Precision Oncology, Biomarker Testing and Clinical Innovation in NSCLC

Lung cancer remains the leading cause of cancer-related deaths worldwide, claiming more lives than colon, breast and prostate cancers combined. The global incidence continues to rise and is projected to be around 4.62 million new cases annually by 2050.

Among lung cancer subtypes, non-small cell lung cancer (NSCLC) is the most prevalent, accounting for roughly 85% of all cases. Yet despite decades of progress in screening and treatment, NSCLC continues to carry a poor prognosis, especially for those diagnosed at later stages.

Even with the best available treatments, the five-year survival rate for metastatic NSCLC remains below 20%, underscoring the need for earlier detection, expanded biomarker testing and new precision-based approaches.

For patients with HER2 (ERBB2) mutations, the need is particularly urgent. Each year, about 40,000 people worldwide are diagnosed with this molecular subtype.

To explore how the field is evolving, Xtalks spoke with two experts from Boehringer Ingelheim, Vicky Brown, Senior Vice President and U.S. Therapeutic Area Head for Oncology and Emerging Areas, and Prof. Norbert Kraut, Senior Executive Scientist. Together, they discussed the challenges of late diagnosis, the rise of targeted therapies, advances in biomarker-driven research and diagnostics and the next steps in lung cancer treatment innovation.

vicky brown, innovation in NSCLC — Vicky Brown
SVP, U.S. Therapeutic Area Head for
Oncology and Emerging Areas
Boehringer Ingelheim

innovation in NSCLC — Prof. Norbert Kraut, PhD
Senior Executive Scientist
Boehringer Ingelheim

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The Urgency of Early Detection

“Lung cancer claims more lives than any other cancer type,” said Brown. “More than 200,000 lung cancer cases are diagnosed in the US on an annual basis.”

She explained that NSCLC often doesn’t fit the conventional image many associate with lung cancer. “When you think of NSCLC, this is typically your non-smokers,” she said. “No one thinks lung cancer. It’s typically on the younger side. It does also skew toward females a little bit more, earlier on in their lifetime.”

Because of that perception, NSCLC is frequently diagnosed at advanced stages, when survival odds are drastically reduced. “Patients are often very advanced, stage three or stage four, and at that point, life expectancy is less than 10% over five years,” Brown noted. “It’s devastating, and the disease has often already metastasized, including to the brain.”

She emphasized that earlier screening and diagnosis are critical to improving outcomes. “What we hear from patients and their families is that no one expects to be told they have lung cancer,” she said. “They’re often diagnosed because of something else, shortness of breath, a persistent cough, and the news is a complete shock.”

Once diagnosed, biomarker testing becomes essential to determine the molecular drivers of the disease. “Understanding what it means to have that diagnosis, and the need for biomarker testing to identify targeted therapy options, is absolutely critical,” Brown said.

The Development of Targeted Therapies for NSCLC

From a research perspective, Kraut described how the trajectory of targeted oncology has shaped NSCLC drug development. “The advances in targeted therapies and immunotherapy have really revolutionized NSCLC treatment,” he said. “However, this cancer type still remains highly fatal, with limited curative options, and we do need broader targeted therapy options.”

He noted that about half of lung adenocarcinomas harbor actionable oncogenic driver mutations, meaning they can be matched with drugs designed to inhibit those mutations. “We see targeted therapies available for EGFR, ALK and a number of other driver alterations,” Kraut said. “And now, with an HER2-selective tyrosine kinase inhibitor (TKI) for HER2 mutations available, we’re addressing additional molecular subgroups.”

Boehringer Ingelheim recently received US FDA, China NMPA and Japan approval for zongertinib, the first orally administered, targeted therapy for previously treated patients with HER2 (ERBB2)-mutant advanced NSCLC.

The evolution of precision medicine in oncology, he added, can be traced back to the approval of imatinib mesylate in 2001. “That approval started the field of precision cancer treatments,” Kraut said. “It inspired many of us in drug discovery to find and target other cancer drivers.”

