Jeannette Moninger

When Penny Isop was diagnosed with chronic lymphocytic leukemia (CLL) in July 2012, her doctor said it was a “good cancer” to have. Isop, then 65 years old, didn’t see it that way. She and her partner, David Needle, had recently relocated from Atlanta to Mount Pleasant, South Carolina, since they “needed a slower pace,” Isop says. She took a part-time job at a travel agency, where she worked until her diagnosis. 

“I didn’t feel good about having cancer,” Isop recalls.

Penny Isop’s cancer team recommended BTK inhibitors after her white blood cell count tripled.

In fact, things weren’t good. Some people who receive a new CLL diagnosis can take a watch-and-wait approach, starting treatments only if the cancer progresses or symptoms worsen. This is because CLL is not generally curable but can be treated and even put into varying degrees of remission, where treatment may not be needed for some period of time. 

However, within a month of her diagnosis, Isop was getting blood transfusions to treat stage 3 or 4 CLL. She was so fatigued and out of breath that the mere act of walking to her car was a struggle.

A subsequent bone marrow biopsy and gene test showed her CLL cells were missing part of the 11th chromosome (what’s known as CLL with an 11q deletion). This meant the cancer was more aggressive and less likely to respond to chemoimmunotherapy, the standard first-line treatment at the time. The test results also demonstrated that the CLL had an unmutated IGHV status, which is a molecular marker that’s typically linked with poorer prognosis and shorter survival.

Isop’s prognosis wasn’t as good as the doctor thought.

In October, Isop sought the advice of a New York City hematologist oncologist. “He said I was a perfect candidate for a clinical trial,” recalls Isop, “but I needed to be in New York for at least four months for treatment and monitoring.” She and Needle moved into an American Cancer Society Hope Lodge, which provides free housing for adults getting cancer treatments.

As a participant in the phase 2 ThRiL trial, Isop received alternating treatments of three immunotherapy drugs: Rituxan (rituximab), Revlimid (lenalidomide) and thalidomide. Her response to the treatments was remarkable, with the cancer quickly going into remission.


The trial followed a scheduled dose reduction, with Isop eventually taking just Revlimid every other day until the trial ended in December 2020.

“The hope was that the cancer would stay in remission after I stopped treatment,” Isop says.

At first, Isop’s blood labs looked promising. But by the end of the year, her white blood cell count had tripled, a sign the cancer cells were multiplying again. That’s when her doctor recommended an oral-targeted therapy known as Bruton tyrosine kinase (BTK) inhibitors.

 target and block an enzyme called Bruton tyrosine kinase. 

“This enzyme transmits signals that promote the survival and uncontrolled growth of leukemic B-lymphocytes,” says Dr. Shuo Ma, a hematologist oncologist at Northwestern University’s Robert H. Lurie Comprehensive Cancer Center in Chicago. “BTK inhibitors cut off the signaling pathway, leading to leukemia cell death and disease remission.”

Imbruvica (ibrutinib) was the first BTK inhibitor to receive approval from the Food and Drug Administration (FDA). But that November 2013 approval was for mantle cell lymphoma, a rare and aggressive blood cancer. Three months later, in February 2014, the FDA approved the drug for CLL, but only for those who had tried at least one other treatment. In July, it extended the approval to those who had CLL with a 17p deletion, another difficult-to-treat form of CLL.

 FDA approved Imbruvica as a first-line treatment for all patients with CLL

. The approval came after a phase 3 clinical trial showed the drug to be superior to chemotherapy in stopping disease progression and extending longevity. A few months later, the FDA approved the drug for small lymphocytic lymphoma (SLL), a blood cancer almost identical to CLL.

The approval of a BTK inhibitor for CLL was a game changer for the more than 200,000 Americans living with the disease as well as the 18,000-plus people who will receive a CLL diagnosis this year. 

“Imbruvica made an incredible impact for patients with CLL,” says Dr. Ian W. Flinn, director of lymphoma research for the Sarah Cannon Research Institute at Tennessee Oncology in Nashville. “People very sick with CLL who received this treatment oftentimes had near-complete resolution of their symptoms, including severe fatigue, fever and night sweats. They were able to enjoy life again.”

