply.”

Thurlow had been smoking at least a pack of cigarettes a day for 40 years (more during his college and graduate school years). By the time the pulmonologist said, “It’s cancer, and I think it’s curable,” he was struggling to light up. What had once brought him immeasurable pleasure was now producing excruciating pain. “For the last several weeks before the diagnosis, I was stretching one to two cigarettes over the course of a day because that’s all I could stand,” Thurlow remembers. “I’d light up, suck in a drag or two then snuff the thing out. I’d repeat the process with the same cigarette a few hours later. I could extract half a dozen such episodes from one cigarette.”

Fortunately, ditching cigarettes has an immediate impact on the immune system, producing a dramatic drop in the body’s natural inflammatory response after someone stops smoking. “Getting rid of that inflammatory load before surgery has a profound impact on treatment outcomes,” says Dr. Matthew Triplette, medical director of the Lung Cancer Early Detection and Prevention Clinic at Seattle Cancer Care Alliance in Washington state.

Plus, there’s strong evidence that people who quit smoking after a lung cancer diagnosis do better than those who don’t. “They live longer and they’re less likely to have a recurrence of the cancer after treatment,” says Dr. Nancy Rigotti, director of the Tobacco Research and Treatment Center at Massachusetts General Hospital in Boston. “They’re also more likely to tolerate the treatment and have fewer adverse events than those who continue smoking.” They also lower their risk for getting a second cancer associated with smoking such as head and neck or bladder cancer.

According to a 2021 study published in the Annals of Internal Medicine, of 517 patients with non-small cell lung cancer, patients who stopped smoking lived almost two years longer without disease recurrence compared with patients who continued smoking (6.6 years versus 4.8 years). Smokers who quit also had higher three- and five-year survival rates than those who kept at it. Other research, including a review of 10 studies consisting of nearly 11,000 patients for the 2020 Surgeon General’s Report, suggests that smoking cessation improves treatment outcomes and increases survival among patients with cancer. The longer a person goes without smoking, the lower their year-to-year risk of getting lung cancer becomes.

For the 40% to 50% of patients who are current smokers when they receive a lung cancer diagnosis, these findings may provide much-needed motivation to quit. “When smokers get a lung cancer diagnosis, they sometimes think that the worst has already happened, so why quit,” Triplette explains.

That was certainly the case for Thurlow, who quit smoking as soon as he found out he had cancer. Unfortunately, doctors weren’t sure they could operate because his tumor was attached to the chest wall, but after eight weeks of low-dose chemotherapy coupled with 15 rounds of radiation, the tumor had shrunk. Thurlow became a candidate for surgery to remove the remaining cancer. He went on a high-powered chemotherapy regimen following surgery to ensure the cancerous cells were gone, and he has been cancer free ever since.

While the perks of quitting are undeniable, walking away from nicotine isn’t easy. Like most addictions, smoking is entangled in a complex web of physiological and psychological factors. Studies show that about 70% of smokers want to quit, and in any given year, 55% of smokers try to do so.

“With each puff of a cigarette, the feel-good hormone dopamine floods your system, and that keeps you coming back for more,” Prochaska explains. “Plus, if you’re used to smoking when you’re drinking coffee or chatting on the phone, smoking becomes almost Pavlovian. You hear the bell; where’s the drug?”

Despite the massive tumor lodged in Thurlow’s chest and permanent pulmonary damage, he still reached for a nonexistent pack in response to a variety of triggers, such as a ringing telephone. “I had a nagging sense of a hole that I couldn’t fill, an itch that I couldn’t scratch,” he explains. Today, Thurlow is 12 years out and he still hasn’t entirely freed himself of these vague yearnings, and he still loves the smell of cigarette smoke when a waft comes his way.

“Preoccupation with my disease and mortality provided a distraction from withdrawal,” says Thurlow. “Psychologically, a belligerent attitude is an undervalued ally in the great battle, and defying my addiction went hand-in-hand with defying my disease. I had to satisfy myself (with the fact) that I was doing everything within my power to get well, and smoking would have violated that commitment. Smoking would also have betrayed the trust of everyone embracing the cause of my recovery — particularly my wife, but also my children and other family; my oncologist, radiologist, and surgeon; an army of nurses and social workers; and countless friends. Had I smoked, I’d have felt guilty. Not smoking, I could enjoy a clear conscience.”

Munday took a more methodical approach. A respiratory nurse at the hospital where she had gallbladder surgery coached her on how to quit. “She told me that a nicotine craving lasts only three minutes and that you can tolerate anything for three minutes,” she says. “She also explained that it takes three days for your body to adjust to a new level of nicotine. So if you gradually cut back each week, you can be done with cigarettes inside of a month.”

Armed with that information, Munday set out to be smoke free before her first chemotherapy treatment. Every five days, she took half a pack of cigarettes and set it aside, starting by dropping from three packs a day to two-and-a- half packs, and then from two-and-a-half packs to two. She also began chewing ice to fill the void of smoking cigarettes. “It took me three to four weeks to stop smoking completely,” Munday says.