“Lung cancer was a priority from the beginning,” he continued. “EGFR driver mutations were discovered shortly thereafter, in 2004. EGFR tyrosine kinase inhibitors provided clear benefits for patients, including afatinib, which was the first Boehringer Ingelheim lung cancer drug from our labs.”

Since that breakthrough, the field has continued to evolve rapidly. “We’ve seen new targeted therapies for lung cancers harboring ALK fusions, ROS1 fusions, BRAF mutations, EGFR exon 20 insertions, KRAS G12C mutations and more,” Kraut explained. “There are also numerous other oncogenic drivers such as HER2 kinase domain mutations, for which we’re now seeing emerging efficacy data.”

He pointed out that Boehringer Ingelheim began working on its HER2-targeted compound project in 2017, which has since demonstrated efficacy in previously treated NSCLC patients. “Based on what we’ve learned in the field, you need highly potent, highly selective drugs that provide clear benefit,” he said.

“The goal is to help patients to a greater degree, improve current therapies and expand targeted therapy options by addressing cancer drivers that were previously considered undruggable.”

– Norbert Kraut

From Small Molecules to ADCs

“On the small-molecule side,” Kraut said, “we’re now going after other KRAS mutations and transcription factors that were once thought impossible to drug. These are high-hanging fruit, but the science is catching up.”

Meanwhile, on the large-molecule side, innovation in antibody-drug conjugates (ADCs) has opened new possibilities.

“ADCs combine the potent cytotoxic effect of the payload with the targeting specificity of monoclonal antibodies,” he explained. “They’ve demonstrated real promise in non-small cell lung cancer. ADCs for HER2, TROP2 or MET are either approved or under clinical investigation, and they’ll further expand the reach of targeted therapies.”

This diversification of modalities, he said, represents a new phase of oncology research.

Precision Medicine Begins with Testing

Building on Kraut’s perspective, Brown highlighted how biomarker testing has become the cornerstone of personalized oncology.

“Oncology and precision medicine are probably the most dynamic they’ve ever been,” she said. “As these mutations and patient subtypes are identified, what becomes critically important is that biomarker testing is done on a standard basis.”

“Gone are the days of everyone getting a blanket approach,” she continued. “It’s now about understanding the biomarker testing results and matching them to the targeted therapies that are best for that patient’s specific tumor type.”

Brown described next-generation sequencing (NGS) as the tool transforming the field. “One should be tested with NGS,” she said. “One should know if there’s a targeted therapy available for your tumor type. That’s how patients can receive the best possible treatment.”

But widespread adoption of testing remains uneven. “The goal is for next-generation sequencing to become standard practice, not just in academic settings, but also in community settings,” she said. “That’s how we ensure all patients have access to personalized medicine.”

She also underscored the need for clear communication. “There’s an alphabet soup of letters and numbers that come out of these tests,” she said. “We need to make sure oncologists, pathologists and patients all understand what those results mean, what treatments are available and what sequencing or treatment pathways should look like.”

When biomarker testing is done early and interpreted effectively, the benefits are clear. “Patients can get on the right therapies faster,” Brown said. “That translates to better outcomes: longer-term benefits and improved survival.”

Adapting Clinical Trial Designs to Match Disease Complexity

As understanding of NSCLC deepens, trial design must evolve with it. “First of all, you need really potent and clean compounds,” said Kraut. “You want to be able to combine them with other modalities, with other modes of action, and you want to bring them as early as possible — ideally to the adjuvant setting, before and/or after surgery.”

He noted that targeted treatments are now being evaluated across cancer subtypes and even repositioned from other diseases. “BRAF inhibitors, for example, were developed against melanoma and later shown to work very well in BRAF-mutated NSCLC, and vice versa,” he explained. “That’s the advantage of understanding the underlying mutations rather than just the tumor location.”