Still, Imbruvica, like all cancer treatments, has side effects. Among them: easy bleeding and bruising, anemia (low red blood cells), neutropenia (low neutrophils or white blood cells), fatigue, muscle and joint pain, diarrhea and respiratory infections. 

It wasn’t until thousands of patients had taken the drug for years that another, more alarming side effect — atrial fibrillation (AFib) — became apparent. This heart rhythm problem (arrhythmia) can cause potentially life-threatening blood clots, strokes, heart failure and other cardiac events. Studies now show that people who take Imbruvica are 10 times more likely to develop AFib.

“CLL predominantly affects people in their 60s and 70s, an age group that’s more prone to heart problems,” says Flinn. “It took a while to connect that the drug was also a contributing factor to arrhythmias.” 

Imbruvica is meant to target the BTK enzyme. But for reasons that aren’t clear, the drug sometimes homes in on and damages healthy enzymes critical for heart function. AFib may occur within a few months of starting the drug or years into treatment. An estimated 4 in 10 people stop taking Imbruvica because of adverse side effects, about 4% of them heart related.

Not everyone who takes Imbruvica for CLL develops an arrhythmia. Dr. Reshma Ramlal, a hematologist oncologist at the University of Kentucky Markey Cancer Center in Lexington and interim director of the center’s Bone Marrow Transplant and Cellular Therapy Program, has patients taking the treatment for years with great success and no heart issues. 

“The good news for those who develop AFib is that the condition typically goes away when you stop the drug,” she says. “And it doesn’t appear to cause long-term heart damage.”

Even better news: Recent studies show that newer second-generation BTK inhibitors are more effective at treating CLL, and they’re less likely to affect the heart.

In April 2018, Dayton, Ohio, resident Brenda Duggins enrolled in a clinical trial for one of the newer BTK inhibitors, Calquence (acalabrutinib). The trial combined the drug with two other targeted therapy drugs, Rituxan and Venclexta (venetoclax). At the time, Calquence had FDA approval for mantle cell lymphoma (just as its predecessor Imbruvica had started out), but not CLL, and tends to have fewer side effects than Imbruvica.

Duggins was aged 62 years when she learned she had CLL in June 2012. By October, the disease had her feeling so poorly, she could barely leave her bed. Her doctor started her on an intensive 12-week combination treatment of Rituxan and the steroid Solu-Medrol (methylprednisolone), which kept the cancer in remission for five years. When blood tests showed an uptick in CLL cells, Duggins enrolled in the Calquence clinical trial.

Brenda Duggins’ blood work has shown no signs of CLL since starting treatment with a BTK inhibitor.

Per the trial’s protocols, Duggins stopped taking Rituxan after five months and Venclexta after one year. But she continued with Calquence, the BTK inhibitor, until September 2022. Since 2020, her bloodwork has shown no signs of CLL. 

“The doctors think the cancer is in a deep remission,” says Duggins, who experienced no adverse heart events. The FDA approved Calquence for the treatment of CLL and SLL in November 2019.

Calquence was also the BTK inhibitor that Isop’s doctor recommended. But the medicine triggered headaches so severe that she couldn’t function. While headaches are a known potential side effect, they’re usually not debilitating. In July 2022, her doctor recommended a different and newer BTK inhibitor: Brukinsa (zanubrutinib).

FDA approved Brukinsa in 2019 for mantle cell lymphoma

 and again in 2021 for marginal zone lymphoma and Waldenström macroglobulinemia. But experts were still tabulating results from clinical trials of Brukinsa for CLL/ SLL when Isop began taking the drug off label. Previously, Isop had told her doctor she wasn’t interested in taking Imbruvica because of the risk of AFib. 

“I was grateful there was another treatment option,” she says.

Isop was on Brukinsa for less than six months when it received 

. The January 2023 approval came after two global, randomized, phase 3 clinical trials showed the drug to be more effective than other CLL treatments and with less risk of serious side effects like AFib.

Findings from the ALPINE trial released in December 2022 showed a superior progression-free survival rate (time during and after treatment that a patient lives with cancer without worsening) as well as an overall response rate (patients with a partial or complete response to therapy) of 80% for Brukinsa compared with Imbruvica (73%) in people with relapsed or refractory CLL/SLL. 

