Emerging Biomarkers Open New Frontiers in Lung Cancer Therapy

Decades of research led to pivotal advancements in cancer therapy, particularly the development of novel targeted agents and immunotherapies. This progress would not have been possible without the discovery of biomarkers.

At the European Society for Medical Oncology 2025 Congress, Natasha Leighl, MD, lead of the Thoracic Medical Oncology Group at the Princess Margaret Cancer Centre, professor in the Department of Medicine, and adjunct professor in the Institute of Health Policy, Management and Evaluation at the University of Toronto, discussed emerging biomarkers in lung cancer.

Biomarkers in Lung Cancer

Lung cancer is the second most common cancer in the United States, with over 260,000 new cases in 2025. NSCLC is the most prevalent type, making up about 80% to 85% of diagnoses. Therapeutic advancements have turned what was once seen as a terminal diagnosis into one that is treatable and, in some cases, curable.¹

Prior to the discovery of biomarkers, patients were limited to cytotoxic agents with modest efficacy and significant toxicity. Biomarkers serve as molecular targets on cancer cells, enabling precisely designed agents to more effectively attack tumors while minimizing off-target effects.²

“It seems so hard to believe that when I started just over 20 years ago, there were no biomarkers for lung cancer and selecting patients for lung cancer therapy,” said Leighl. “Now we look at least 9 genes plus 3 protein markers, and it seems like every year there's a new biomarker for our patients with lung cancer.”²

The first biomarker identified was EGFR, which occurs in 10% to 15% of lung adenocarcinomas. Its discovery led to the development of the novel tyrosine kinase inhibitor (TKI) osimertinib (Tagrisso; AstraZeneca). Identification of other biomarkers, such as ROS1, also paved the way for targeted therapies like entrectinib (Rozlytrek; Genentech) and crizotinib (Xalkori; Pfizer), expanding personalized treatment options and improving outcomes for patients with genetically defined subsets of lung cancer.^1,2

ROS1 is less common than EGFR and ALK at about 1% to 2% of patients ROS1-positive NSCLC shares many clinical features with ALK-rearranged disease; however, ROS1, EGFR, and ALK alterations rarely occur together. Following TKI therapy, some ROS1-driven tumors develop additional driver mutations, most often involving KRAS or EGFR. There are 2 approved agents for patients with NSCLC with ROS1 mutations: entrectinib (Rozlytrek; Genentech), crizotinib, and epotrectinib (Augtyro; Bristol Myers Squibb).^1,2

HER2 mutations are even less common at 0.2%. Despite its rarity, this small subgroup of patients requires treatments that overcome the aggressive nature of HER2. In 2025, the FDA approved 2 HER2-targeting agents datopotamab deruxtecan-dlnk (Datroway; Daiichi Sankyo, Inc) and zongertinib (Hernexeos; Boehringer Ingelheim Pharmaceuticals, Inc).^1,2

Emerging Targets

However, some patients—particularly Asian patients—lack oncogenic drivers crucial for targeted therapy, highlighting the need for new biomarker discovery. Leighl emphasized several promising areas, including rare kinase alterations, tumor suppressors such as TP53, and surface proteins. Knowledge of these biomarkers is still emerging, but they are actively being evaluated in ongoing clinical trials.²

Leighl brings attention to TP53, noting persistent difficulty targeting this biomarker and its poor prognostic implications. There are various clinical trials investigating TP53 restoration, but these are ongoing.²

Other notable genetic alterations include MTAP deletions, SMARCA4 alterations, and CDK pathway alterations, each representing potential future targets for therapeutic development.²

Rare Kinase Alterations

Rare kinase alterations represent a critical area of investigation in lung cancer. These include less common driver mutations that may provide opportunities for targeted therapies, particularly for patients who lack the more prevalent EGFR, ALK, or ROS1 alterations.²

MTAP Deletions

MTAP deletions are found in roughly 15% to 16% of lung cancers, representing a promising therapeutic target. Loss of MTAP leads to the accumulation of upstream MTA substrate, which can suppress purine T5 activity and create a vulnerability for synthetic lethality.²

However, identifying these deletions poses diagnostic challenges. Next-generation sequencing may not always be sensitive enough to detect MTAP loss, making immunohistochemistry the preferred method.²

