Lung cancer, the leading cause of cancer-related mortality worldwide, poses significant challenges to patients, caregivers and health care professionals alike. This special issue of CURE provides information on recent treatment developments, as well as insight into some of the issues currently faced by patients.

We look at news from the Food and Drug Administration, which recently approved both Tagrisso (osimertinib) in combination with platinum-based chemotherapy for adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations and Tepmetko (tepotinib) for adults with metastatic NSCLC with mesenchymal-epithelial transition exon 14 skipping alterations. These developments underscore the importance of molecular profiling and precision medicine in optimizing patient outcomes.

Elsewhere in this issue, we shine a spotlight on treatment advancements for ALK-positive NSCLC. Although it is a relatively rare diagnosis, one patient recalls that his doctors told him it was “like hitting the lottery,” due to the targeted therapy treatment options that are available for this disease subtype. Treatments for ALK-positive NSCLC continue to make waves as targeted therapies are explored for patients earlier in their cancer journeys and advancements are made in postsurgical treatment options.

This issue also reports on some of the latest efforts in treating small cell lung cancer, a type of cancer that is relatively less common, making up approximately 15% of lung cancer diagnoses, but is also more aggressive and diagnosed at later stages when compared with NSCLC.

“For decades, we didn’t have a lot of options to offer patients with lung cancer. Chemotherapy was kind of the standard approach to managing that diagnosis. But we’ve seen a lot of recent progress that offers hope for patients who are diagnosed with small cell lung cancer,” Amy C. Moore, vice president of global engagement and patient partnerships for the LUNGevity Foundation, told CURE as part of our “Speaking Out” series.

In breaking down the science behind these innovative therapies and looking at the practical aspects of treatment decision-making, we hope to empower patients and their loved ones with the knowledge and resources needed to make informed choices and advocate for optimal care.

As always, we hope you find our stories inspirational and informative. Thank you for reading.

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Articles

The CURE® 2024 Lung Cancer Special Issue provides insight into the ever-changing innovation in the lung cancer space.

Hope and Innovation in the Lung Cancer Space

In this special issue of CURE, we examine some of the latest developments in the treatment of ALK-positive non-small cell lung cancer (NSCLC). This subtype of lung cancer, representing about 5% of NSCLC diagnoses, is characterized by a fusion of the anaplastic lymphoma kinase, or ALK gene, and has seen impressive advancements in recent years. Since the protein encoded by the ALK fusion gene is unique to the cancer cells, it can be targeted specifically with drugs that inhibit its enzymatic activity.

There are approximately 10,000 new cases of ALK-positive NSCLC each year, with an average survival of seven years and approximately 70,0000 patients with the disease currently living in the United States. And, there are between 90 and 100 clinical trials in the United States and the European Union allowing patients with ALK-positive NSCLC, Dr. Ken Culver, director of research and clinical affairs for ALK Positive, tells CURE.

Alecensa (alectinib) was initially approved by the Food and Drug Administration in 2015 for the treatment of ALK-positive NSCLC that had metastasized, or spread to other areas of the body, and progressed on targeted therapy Xalkori (crizotinib). Findings from the phase 3 ALINA trial have shown that treatment with Alecensa reduced the risk of death or disease recurrence by 76% when compared with platinum-based chemotherapy in patients with stage 1B to 3A ALK-positive NSCLC.

More CURE® coverage of ALK-positive NSCLC:

Phase 2 Trial Assessing Novel TKI Begins in ALK-Positive NSCLC, Solid Tumors

FDA Grants Priority Review for Alecensa in Some ALK-Positive NSCLC

Iruplinkalkib Reduced Risk of Progression, Death in ALK-Positive NSCLC

Alecensa Reduces Recurrence, Mortality Risk in Lung Cancer Subset

Other research has demonstrated a postsurgical benefit from Xalkori-based therapy among patients with operable disease, with authors of one retrospective study writing that their findings “confirmed the effective and feasible therapeutic approach of postoperative targeted therapy” for patients with ALK-positive NSCLC. Researchers are also calling for therapies to become even more specific in order to target subtypes of ALK-positive NSCLC.

“Finding those differences and leveraging the advantage is really key to the future,” says Dr. Stephen Liu of Georgetown University's Lombardi Comprehensive Cancer Center.