There were more than twice as many AFib incidents on Imbruvica compared with Brukinsa. Six study participants died of cardiac events while taking Imbruvica, while there were no cardiac deaths among those on Brukinsa. The trial also found Brukinsa to be more effective at treating CLL with chromosomal deletions and gene mutations.

The SEQUOIA clinical trial compared the use of Brukinsa as a frontline CLL treatment over two years to a more commonly used combination treatment of Rituximab and the chemotherapy drug Treanda (bendamustine). The study found that Brukinsa offered an 86% progression-free survival rate at 24 months versus 70% for chemoimmunotherapy.

“People with harder-to-treat CLL with chromosomal deletions also fared better,” says Flinn, one of the study’s authors, who noted there were also fewer incidents of AFib. “Second-generation BTK inhibitors appear to be more selective at targeting only the BTK enzyme and not healthy enzymes that aid heart function.”

There are no studies underway to directly compare Brukinsa and Calquence. Instead, researchers are focused on developing new CLL treatments, such as third-generation BTK inhibitors that can overcome drug resistance, combination therapies that pair BTK inhibitors with BCL-2 inhibitors like Venclexta or other drugs, CAR-T cell therapies and treat- ments for Richter transformation (Richter syndrome), an aggressive and hard-to-treat lymphoma that develops in as many as 1 in 10 people with CLL.

“There have been so many advancements in CLL treatments since my diagnosis more than a decade ago,” says Isop, who is back to enjoying her retirement, traveling to Portugal and Mexico last fall. At the start of this year, she received the best blood lab results since the CLL diagnosis. “I try not to waste time worrying about the cancer coming back. I’m confident there will be a new treatment or clinical trial when I need it.”

For more news on cancer updates, research and education, don’t forget to 

Articles

Bruton tyrosine kinase inhibitors have changed the space for treating patients with CLL or SLL, with more on the way to potentially address drug resistance.

BTK Inhibitors Offer a Revolutionary Treatment of Relapsed CLL/SLL

When Aleah Hockridge was undergoing cancer treatments in spring 2015 for stage 3a breast cancer, the then 31-year-old resident of Santee, California, longed to hear the words “no evidence of disease.” 

Aleah Hockridge, a survivor of stage 3a breast cancer, says that she longed to hear that her cancer was gone. However, the California resident, explains that she has anxiety that her cancer may recur every time she faces a big change or life decision.

However, when those words finally came 15 months later, Hockridge didn’t breathe a sigh of relief. Instead, she worried — a lot.

“For the first two years, I couldn’t shake the idea of the cancer coming back or spreading."

Even hitting the five-year milestone in February 2020 didn’t ease Hockridge’s fears. “I never feel like I’m out of the woods,” she says. “I don’t know if I’ll ever feel like this is behind me.”

It’d be hard-pressed to find a cancer survivor who hasn’t occasionally pondered their vulnerability to a cancer recurrence or metastasis. 

Although many individuals eventually move past this worry, some survivors develop what experts call a fear of cancer recurrence (FCR). Their persistent worries, fears and anxiety consume their thoughts, negatively affecting their ability to get on with their lives. 

This preoccupation about a cancer recurrence makes them hypervigilant to any physical symptoms that hint that the cancer is back or progressing.

“Fear of cancer recurrence is more intense and persistent than ‘scanxiety,’ which goes away after a scan. It’s also different from post-traumatic stress disorder, which causes you to relive past events,” says Heather Jim, a clinical psychologist at the Moffitt Cancer Center in Tampa, Florida. 

“A survivor with fear of cancer recurrence ruminates about future events they have no control over. Even though a recurrence may never happen, they can’t break free from this cycle of worry.”

As many as 2 in 3 cancer survivors have FCR, according to findings from a 2022 study published in the 

Hockridge says that she is grateful to be marrying her fiance, Brandon La Flair, but notes that she still worries that her breast cancer may come back.

Despite its pervasiveness and the fact that this fear has certainly plagued some survivors, it wasn’t until the early 2000s that experts recognized FCR as one of the biggest unmet needs among cancer survivors. 

