ALK-Positive Lung Cancer in Focus

DanWhen Daniel Wilson, a then-34-year-old father and husband in Chalfont, Pennsylvania, went to the emergency room for what he calls “a cold that didn’t go away” that caused coughing 200 to 300 times a day, “the last thing” his doctors expected to find was lung cancer, he says.

Not only did Wilson receive a diagnosis of stage 4 non-small cell lung cancer (NSCLC) in February 2019, but the news was delivered with what he and his wife found to be a surprising degree of optimism.

Daniel Wilson’s treatment for ALK-positive NSCLC has resulted in side effects including sensitivity to sunlight, he says.

Photo credit: Robert Barilla

“They shared that it was ALK-positive lung cancer. That didn’t mean anything to my wife and I, but they went on to say it was like hitting the lottery,” Wilson says. “How do you receive a stage 4 cancer diagnosis, lung cancer specifically, without having a past of any environmental factors that would lead to it? And be told, ‘Yeah, you hit the lottery.’ What we didn’t understand was that [the diagnosis] gave us opportunities to [try] some targeted therapies to extend my life as opposed to just straight immunotherapy and chemotherapy.”

Wilson is taking Alecensa (alectinib), an oral medication known as an anaplastic lymphoma kinase (ALK) inhibitor, which inhibits the growth of tumor cells that overexpress ALK, a protein that controls cell growth, as explained by the National Cancer Institute. Alecensa is among the drugs focused on ALK that continue to make waves in the oncology world nearly a decade after its introduction, as targeted therapies become available for patients at earlier disease stages and advancements are made for patients whose tumors can be surgically removed.

‘It’s Made All the Difference’

Alecensa initially received accelerated approval from the Food and Drug Administration (FDA) for patients with ALK-positive NSCLC that had metastasized (spread from the lungs to other parts of the body) and who had progressed on Xalkori (crizotinib; the first approved ALK-targeting treatment) in 2015, then as a frontline treatment in 2017.

“ALK … is a gene that’s expressed during fetal development, and then your body turns it off,” explains Dr. Ken Culver, director of research and clinical affairs for the organization ALK Positive. “But for reasons we don’t understand, this gene gets reactivated in some people. That reactivation leads to the cells growing faster than they should. And that manifests itself in cancer, [including] lung cancer.”

“When we talk about ALK-positive lung cancer, we’re really describing [NSCLC], which is the most common type of lung cancer, harboring a specific genetic change. We don’t mean genetic in the sense of something that’s inherited. We mean genetic in the sense that it’s the result of changes in our genetic material or DNA,” explains Dr. Stephen Liu, a medical oncologist who leads the Thoracic Oncology and the Developmental Therapeutics sections at Georgetown University’s Lombardi Comprehensive Cancer Center in Washington, D.C.

“The specific change here is a chromosomal rearrangement or a gene fusion. … We know that within [types of ] adenocarcinoma of the lung, there are a lot of different cancers, and if we look at the DNA level, we can see significant changes,” Liu says. “These changes define different subsets of cancer, they define the biology, they dictate how those cancers behave, and now we finally have the ability to leverage those changes in treatments. We use those specific genetic changes to help guide which treatments to give and which not to give. The general model for that is precision oncology, precision therapy and biomarker-driven treatment for lung cancer, and it’s made all the difference.”

Postsurgical Treatment Advancements

Liu highlights the phase 3 ALINA trial, which showed that among patients with stage 1B to 3A ALK-positive NSCLC, treatment with Alecensa resulted in a 76% reduction in the risk of death or disease recurrence when compared with treatment via platinum-based chemotherapy.

Based on the ALINA findings, the FDA accepted a supplemental new drug application and granted priority review to Alecensa as an adjuvant (postsurgical) treatment for patients with early-stage ALK-positive NSCLC.

A retrospective study published in Scientific Reports found that Xalkori-based adjuvant therapy also improved the outcomes of patients with ALK-positive lung cancer, with researchers writing that the study “confirmed the effective and feasible therapeutic approach of postoperative targeted therapy in ALK-positive lung cancer.”

“We don’t necessarily think we cure people with the targeted therapies,” says Dr. Heather Wakelee, Winston Chen and Phyllis Huang Professor and Chief of the Division of Oncology at Stanford University in California. “We substantially delay time before cancer comes back with these treatments, if it’s going to come back, and that is a really meaningful outcome, because living without known active cancer [and having to take] a medication every day is different, and most would say much better, than that feeling of waiting for when [the disease is] going to come back or living with known active cancer and then taking the medication [after the fact].”

Other noteworthy trials, Wakelee says, include the phase 3 ALCHEMIST trial evaluating Xalkori for patients with stages 1B to 3A ALK-positive NSCLC that has been surgically removed and the phase 3 CROWN study in metastatic disease that showed the ALK inhibitor Lorbrena (lorlatinib) conferred a “durable benefit … over [Xalkori] in patients with treatment-naive, ALK-positive [NSCLC],” according to findings published in The Lancet Respiratory Medicine. Lorbrena received accelerated FDA approval in 2018 for second- or third-line treatment of ALK-positive metastatic NSCLC.

Addressing Unmet Needs

There are between 90 and 100 current clinical trials in the United States and the European Union allowing patients with ALK-positive NSCLC, Culver says, with 15 or so being for treatments specifically designed to target ALK-positive disease.

ALK fusions exist in 3% to 5% of patients with NSCLC, Liu says. Their presence is not associated with a history of smoking, and ALK-positive cancers have a high likelihood of spreading to the brain.