Munday had tried to quit before. She even paid $900 for hypnosis sessions, but her attempt to quit lasted less than a month, in part because her fiance was also a smoker. This time, however, they kept a smoke-free zone on one side of their home, and she used a nicotine pen to take the edge off. “I used the pen part-way through chemotherapy and radiation and then just titrated down my use the same way I had with the cigarettes,” she says.

According to Triplette, a week or even a day without cigarettes before smoking again isn’t a sign of failure. Instead, it shows that they can break the biochemical addiction and be able to do it again. The threat of a cancer diagnosis may even make the idea of quitting more palatable. “Cancer is a teachable moment. Something profound that happens in your life that you can directly tie to a behavior,” says Triplette. “When you make that link for the patient, it can improve the success of their quit attempt.”

After receiving a lung cancer diagnosis, some people can quit more easily than they imagined because smoking becomes physically difficult. But many others struggle
to quit. Navigating cancer is stressful, and many turn to cigarettes when they’re stressed. Yet according to the 2020 Surgeon General’s Report, less than one-third of people who try to quit smoking use evidence-based smoking cessation treatments.

With smoking, there is a very addictive, habit-forming behavior in addition to a substance — nicotine — that is physiologically addictive. To address both parts of the equation, a growing number of comprehensive cancer centers are offering patients a full buffet of options, including evidence-based counseling approaches, medications to help reduce withdrawal symptoms and curb cravings, and nicotine replacement therapy. Cessation programs that combine counseling with pharmacotherapies show cessation rates up to 57% in the first six months after starting the program, according to some studies. “Each of these approaches can work alone but they work better when they’re combined,” Rigotti says.

To give patients who smoke the best shot, many cancer centers incorporate tobacco treatment into standard patient care unless a patient opts out. At Seattle Cancer Care Alliance, for example, patients who indicate they are current or former smokers are automatically connected with the smoking cessation team. They don’t have to worry about getting a referral for treatments like counseling and medication for tobacco dependence.

“Patients may be hesitant to share that they’re smoking or even that they’re former smokers, so we’ve worked hard to overcome barriers around stigma,” Triplette says.
Social workers can also help connect smokers and former smokers with support groups specific to patients with cancer who are trying to quit. Prochaska’s team even uses breath sample analysis to show former smokers how their CO levels have dropped to zero. “That can be motivating both for the patient and for those who are in the group,” she says.

Other avenues of support include the federal government-sponsored quit line (1-800-QUIT-NOW), where a tobacco counselor guides individuals through a quit process through telephone appointments. “Many free resources, including the quit line, also provide nicotine replacement therapies, such as patches, lozenges and gum, to help people quit smoking,” Rigotti says.

For many smokers, that support is critical, and it’s one reason Thurlow became a volunteer with the Cancer Hope Network, a nonprofit organization that matches patients to survivors by diagnosis and treatment. Although he was able to quit cold turkey, he recognizes that it is often harder for most and always suggests hospital-based cessation programs first. “But the best thing I can tell a match is that despite a dreary prognosis, I’ve been cancer free for 12 years, in no small part because I have had a team of supporters in my corner, including my wife and children.”

While Munday’s loved ones, friends and medical team applauded her efforts to quit smoking and reveled in her success, she didn’t have that same support at home. After four total weeks of chemotherapy and 37 rounds of radiation, Munday realized she couldn’t stay with her fiance. “He refused to stop smoking in our home and our cars,” she explains. “There were other reasons, too, but that was a huge one.” She ended the 18-year relationship and moved into her own place a few months after completing cancer treatment.

“When I went back to the oncologist two months shy of my five-year mark, he said, ‘You’re 100% cancer free,’” she says. That was a welcome turn of events for Munday, who was once told that her odds of surviving the disease were 20% to 30%. Could ditching cigarettes be the reason she survived? No one knows for sure. But there’s no doubt that going smoke free has given Munday a second lease on life.

Studies show that quitting smoking after a lung cancer diagnosis has a huge payoff for patients. Many smoking cessation programs in cancer centers have tools to help patients quit.

CURE^® Lung Cancer 2021 Special Issue 2

Targeting Lung Cancer From a New Direction

Staying on Path: Targeted Therapies Are an 'Incredible Win' for HER2-Mutated NSCLC

A ‘Miraculous Class of Drugs’ to Increase Accessibility in Lung Cancer

9/11 Firefighters and Unending Tragedy: 'Together as One Neighborhood'

Facing Disparities in Lung Cancer Mortality Rates

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

Programs May Help Patients Go Smoke-Free After a Lung Cancer Diagnosis

Latest News

CURE® Lung Cancer 2021 Special Issue 2

Targeting Lung Cancer From a New Direction

Staying on Path: Targeted Therapies Are an 'Incredible Win' for HER2-Mutated NSCLC

A ‘Miraculous Class of Drugs’ to Increase Accessibility in Lung Cancer

9/11 Firefighters and Unending Tragedy: 'Together as One Neighborhood'

Facing Disparities in Lung Cancer Mortality Rates

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

Programs May Help Patients Go Smoke-Free After a Lung Cancer Diagnosis

Latest News

CURE^® Lung Cancer 2021 Special Issue 2