That’s when a panel of psychosocial-oncologists developed a Fear of Cancer Recurrence Inventory (FCRI). This 42-item questionnaire uses a scale of 0 (not significant) to 4 (very significant) to determine how a person thinks about a cancer recurrence. There’s also the FCRI-Short Form (FCRI-SF), with nine questions. 

For researchers, the FCRI provides a uniform way to measure FCR among survivors. It also gives clinicians a tool to gauge when a person needs help.

Normal or low levels of FCR can also be helpful, as they may motivate a survivor to get follow-up scans and examinations and make healthy lifestyle changes such as exercising more or changing their diet. 

It’s those with clinically significant results who worry Sophie Lebel, a clinical psychologist and professor of psychology at the University of Ottawa in Canada. 

“The more severe the fear — meaning an almost daily preoccupation with cancer recurrence — the greater the negative impact on quality of life,” Lebel explains. “Studies, including my own, show a strong correlation between clinical fear of cancer recurrence and depression, anxiety, distress and post-traumatic stress symptoms (such as) hypervigilance, intrusive thoughts and panic attacks.”

Lebel says she often sees patients who have adopted a what’s-the-point attitude. 

“They’re unable to plan a vacation, return to work or buy new clothes for fear that cancer will interfere with their plans.”

Anyone on the receiving end of a cancer diagnosis can experience FCR, regardless of gender, race, cancer type, stage or prognosis. But results from a study published in the 

 suggest that the fear and its impact may be greatest among young adult cancer survivors. 

“Perceiving a greater number of years ahead of them may be interpreted as more opportunity for the cancer to come back or spread and a greater burden to remain cancer free,” explains Maurade Gormley, an assistant professor at the University of Connecticut School of Nursing in Mansfield.

Gormley’s studies on genomic testing for risk of recurrence among hormone receptor-positive breast cancer survivors found that those with a greater risk of recurrence had higher FCR; however, some still had a disproportionately high level of fear, even when their genomic test results indicated a low risk of recurrence. 

“Factors such as how the individual perceives their illness and its consequences may be more important than their objective risk of recurrence,” she says. “This suggests that patients with cancer may benefit from closer follow-up of their emotional response to diagnostic and prognostic testing, regardless of their individual risk of recurrence.”

This need for improved communication is especially crucial when a patient transitions from active treatment to survivorship. 

“I wasn’t prepared for what life would be like when the routine of scans, treatments and doctor visits ended,” says Keith Tolley, a resident of Warwick, Massachusetts. 

Tolley was 61 years old in June 2017 when he was diagnosed with stage 3 melanoma. A year and a half later, the cancer spread to his liver and then to other areas. He underwent surgeries, an immunotherapy clinical trial, radiation therapy and additional immunotherapy treatments, scans taken in July 2020 showed a complete response to the treatments. 

After his treatments ended, Tolley found himself occasionally struggling with the loss of security he felt while receiving regular medical care. 

“It can be a struggle to shake that feeling of vulnerability and fear,” he says. “Early on, there were times when I would wake up in the middle of the night, worrying about the cancer coming back.”

Sleep problems, fatigue and pain are common issues among individuals with FCR. These symptoms can drive them to see their doctors more often, seeking reassurances that everything is OK. These actions can unnecessarily fuel anxiety and lead to higher health care expenses. 

After Hockridge had a couple of scans to look for the source of back pain that she was sure was metastatic bone cancer (it wasn’t), she made a new rule. 

“I track any unusual symptoms in a journal for two weeks and only call my oncologist if the symptoms worsen or don’t go away.”

When thoughts of a cancer recurrence become so intrusive that they affect the ability to function, enjoy life or plan for the future, mental health counseling can help. 

Studies suggest that clinically significant FCR won’t get better over time without treatment, and one of the most effective treatments is cognitive behavioral therapy (CBT).

When anxiety from the fear of cancer recurrence takes over, Keith Tolley says he finds talking to someone in his support system, like his wife Esmeralda Tolley, to be helpful. 

