The vital role of biomarker testing in early-stage NSCLC patients

In the autumn of 2016, Terri Conneran was having trouble breathing. At first, she thought her allergies were acting up. She consulted her doctor, who diagnosed asthma and sent her home with a prescription for an inhaler. But by Christmas, she was still wheezing. An X-ray indicated that her condition was more serious – she had pneumonia – but it also showed more ominous looking lesions on her lungs. A biopsy confirmed the shocking diagnosis: stage III non-small-cell lung cancer (NSCLC).

Conneran was completely floored. She had never smoked more than an occasional cigarette at social events, and that was during college, more than 25 years earlier. She immediately began treatment, which involved surgery, radiation and chemotherapy.

Millions of people are diagnosed with lung cancer every year – 10 to 20% of whom are non-smokers. Lung cancer also claims more lives worldwide than any other cancer, according to the Global Cancer Observatory (1). This is mainly because it is often detected late. Unlike some other cancers, lung cancer frequently remains asymptomatic in its early stages, silently progressing without warning signs (2).

“There are no pain receptors in the lungs, which is why people don’t notice,” says Dr. Colin Lindsay, consultant medical oncologist and lung cancer specialist at the Christie Hospital in Manchester, UK.

A better life expectancy

A lung cancer diagnosis used to mean a quick death sentence. “We've gone from a place where we were quoting an average survival of 10 to 12 months to advanced NSCLC patients 10 to 15 years ago to somewhere in the region of 2 to 3 years nowadays,” says Dr. Lindsay. “That's been an absolutely seismic shift for many patients and their families.”

Much of the gains in life expectancy have come from better treatments, streamlined by improved patient selection. Unlike traditional chemotherapy, which broadly attacks rapidly dividing cells, targeted therapies such as osimertinib pinpoint specific genetic mutations or proteins that drive cancer cell growth. By precisely targeting these molecular biomarkers, such therapies have been remarkably effective, particularly in patients with NSCLC, which accounts for approximately 85% of all lung cancer (4).

Among the most common biomarkers tested in NSCLC are mutations in the epidermal growth factor (EGFR) gene, which occur in about 10 to 15% of NSCLC patients (5). EGFR mutations can dictate the use of targeted therapies like lazertinib and osimertinib.

Another frequently observed lung cancer causing gene mutation is the anaplastic lymphoma kinase (ALK) rearrangement. Patients with ALK-positive NSCLC often respond well to drugs such as brigatinib, alectinib, and others targeting the ALK fusion gene (6).

Additionally, ROS1 rearrangements, BRAF mutations and others are also recognized biomarkers that indicate specific treatments for patients whose cancers carry these genetic alterations (7).

The most frequently mutated oncogene in cancer and in NSCLC is Kirsten rat sarcoma viral oncogene homolog, or KRAS, and was the mutation responsible for Terri Conneran’s cancer.  This mutation was initially discovered over 40 years ago, but finding a drug to target KRAS has been challenging because of the complex biochemistry of the KRAS protein. However, the drugs sotorasib and adagrasib have shown to be effective in treating patients with the KRAS G12C mutation, one of several known cancer-causing mutations in the KRAS gene (8). 

A shifting landscape of cancer diagnostics

In the shifting landscape of lung cancer diagnostics and treatment, it is clear that biomarkers such as EGFR, ALK and KRAS have emerged as powerful tools. Oncologists can now detect, diagnose and ultimately, better treat this disease.

However, access to testing for an NSCLC patient at any stage remains patchy. “Unfortunately, the majority of lung cancer patients around the world are not having the biomarker profiling that they deserve to put them in the best treatment scenario. This is both a local and a global problem,” says Dr. Lindsay. And even when biomarker testing is readily available, the turnaround time between test and result can be too long, thus delaying effective treatment in some cases, he adds.

A study reported at the American Society of Clinical Oncology (ASCO) meeting in 2021 showed that less than 50% of lung cancer patients are tested for five or more biomarkers in the US. "Meanwhile, lung cancer experts are now recommending testing for 10 biomarkers or more – all of which might be relevant to a patient’s treatment" , explains Dr. Lindsay.

Recent studies suggest that patients with early-stage NSCLC could benefit from biomarker testing. Results from the ADAURA study presented during the 2023 ASCO meeting, for example, showed that the targeted therapy osimertinib improved overall survival by 10% over placebo in patients with stage IB to IIIA NSCLC and EGFR mutations at 5 years median follow up (11).