He also emphasized the growing importance of tackling treatment resistance. “Over time, tumors can evade therapy and become resistant,” Kraut said. “We saw that with early EGFR inhibitors until resistance mutations emerged. Then next-generation inhibitors like osimertinib were then able to address both the initial driver mutations and the new resistance mutations, and a similar story exists in the ALK inhibitor space and other areas of NSCLC.”

Learning from these resistance mechanisms, he said, requires comprehensive tumor profiling and continuous adaptation of therapeutic strategies. “You learn from the clinic, identify the resistance mechanisms, then design the next generation of inhibitors or combination therapies to overcome it.”

Brown added that real-world data (RWD) continues to play a crucial role beyond clinical trials. “It’s about continuous exploration in real-world populations,” she said. “Understanding how therapies work in the clinic and beyond helps oncologists make informed choices and helps patients understand how drugs can be effective for them.”

Expanding Trial Access and Representation

Diversity in clinical trials remains a key focus for both leaders. “Patients want to know, ‘Does this drug work in a patient like me?’” said Brown. “That’s why diversity and representation are so important.”

She acknowledged the challenge of enrolling rare subgroups, such as HER2-mutated NSCLC, but said partnerships with advocacy and professional organizations are making a difference. “Patients often turn to these groups as trusted partners to learn what’s out there,” she said. “Those connections are essential.”

Boehringer Ingelheim is also implementing more flexible trial models to improve participation. “We’re seeing more flexibility in how sites are initiated and stood up, especially for rare populations,” Brown explained. “It’s about ensuring broad access and multiple cohorts so we can capture patients at different stages of treatment.”

Equally important, she said, is understanding what patients want from endpoints. “It’s not just about what regulators look for, it’s about what matters most to patients,” she said. “That also means transparent communication, addressing hesitations and making information understandable.”

By partnering early with community oncologists, advocacy organizations and patient groups, Boehringer Ingelheim aims to create trials that reflect real-world populations and generate data beyond regulatory requirements.

“We want to make sure we’re not only running the most effective and well-designed clinical trials but also understanding what the community wants to see.”

– Vicky Brown

Looking Ahead: Early Detection, Resistance Biology and Data-Driven Discovery

Kraut emphasized three areas of focus in the near future: early detection, resistance research and research into combining different modalities.

“Earlier diagnosis can dramatically improve survival rates,” he said. “But it’s especially difficult for NSCLC due to a lack of symptoms and frequent misdiagnosis. Most patients still present with late-stage disease.”

He also pointed to the need for therapies with intracranial efficacy to address brain metastases, a major unmet need in advanced NSCLC.

Beyond new drugs, the field is rapidly integrating cutting-edge technologies. “We’re seeing major advances in drug discovery and data science,” Kraut said. “Tools like single-cell sequencing, spatial transcriptomics and multiplex imaging allow us to study how tumors respond to therapy at the cellular level, but further efforts are required to incorporate those into clinical research.”

He added that combining chemotherapy, immunotherapy, targeted therapy and emerging modalities such as ADCs and molecular glue degraders will define the next generation of lung cancer research.

Brown agreed that communication and education will be just as crucial as scientific discovery. “With all these advancements, how do we make sure the information remains clear, accessible and actionable?” she asked. “Patients need to know what’s available, and clinicians need to know how to connect them with the right therapy.”

Ultimately, both leaders expressed optimism about where the field is headed. “NSCLC has become a leader in shaping innovation that benefits the entire field of oncology,” Kraut said. “We’re learning so much, but there’s still more to do.”

Brown echoed that sentiment. “There’s so much progress happening,” she said. “The key now is ensuring that everyone, from oncologists to patients, understands the options available, so people can get on the right therapy as early as possible.”

The Urgency of Early Detection

The Development of Targeted Therapies for NSCLC

From Small Molecules to ADCs

Precision Medicine Begins with Testing

Adapting Clinical Trial Designs to Match Disease Complexity

Expanding Trial Access and Representation

Looking Ahead: Early Detection, Resistance Biology and Data-Driven Discovery

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