“(CBT) gives you the tools to change negative thought patterns by breaking down what makes you anxious or scared and finding healthy ways to think about and manage them,” says Lynne Wagner, psychologist and professor of social sciences and health policy at Wake Forest University School of Medicine in Winston-Salem, North Carolina, who is conducting research on effective treatments for fear of recurrence.

One way to do this, Wagner says, is by scheduling worry sessions. 

“You set aside five to 10 minutes every day for three weeks to think about your fears and how you would handle a situation, should it come true,” she says. “Push aside any fears that crop up outside the session (or write them down) until it’s worry time. You decide when you’re going to worry. The sessions challenge the idea that worrying gives you control over a situation or its outcome. You learn to say, ‘Let me focus on what I can control’ whenever intrusive thoughts creep in.”

Wagner also teaches her patients how to use diaphragmatic breathing exercises at the end of each worry session to help ground them. 

“Deep breathing, mindfulness and meditation are great tools for coping with fear of cancer recurrence,” she says. “In some ways, a worry session is a type of mindfulness. The goal isn’t to change a thought but to become more comfortable with it.”

Facing his fears head-on is one way Tolley copes. 

“I analyze a fear to figure out what I’m feeling and why,” he explains. “I try to determine (whether) this fear is driven by something I can or cannot control and whether it’s based on what is actually true or what I’m imagining to be true.”

Tolley also sticks to a commitment he made to himself to never go through this journey alone. “When I can’t shake fear or anxiety, I talk to someone in my support system,” he says. “(Often), just verbalizing the fear to someone else takes away its power.”

Tolley learned some of these strategies through a survivorship program at his cancer center. But many centers, and even cancer specialists, are just now recognizing the importance of talking to cancer survivors about FCR. 

Psychosocial-oncologists are encouraging a two-pronged approach to raise patient awareness about FCR. 

The first step involves educating patients during and after treatments about the signs of clinical FCR and when to seek help. This educational step also includes making sure patients understand their actual risk of recurrence based on their unique diagnosis and what signs to look for. 

The second step encourages cancer care teams and primary care physicians to use the FCRI to identify those who need help.

However, finding that help may still be a challenge, Lebel admits. 

“This is still a developing field, so it’s often difficult to find a therapist who has experience helping people overcome this fear,” she says. 

If your cancer center doesn’t have a social worker or therapist who can help, Lebel recommends looking for a provider who specializes in treating anxiety and depression with CBT and mindfulness techniques. 

“There’s strong evidence that these interventions help, and you don’t need a lifetime of therapy,” she explains. “Many people see improvements after doing six weeks of once-a-week group sessions, or you can do personal sessions or even teletherapy.”

Hockridge tried teletherapy sessions during the height of the pandemic but decided they weren’t for her. “I’ve found some healthy ways to cope, like yoga, mindfulness and challenging myself to try new things like surfing and kayaking,” she says. “It’s been a lot of trial and error, and I still struggle.”

That struggle intensified this year while Hockridge was planning her fall wedding. 

“The fear of cancer recurrence comes back anytime I’m faced with big life decisions or changes,” she says. “I’m so grateful that I’m here to marry my soulmate and celebrate with our families. And yet, I have thoughts like, ‘Should we be spending money on a wedding if we need it to pay for future cancer treatments?’” Hockridge likens her fear to an invisible boulder hanging perilously from a rope above her head. 

“I try to pretend it’s not there because when I look up, the rope looks more frayed,” she says. “I fight the urge to look. Instead, I do what I can to cultivate joy, reduce stress and keep my eyes focused on the future. I must choose to believe that the boulder won’t come crashing down.”

Cognitive therapy, teletherapy, journaling and taking up other daily
activities may help cancer survivors overcome their fear of recurrence.

Getting Out of the Woods: Strategies to Cope With Fear of Cancer Recurrence

Atlanta resident Gwen Cesta-Persichetti was visiting family in New York City in July 2020 when she started coughing up blood. 

“I attended my nephew’s graduation party and then headed to the nearest urgent care,” says Cesta-Persichetti, who was 64 at the time. “I thought I might have pneumonia or perhaps a blood clot from traveling.” 

But imaging scans showed she had stage 4b lung cancer that had spread to her brain, spine and lymph nodes. 