“The ADAURA study really reinforced the need for biomarker testing at the earliest stage of lung cancer,” says Dr. Lindsay. “With the overall survival benefits concluded, such studies have really changed how we approach patients.”  

New and better treatments with biomarker studies

There are thousands of registered ongoing clinical trials of new drugs or new drug combinations to treat NSCLC (12). Each new study informs clinical practice. Dr. Lindsay has already adopted the insights gleaned from trials of targeted therapy in early-stage lung cancer into practice.

Based on the ADAURA study, he would now treat with 3 years of adjuvant osimertinib for EGFR-positive patients with early-stage NSCLC, for example.

The drug comes in tablet form, which is a huge advantage from a patient’s quality of life perspective, and is well tolerated, says Dr. Lindsay. But there are still many open questions that only additional research can answer, he adds.

There is concern that cancers may grow resistant to osimertinib over time, for example, or whether giving the drug for 3 years is the optimal treatment time since the drug does cause side-effects – half as long might prove just as beneficial, as has been shown with other cancer drugs such as trastuzumab for breast cancer.

Apart from optimizing treatment protocols, what’s also clear from the research is that “we should be doing as much biomarker profiling as possible in all stages of disease,” says Dr. Lindsay.

“Our best treatments are now moving into earlier stages of care. That means that if a patient relapses, we should be able to use biomarker-driven studies to devise newer and better treatments for those patients.”

Digital PCR holds promise in monitoring cancer relapse

Researchers are employing a variety of technologies to monitor the effectiveness of treatment or to detect relapse to improve outcomes even further. Techniques such as digital PCR are increasingly being studied in a cancer monitoring setting. Combined with liquid biopsy – biomarker analyses from a blood sample ­­­– such technologies hold promise to improve cancer outcomes even more.

“Digital PCR is definitely something that we can call on for analyzing liquid biopsy,” adds Dr. Lindsay. “It offers the greatest sensitivity for finding very small amounts of circulating tumor DNA.”  Liquid biopsies are also non-invasive and much easier to obtain than cancer tissue samples.

At the University of Pisa, Marzia Del Re, Pharm D, PhD, assistant professor in the Department of Clinical and Experimental Medicine is using blood samples from lung and colon cancer patients to monitor genetic changes in cancers. Using dPCR, she analyzes samples before and after each follow-up.

Based on whether the level of mutations is increasing or decreasing “we can predict if the disease is progressing or whether treatment is having an effect,” she explains. dPCR may even be able to predict which patients will relapse before metastases happens, says Dr. Del Re. “That’s powerful information we can use to change treatment and perhaps drastically improve outcomes in patients with advanced cancer.”

We have effective targeted therapies, which are prolonging lives, but we need much more study on combined treatments,” explains Dr. Del Re.

This use case scenario of using analyzing liquid biopsies with dPCR as a monitoring tool is not yet standard clinical practice­­ – it is still in the research phases. As this progresses, clinical trial design will need to shift towards incorporating new technologies and studying whether liquid biopsies paired with a treatment intervention improves outcomes, says Dr. Lindsay. “This is a huge challenge that is constantly evolving.”

Empowerment through biomarker information

Enhancing access to testing also involves educating patients. Terri Conneran emphasizes that when patients grasp the significance of biomarkers, they are better equipped to request targeted testing.

“Every patient should be informed of their biomarkers,” she says, explaining how she only found out about her KRAS mutation two years after her initial diagnosis.

“It gives us, the patients, the information we need to know to find out what may or may not work for us so we can ask the experts the right questions.”

By disseminating up-to-date information to people with lung cancer, Conneran hopes that KRAS Kickers will help improve access and outcomes for all lung cancer patients. Information empowers patients to take initiative in their own health care, Conneran says, whether that means asking for specific tests, such as biomarker analysis, or deciding to take part in clinical trials.

“Patients want the information. We're desperate. KRAS Kickers is that information hub.”

Today, KRAS Kickers is active in over 90 countries worldwide and is connected to over 5000 people, she says. “We gather the information. We talk to each other. We have this sense of commonality. That's powerful. We focus our energy to make a difference. Together, we aim to kick cancer’s KRAS! ”