With advancements in ALK-targeting treatments making waves in the oncology world, patients are experiencing extended survival and improved outcomes. Research continues to propel progress forward, with ongoing clinical trials and novel treatments on the horizon.

As we navigate the complexities of cancer treatment and care, it is essential to recognize the integral role of research and innovation in driving progress. The field of oncology continually witnesses rapid evolution, offering new avenues of hope for patients and their loved ones. While challenges persist, so do creativity and the next generations of clinical trials and ultimately more successful options for patients.

Professor of Medicine Chair, Department of Breast Medical Oncology
The University of Texas MD Anderson Cancer Center

This special issue of CURE Lung Cancer takes a deeper dive into ALK-positive non-small cell lung cancer. 

Targeting ALK-Positive NSCLC

It’s a time for patients with small cell lung cancer (SCLC) to be hopeful, as Amy C. Moore, vice president of global engagement and patient partnerships for the LUNGevity Foundation said. “There have been various reasons why we haven’t seen as many gains in this space,” Moore said. “I think it’s just a much different beast than non-small cell lung cancer (NSCLC) for a variety of reasons. But we’re more hopeful now than we’ve been in quite some time.”

For example, data from the phase 3 IMpower133 trial showed a five-year overall survival (how long patients lived following treatment, regardless of disease status) rate of 12% among patients treated with the immunotherapy Tecentriq (atezolizumab) plus chemotherapy.

“While that doesn’t sound like a very high number, for comparison, in patients receiving only chemotherapy, the overall survival is only 2%,” Moore noted.

The Food and Drug Administration (FDA) approved Tecentriq plus chemotherapy as a treatment for patients with extensive-stage SCLC in 2019 based on the results of IMpower133, which was followed by the FDA’s approval of the immunotherapy Imfinzi (durvalumab) plus chemotherapy for extensive-stage SCLC in 2020 based on findings of the phase 3 CASPIAN trial.

The research continues. The first patients were recently dosed in a phase 1/2 trial of the immunotherapy HPN328 and Tecentriq, while the FDA has also granted a priority review to a biologics license application for the immunotherapy tarlatamab for patients with advanced SCLC.

Moore discussed the science behind these treatments and explained why they represent a sea change for patients with SCLC as part of CURE’s “Speaking Out” series.

Q:What should patients with SCLC know about the current advancements in research for treatments?

Small cell lung cancer is one of the two main types of lung cancer, accounting for about 15% of all lung cancer diagnoses. And historically, it’s been more difficult to treat. For decades, we didn’t have a lot of options to offer patients with lung cancer. Chemotherapy was kind of the standard approach to managing that diagnosis. But we’ve seen a lot of recent progress that offers hope for patients who are diagnosed with small cell lung cancer.

Q: What are some trials that patients should be providing particular attention to and why?

 There’s one called IMpower133, which [was] a study looking at the use of an immunotherapy drug called [Tecentriq] in combination with the platinum-based chemotherapy carboplatin or cisplatin that’s typically been used for treating small cell lung cancer along with a [chemotherapy] drug called etoposide. ... So, we’re starting to see some gains in survival, a durable survival benefit in some patients with small cell who are receiving that combination of immunotherapy and chemotherapy. One of the challenges with that study is that we can’t yet predict who those patients are who are going to derive that benefit.

That’s an area of ongoing investigation by researchers: Are there specific biomarkers that may predict who will get the most benefit from the addition of immunotherapy to their treatment regimen?

Another similar study is the CASPIAN study, which evaluated the use of a drug called [Imfinzi] in combination again with platinum-based chemotherapy, compared to patients receiving chemotherapy only. What they found in that study is that there were three times more survivors at three years in the [group of] patients receiving immunotherapy in combination with chemotherapy compared to the patients receiving chemotherapy alone.

In both these studies, IMpower133 and the CASPIAN study, they’re looking at the combination of immunotherapy added to traditional chemotherapy. And in both cases, you’re seeing a survival benefit and long-term survival in patients.

Going forward, we need to understand and be able to predict who those patients are that may derive that biggest benefit from the addition of immunotherapy, but [it’s] still very exciting and a sign of encouragement and, again, it validates the use of immunotherapy combined with chemotherapy in the first-line setting for patients diagnosed with extensive-stage small cell lung cancer.

Q: How does immunotherapy work to help the patient’s body deal with cancer?