Cesta-Persichetti was no stranger to cancer. Fifteen years earlier, she had a double mastectomy to treat stage 1b breast cancer. The surgery was followed by five years of Arimidex (anastrozole), an endocrine therapy for hormone receptor-positive breast cancers. 

“I knew I could handle the cancer treatments,” says Cesta-Persichetti. “It was the stage 4 diagnosis that scared me.” Both her parents had died within six months of receiving stage 4 cancer diagnoses; her mother had breast and lung cancer and her father had prostate cancer. “I didn’t see how anyone could survive cancer in the lungs, brain and spine for very long,” she recalls. “I cried when I realized I might not see my daughter get married the following year.”

Gwen Cesta-Perschietti said that the treatment targeting her KRAS G12C mutation stabilized the lung cancer and allowed her to make it to her daughter’s wedding.


The oncologist Cesta-Persichetti met with in New York had a different perspective. A biopsy of the lung tumor showed that Cesta-Persichetti had non-small cell lung cancer (NSCLC), the most common type of lung cancer. Genomic testing on the tumor also showed the cancer was caused by a gene mutation called KRAS G12C (short for Kirsten rat sarcoma viral oncogene homolog). For decades, this mutation was considered untreatable. 

But a new drug designed to target the aberrantly active RAS protein encoded by the mutant KRAS gene being tested in clinical trials — Lumakras (sotorasib) — was showing tremendous promise in treating KRAS G12C-mutated NSCLC. Cesta-Persichetti’s doctor thought she was a perfect candidate. 

After radiation therapy to shrink the tumors in her brain, Cesta-Persichetti began taking Lumakras in August 2020. She noticed improvements almost immediately. 

“Within 10 days, I could take a deep breath without coughing,” she recalls. “In fact, I stopped coughing altogether.” 

Imaging scans four weeks later showed a noticeable decrease in the size of the tumors in her lungs and lymph nodes.

More than 120 other participants in the national CodeBreaK 100 clinical trial, which began in 2018, experienced similar results. The Food and Drug Administration (FDA) took notice, giving the drug breakthrough therapy designation in December 2020 and moving it quickly through the approval process. On May 28, 2021, the 

FDA approved the drug as the first targeted therapy

KRAS (pronounced KAY-ras) is a group of genes that help control how cells grow and divide. It is the most frequently mutated gene leading to the development of cancer (what cancer specialists call an oncogene). A mutated KRAS oncogene makes abnormal proteins that fuel the growth and spread of cancer cells. 

There are different KRAS subtypes, with the G12C subtype linked to not just lung cancer but as many as 3% to 5% of colorectal cancers as well as cancers of the pancreas, endometrium and appendix. 

“The KRAS G12C mutation drives lung cancer growth and is associated with poor outcomes with higher rates of relapse, shorter progression-free survival (time during and after treatment when the patient lives without disease progression) and diminished overall survival (time from diagnosis or treatment start when patients are alive) compared (with) other types of lung cancers,” says Dr. Bob Li, a medical oncologist and physician-scientist at Memorial Sloan Kettering Cancer Center in New York City. 

For reasons that are not clear, White women, Asian males and people who are Black are more likely to have this mutation. The altered gene is not something you are born with, so you cannot pass it to future generations. 

“There are some inherited mutations in RAS pathway genes that can lead to rare developmental syndromes known as RASopathies. However, KRAS G12C isn’t one of them,” explains Dr. Ferdinandos Skoulidis, associate professor in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston. 

“KRAS G12C is a somatic mutation, which means something happens after you’re born that changes the DNA in the tissue that becomes cancerous,” he says. “We typically see this mutation in people who have a history of smoking.” Skoulidis calls tumors with KRAS mutations “one of the worst ones to have because up until now there have been no effective targeted therapies.” 

KRAS G12C-mutated tumors are resistant to other treatments like EGFR inhibitors. Some people with KRAS G12C-mutated NSCLC may respond to immunotherapies like Keytruda (pembrolizumab) or a combination of immunotherapy and chemotherapy. But for those whose tumors do not respond or relapse, the outlook was often bleak. 

Researchers first identified the KRAS G12C mutation as a driver of NSCLC in 1982. They would spend nearly 40 years searching for a way to stop it. 