“It’s cheaper and faster,” Leighl noted, “but it’s not perfect either. The results are very sensitive to tissue fixation and preparation, and pathologists don’t always agree on whether something is positive or negative. Low-level positivity, in particular, can be a real challenge.”²

Patients with MTAP deletions occur in patients with more aggressive disease in younger patients who often have no smoking history. MTAP is seen across other cancer subtypes, such as adenocarcinoma, squamous cell, and neuroendocrine cancers. It is not typically seen in small cell carcinoma.²

“What’s interesting is that when MTAP loss occurs, it’s often located very close to the CDKN2A and CDKN2B genes, said Leighl. “So, if you have MTAP loss, you almost always see a concurrent loss of CDKN2A—but the reverse isn’t always true. In other words, CDKN2A deletions often coincide with MTAP loss, but not in every case.”²

Leighl highlights multiple treatment strategies for MTAP deletions such as PRT5 inhibitors and MTA cooperative agents. Some promising drugs include²:

• AG-270 (Agios): 29% response rate
• IDE-397 (IDEAYA Biosciences): 33% response rate
• AMG-193 (Amgen): crosses blood-brain barrier
• BMS compound (Bristol Myers Squibb): 31% response rate, 10.5 months median duration

SMARCA4

SMARCA4 alterations are found in approximately 7% of lung cancer patients, most commonly as biallelic homozygous deletions. These alterations fall into 2 main classes: class 1 mutations lead to loss of SMARCA4 protein, whereas class 2 missense mutations retain the protein.²

Patients with SMARCA4-altered tumors tend to be older, more often male, smokers, and present with less well-differentiated, more advanced disease. These tumors are associated with a poor prognosis, with median PFS of only 2.7 months and overall survival under one year.²

Therapeutic strategies are in development, including SMARCA2 degraders, and early studies such as PRT-3789 (NCT06561685) have demonstrated activity in non-small cell lung cancer. Additional drugs targeting SMARCA2 and SMARCA4 are also under investigation.^2,3

CDK alterations

CDK alterations frequently co-occur with MTAP deletions due to their close proximity on the genome. In cases of MTAP loss, CDK alterations are almost always present, although the reverse is not consistently true. This relationship has implications for understanding tumor biology and designing targeted therapies.²

MET

MET amplification is a recognized mechanism of resistance to EGFR inhibitors and has become an important target in patients whose cancers progress after EGFR-directed therapy. In a recent randomized trial, patients with MET-amplified tumors received either osimertinib (Tagrisso; AstraZeneca) combined with savolitinib (Orpathys; HUTCHMED, AstraZeneca) or platinum-based chemotherapy. The targeted combination showed superior outcomes, with a response rate of 58% compared with 34% for chemotherapy, and a longer median progression-free survival (PFS) of 9.8 months versus 5.4 months, highlighting the potential of dual-targeted approaches in this patient population.²

Surface Proteins

Surface proteins represent a promising class of therapeutic targets due to their accessibility and tumor-specific expression. These include Nectin-4, Integrin β6, and Folate receptor alpha, each being actively studied for antibody-drug conjugates (ADCs) and other targeted strategies. Targeting surface proteins may allow more precise delivery of cytotoxic payloads while limiting damage to normal tissues.²

Nectin-4

Nectin-4 is a cell adhesion molecule detected using immunohistochemistry and is overexpressed in more than 60% of lung cancers. It has been widely studied in malignant disease and is emerging as an important therapeutic target.²

Clinical data published in the European Journal of Cancer evaluated Nectin-4 expression in a cohort of approximately 43 patients. Investigators observed a 14% response rate among those with non-squamous lung cancer, though activity was limited in the squamous subtype. The median duration of response was reported at 10 months. Common toxicities associated with therapies targeting Nectin-4 included rash, pruritus, and sensory neuropathy.²

Emerging technologies are now being developed to enhance the therapeutic precision of Nectin-4–targeted treatments. One promising approach involves bicycle toxins—smaller compounds designed to attach a therapeutic payload, penetrate tumor targets more efficiently, and clear from circulation faster, potentially reducing toxicity compared with larger ADCs.²

Ongoing trials are currently exploring therapies in patients with Nectin-4 amplification including the use of bicycle toxin conjugates, ADCs, and radiopharmaceutical targeting agents.²