Basically, immunotherapy harnesses the patient’s own immune system to go after and target the cancer. People hear about the brakes of the immune system and PD-L1 and PD-1 inhibitors, so there are these checkpoint inhibitors that scientists have learned how to manipulate, and they can basically activate the patient’s own immune system to try to go after and target the cancer. And that’s the goal here, to tap into the patient’s own ability to go after and treat the cancer.

Q: What are some roadblocks to treatment advancements that might exist due to factors such as the relative rarity of SCLC compared to NSCLC?

Of the two main types of lung cancer, we have non-small cell lung cancer and we have small cell lung cancer where small cell contributes about 15% of all diagnoses. It has typically been categorized as what we call recalcitrant cancer — that means it’s refractory or resistant to treatment.

Despite all the advances we’ve made in the treatment of non-small cell lung cancer, where we have several actionable biomarkers and targeted therapies and immunotherapy that have really opened up the survival and quality of life for those patients, we haven’t seen the same gains in patients diagnosed with small cell.

We’re trying to understand biologically what’s different about small cell.

Patients tend to be diagnosed at late stages [and] it’s a more aggressive form of lung cancer. So, it often responds well initially to chemotherapy, but then the tumor does what it does and patients can find that the chemotherapy [eventually] stops working.

And so, we just don’t have as many options available for small cell as we do for non-small cell, but it’s an area of intense investigation.

There are some other classes of drugs that are being evaluated to treat it. Another study ... is the DeLLphi-301 study, which looked at a drug called tarlatamab, which belongs to a new class of [immunotherapy] drugs called bispecific T-cell engagers. Back to this idea of harnessing the patient’s own immune system to go after and attack cancer, what bispecific T-cell engagers do is they allow us to bridge the small cell lung cancer cell with a T cell so they can bind to a molecule that is expressed by the small cell lung cancer tumor itself, a molecule in this case called DLL3, as well as a molecule expressed on the surface of the T cell called CD3. By linking those cells together, the T cell can then go in and lance or burst the small cell lung cancer cell.

It’s a novel class of drugs harnessing the patient’s own T cells to go in and attack and kill the small cell lung cancer. ... This was based on a phase 2 study where the objective response rate (patients who responded partially or completely to treatment) was roughly 40% and we saw median overall survival at 14.3 months.

Some [of the] safety considerations are that in some patients, because you’re stimulating the immune system, their immune systems go into overdrive, and [as a result] you can have something called cytokine release syndrome, where your body starts producing too many [proteins known as] cytokines, and you can have some complications from that. Another is that you can get some immune-associated neurotoxicity.

But again, it’s a novel class of drug that’s using the immune system, and it’s something that I think is very promising and that we’ll continue to evaluate.

A second class of drugs is antibody-drug conjugates [ADCs]. That’s another space where you’re using an antibody molecule to … bind a certain molecule, again, expressed on the small cell lung cancer surface. In this case, investigators looked at ADCs that bound to that DLL3 marker on the small cell cancer, and then the antibody brings in a payload of a drug that can go in and selectively, specifically treat the cancer.

We’re seeing mixed results on the use of [ADCs], both in the non-small cell lung cancer space as well as the small cell space, but it’s an area that’s the subject of a lot of research right now, and shows a lot of potential.

It’s a time for patients with small cell to be hopeful. There have been various reasons why we haven’t seen as many gains in this space. It’s just a much different beast than non-small cell lung cancer for a variety of reasons. But we’re more hopeful now than we’ve been in quite some time.

Transcript edited for clarity and conciseness.

Speaking Out

Patients with small cell lung cancer have reasons to be optimistic these days, as one expert explains to CURE.

Small Cell Lung Cancer: It’s a Time to Be Hopeful 

When 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.

“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.

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.”

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.

 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 

. Lorbrena received accelerated FDA approval in 2018 for second- or third-line treatment of ALK-positive metastatic NSCLC.

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 

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.

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.

“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.’”

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.”

What advancements for ALK-positive non-small cell lung cancer are on the way, from treating earlier stages of disease to postsurgical options? 

Lung Cancer Special Issue 2024 | CURE

Hope and Innovation in the Lung Cancer Space

Targeting ALK-Positive NSCLC

Small Cell Lung Cancer: It’s a Time to Be Hopeful

ALK-Positive Lung Cancer in Focus

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