“The KRAS protein encoded by the gene is round and smooth, which makes it very difficult for a drug to bind to it,” says Li. 

For three decades, the KRAS G12C mutation was deemed undruggable and therefore, untreatable. And then, in 2012, researchers made a remarkable discovery.

Hope For People With KRAS G12C-Mutated NSCLC 

The development of Lumakras and another promising drug, adagrasib (which received FDA breakthrough therapy designation in June 2021), was made possible after researchers located a hidden pocket or groove in the KRAS G12C protein that only exists when the protein is inactive or dormant. The drugs target these inactive proteins, working their way into the pocket and binding to the protein. 

“The drugs essentially lock the protein in an inactive state,” says Dr. Hatim Husain, a medical oncologist who treats lung cancer at Moores Cancer Center at UC San Diego Health. “Once that happens, the protein can’t send the signals that cause cancer cells to multiply. Cancer cells start to die, causing tumors to shrink.” 

In the CodeBreaK 100 clinical trial, Lumakras stopped tumor growth for 8 in 10 people. For 1 in 3 participants, the tumors got substantially smaller. The drug kept tumors stable for at least six months, with a median overall survival time of 12 and a half months. Results from phases 1 and 2 of the KRYSTAL clinical trial of adagrasib are also encouraging. More than 40% of participants saw tumor shrinkage, whereas close to half had disease stabilization. 

The Lumakras treatment involves taking eight 120-milligram tablets each day (for a total of nearly 1 gram). Clinical trials are underway to see whether a lower dose might be equally effective. About 2 in 3 people experience manageable medication side effects like diarrhea, nausea, fatigue and muscle or bone pain.

Because elevated liver enzymes are a potential complication, people who take Lumakras need regular tests to assess liver function. 

Although Cesta-Persichetti saw tremendous improvements while taking Lumakras, she was only able to take the drug for about five weeks. “My lungs looked great, but the tumors in my brain and spine kept growing,” says Cesta-Persichetti, who now receives Keytruda infusions every three weeks. 

Still, she credits Lumakras with stabilizing the lung cancer and helping her be around to dance at her daughter’s wedding this past December. Cesta-Persichetti considers herself fortunate. At the time of her diagnosis, she had access to top cancer specialists in New York who knew to test for the KRAS G12C mutation. They also knew how to connect her with a clinical trial near her home in Atlanta. 

“Unfortunately, many people with NSCLC still don’t get molecular testing to check for targetable gene mutations,” says Husain. “There’s a need for better education about genomic tumor testing among patients and their doctors.” 

After advocating for herself, Laurie Seligman said she felt like she won the lottery and benefited from a newly approved therapy targeting the KRAS G12C mutation.

Advocating for Genomic Testing of Lung Tumors

Laurie Seligman, a 61-year-old resident of Palmetto, Florida, took it upon herself to learn all she could about NSCLC after receiving a stage 3a diagnosis in January 2018. Her initial treatment included multiple rounds of chemotherapy and radiation therapy followed by Imfinzi (durvalumab). 

It was at a LUNGevity Foundation Hope Summit in 2019 that Seligman first heard the words KRAS and genomic testing. 

“When I asked one of the doctors in attendance whether I should get tested, he said I didn’t need it unless the cancer progressed,” Seligman recalls. 

But in September 2020, scans found a mass in a lymph node near her clavicle. Before getting the biopsy that would confirm the cancer had spread, Seligman asked her doctor if they could test the tissue for gene mutations. When the tissue sample turned out to be too small for genomic testing, Seligman asked for a blood test. 

“My doctor tried to dissuade me because insurance companies don’t always cover the costs of tumor testing,” she says. 

Depending on the test, costs for genomic testing can range from $300 upwards to $10,000. Test results showed Seligman had the KRAS G12C mutation. 

“I was excited because I had some knowledge of KRAS. When I heard it was the G12C subtype, I felt like I won the lottery!” she says. “An oncologist I saw for a second opinion had told me there were clinical trials underway to find a treatment for this genetic mutation.” 

Seligman, who was living in San Antonio at the time, decided to move to Florida to be closer to family. 