“Nectin-4–targeted ADCs are really revolutionizing cancers like bladder cancer and other malignancies, and there’s also growing interest in their role in lung cancer,” said Leighl.²

Integrin β6

Integrin β6 (ITGB6) is a cell surface protein highly expressed in various cancers, including lung cancer. It plays a key role in activating transforming growth factor beta (TGF-β) and contributes to tumor progression, cell migration, and invasion. Because of its restricted expression in normal tissues and high prevalence in tumors, integrin β6 is an attractive target for ADCs and other targeted therapies.²

Sigvotatug vedotin (SGN-B6A; Pfizer Inc) is an investigational ADC that targets integrin β6 and delivers a monomethyl auristatin E payload, a potent microtubule-disrupting agent. In early-phase clinical trials, it demonstrated a confirmed overall response rate (ORR) of 19% in heavily pretreated NSCLC patients and up to 31% in less pretreated, non-squamous NSCLC patients.²

When combined with pembrolizumab, the ORR increased to 42.9% in a small cohort. The median PFS in the less pretreated subgroup was 6.4 months. Common adverse events included peripheral neuropathy, fatigue, gastrointestinal effects, and a 12% incidence of pneumonia.²

Sigvotatug vedotin is currently being evaluated in the phase 3 Be6A Lung-01 trial (NCT06012435) comparing it with docetaxel in patients with previously treated NSCLC.^2,4

Folate Receptor Alpha

Folate receptor alpha (FOLR1) plays a key role in folate metabolism and acts as a transcription factor. It is highly expressed in lung adenocarcinoma but less common in squamous cell carcinoma. Early-phase studies have demonstrated at least one response in lung cancer patients, suggesting potential as a therapeutic target. Reported toxicities associated with therapies targeting FOLR1 include cytopenia and transaminitis.²

AI Biomarker Identification

Artificial intelligence is increasingly being applied to accelerate target discovery, simplify the identification of rare genetic alterations, and optimize drug design. By doing so, AI has the potential to reduce the number of agents entering clinical development and streamline the pathway from discovery to patient treatment.²

Network-based approaches help researchers find the “needle in a haystack” rare alterations and identify profound changes relevant to patients with rare cancers. Computational modeling further optimizes drug design, increasing the likelihood of hitting the intended target while decreasing the number of experimental agents needed. Generative AI can analyze initial datasets, review clinical trial results, assess toxicity and efficacy, and examine post-marketing data, enhancing decision-making at multiple stages of drug development.²

The promise of AI in oncology is significant. It could enable researchers to move from target identification to a viable drug in 30 days or less, reduce the number of agents entering clinical trials, and accelerate the development of targeted therapies.²

According to Leighl, “AI is already here to help us with target identification and drug development. More than ever before, these amazing improvements in drug design will really accelerate not just target discovery, but also targeted therapies development.”²

Looking Ahead

The landscape of lung cancer treatment continues to evolve rapidly with the discovery of novel biomarkers, targeted agents, and immunotherapies. Advances in rare kinase alterations, surface protein targeting, and the integration of AI promise to expand treatment options and improve outcomes for patients. Continued research and clinical trials will be essential to translate these scientific discoveries into real-world benefits, offering hope for more precise, effective, and personalized lung cancer therapies.

REFERENCES

1. Gerlach A. From mutation to medicine: Targeted therapies in lung cancer. Pharmacy Times. October 18, 2025. Accessed October 19, 2025. https://www.pharmacytimes.com/view/from-mutation-to-medicine-targeted-therapies-in-lung-cancer

2. Wolf J, Jänne P, Leighl N. Targeting oncogenes in NSCLC. Presented at: European Society for Medical Oncology 2025 Congress. October 17, 2025, to October 21, 2025. Berlin, Germany.

3. A study of LY4050784 in participants with advanced or metastatic solid tumors. Clinicaltrials.gov. Updated September 15, 2025. Accessed October 19, 2025. https://clinicaltrials.gov/study/NCT06561685

4. A study of SGN-B6A versus docetaxel in previously treated non-small cell lung cancer. Clinicaltrials.gov. Updated September 12, 2025. Accessed October 19, 2025. https://clinicaltrials.gov/study/NCT06012435