“Typically, patients tend to be younger, but we see this in every demographic: young, old, male, female, and [it’s] something we see all over the world,” Liu says. “Importantly, you cannot tell if someone has or does not have an ALK fusion just by looking at them, just by talking to them. The only way to know for sure is to test [the tumor] for the fusion. And because this is such an important alteration, and one we cannot afford to miss, everyone with lung cancer should be tested for the presence or absence of ALK fusion.”

There are approximately 10,000 new cases of ALK-positive lung cancer each year, with an average survival of seven years and approximately 70,000 patients with ALK-positive lung cancer currently living in the United States, Culver says.

Treatment with the next-generation inhibitor, iruplinalkib, reduced the risk of disease progression or death by 66% when compared with Xalkori, which was originally approved by the FDA in 2011 for patients with metastatic or locally advanced (meaning it spread to nearby tissue or lymph nodes) ALK-positive NSCLC, as a first-line treatment among this patient population, according to findings from the phase 3 INSPIRE trial published in the Journal of Thoracic Oncology.

Looking forward, Liu says therapies can become even more specific, targeting ALK-positive subtypes.

“Finding those differences and leveraging the advantage is really key to the future,” Liu says.

Among the promising new treatments, Liu says, is the novel drug NVL-655, which, in the recent phase 1/2 ALKOVE-1 trial, was found to elicit an objective response rate (patients whose disease responded partially or completely to treatment) of 39%, with treatment-related side effects leading to discontinuation or a dose reduction in 2% and 5% of patients, respectively.

‘I Did Have a Little Cough’

For Brandi Bryant, whose cancer journey began with shortness of breath, her condition had to drastically worsen before she was given access to targeted therapy.

A mother of four in Decatur, Georgia, Bryant was 39 in November 2017 when she began experiencing shortness of breath while talking on the phone. Bryant, who says her regular exercise regimen used to include walking several miles a day, notes that she had also been dealing with a tiny, yet persistent, cough.

Brandi Bryant, who received an initial diagnosis of stage 3B ALK-positive NSCLC in January 2018, has been taking Alecensa for nearly six years.

Photo provided by Bryant

“It wasn’t annoying,” Bryant says. “It wasn’t anything that kept me up [at night]. My ex-husband, at the time [he] told me that, ‘Sometimes you cough at night,’ but it didn’t interrupt my sleep, so it was never anything that [concerned me].”

Bryant received an initial diagnosis of stage 3B ALK-positive NSCLC in January 2018 and was told she would be started on a treatment plan of six rounds of chemotherapy and 30 rounds of radiation.

“Once my doctor told me that my biomarker test results were in, this was like three weeks after they had been sent out [and] three to four weeks before I started my chemo, I asked her, ‘Why can’t I do this [targeted therapy]?’ And she said, ‘We’re going with the standard of care, and with curative intent,” opting for a chemoradiation regimen, she says.

Bryant connected with ALK Positive and researched her disease.

“I was just thinking about the people who I saw, who I knew were on a targeted therapy of some sort, versus the people who I saw in my infusion room when I was getting chemo, and I really just wanted to be able to take that. I knew that it would be an easier route for me,” Bryant said.

After completing four rounds of chemotherapy and approximately 20 rounds of radiation, Bryant was hospitalized for a fever and had trouble breathing and performing actions such as going up and down stairs. Doctors, she says, drained fluid from around her heart that they discovered was “full of malignant cells,” and determined that her cancer had metastasized, reaching stage 4.

“After I was released from the hospital, I had a meeting with my oncologist and she told me, ‘Well, now you’re eligible for targeted therapy,’” Bryant says.

Bryant started treatment with Alecensa in May 2018, and her condition quickly improved. “Honestly, within just a couple of weeks, other than the side effects for [Alecensa] like a sluggish feeling, heavy legs and being fatigued, I didn’t have that many issues,” she says. “And within two to three weeks, I was able to easily climb the stairs again. [I thought,] ‘Oh my gosh, I know this is working.’”

‘A Very Significant Health Problem’

Wilson, who was treated with radiation shortly after his diagnosis, began taking Alecensa in March 2019. “That’s been my first-line therapy since I was diagnosed,” he says. “I have had some additional radiation done to my chest, where it wasn’t targeted previously, just to clean up some residual cells, and I’ve been stable [in] scans since 2021.”

Wilson experienced digestive issues, which required attention to his diet, and sunlight sensitivity.

“Anybody who does know me is used to seeing me in long sleeves at any point of the year, and also seeing me in a hat, most likely a bucket hat, just to protect myself because even 10 minutes of direct sunlight [causes] burning on the hands. It feels like a chemical burn. So, it can be kind of tough, having kids and being active coaching both of their soccer teams, and being outdoors, trying to balance being that active dad, being present, and hiding from the sun at the same time.”

“Think about diabetes,” Wakelee says. “We don’t cure diabetes; people live their life chronically on medications. That’s OK. That’s still a win. I think that we would love to be able to think about cancer as ‘It’s gone, gone, gone,’ [but] if people end up living out the life that they would have lived otherwise, having to take medication with minimal side effects, it’s not quite as good as cancer being gone, gone, gone. But it’s certainly much better than living with symptoms from your cancer.”

Nearly six years after starting treatment, Bryant is still taking Alecensa.

“I thought I was going to be dead in six years,” she says. “And I’m clearly not going to die anytime soon, unless an Acme anvil hits me. That’s the only thing that’s going to take me out right now. So, I’ve got some time.”

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