“I also thought I might have better access to clinical trials in Florida,” Seligman says. The process of moving took all of Seligman’s strength. “I couldn’t pack one box without stopping to rest,” she says. 

Soon after she relocated to Florida, a trip to an urgent care showed her right lung had collapsed. After undergoing treatment, Seligman started the combination immunotherapies Opdivo (nivolumab) plus Yervoy (ipilimumab). But after receiving just two infusions at the start of 2021, she was hospitalized for almost a month with pneumonitis, a lung inflammation.

After her hospitalization, Seligman learned that since the cancer was now stage 4, she was eligible for the CodeBreaK 100 trial. 

“I started the paperwork in May to enroll in a trial that was getting underway at the Moffitt Cancer Center in Tampa,” says Seligman. Two days before she was scheduled to get a tumor biopsy (the last step before starting the clinical trial) the FDA granted full approval to Lumakras. “Again, it felt like winning the lottery,” she says.

Seligman started taking Lumakras towards the end of June in 2021. 

“My cough seemed better in just two days, but I thought I was imagining it. It seemed too soon to notice any health changes,” she recalls. But in two weeks, her cough was gone. “It had been a long time since I could have a conversation without getting winded or having a coughing fit.”

Her first imaging scan at five weeks showed a significant reduction in the size of the lung tumors. By the third scan on Jan. 6 of this year her doctor said, “For all intents and purposes, you’ve had a complete response to the drug.” 

Seligman didn’t know exactly how to interpret those words, but an internet search suggested she was in remission. 

“I still can’t believe it,” Seligman says. “A year ago, my prognosis was terrible, and now I’m in remission. I know the drug could stop working at any time. I have to hope that if that time comes, there’s another drug — one that’s probably in clinical trials right now — that will help.”

The KRAS G12C gene mutation in non-small cell lung cancer has been deemed “undruggable,” but recent effective therapies have successfully targeted this mutation, leading to shrinking of tumors and longer survival.

KRAS G12C Lung Cancer: New Therapies Treat the 'Undruggable'

The brain isn’t the part of the central nervous system where primary cancers spread.

Studies have shown that for up to 5% of people, cancer moves to the cerebrospinal fluid that surrounds the brain and spinal cord or to the brain and spinal cord lining (called the leptomeninges). The condition, known as leptomeningeal disease or leptomeningeal carcinomatosis, most commonly affects those with melanoma, lung cancer or breast cancer.

Because the cancer cells float freely in the cerebrospinal fluid, the disease quickly spreads throughout the central nervous system, leading to an approximate three-month survival rate after diagnosis.

“People have tumor cells in the brain, as well as the fluid and tissue that coat the brain and brainstem,” says Dr. Chetan Bettegowda, a Jennison and Novak Families Professor of Neurosurgery at Johns Hopkins Medicine in Baltimore.

Symptoms are similar to brain metastases but may also include facial or other muscle weakness or pain, difficulty swallowing, double vision and difficulty thinking clearly. The number of people developing leptomeningeal disease is increasing for the same reason that diagnoses of brain metastases are on the rise: 

, giving cancer more time to spread. Doctors use MRIs and spinal taps (lumbar punctures), to make a diagnosis.

Treatments have been limited to radiation therapy to shrink tumors and intrathecal chemotherapy delivered directly into the spinal fluid through a small, quarter-sized port called an Ommaya reservoir implanted underneath the skin on the scalp. Less commonly, chemotherapy is injected into the fluid via a spinal tap procedure. These treatments, however, are considered palliative — they ease symptoms but won’t stop the disease. Clinical trials are underway to identify molecular changes to primary cancer cells that may signal a higher risk of leptomeningeal disease.

This new knowledge could lead to the use of 

targeted therapies to treat metastatic cancer

 and prevent it. Ongoing trials are also showing encouraging results of immunotherapy and certain targeted therapies.

most recent seasonal issue on the tremendous hope that surrounds emerging therapies for cancer that has spread to the brain, 

The number of people developing leptomeningeal disease is increasing for the same reason that diagnoses of brain metastases are on the rise: People are living longer, giving cancer more time to spread.

Jeannette Moninger

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