Dr Herzberg on Management Challenges in STK11/KEAP1+, SMARCA4-Deficient Undifferentiated Tumors and NUT Carcinoma

“It's been known for a while that STK11/KEAP1 and SMARCA4 [mutations], especially when found in association with a KRAS mutation, confer particularly poor prognosis when [patients are] given chemotherapy, immunotherapy, and radiation therapy. The most important thing to know is that when I see these mutation patterns…I'm worried about these patients with our conventional therapies.”

Benjamin Herzberg, MD, a medical oncologist at the Herbert Irving Comprehensive Cancer Center, discussed the clinical significance and management challenges associated with several aggressive molecular and pathological subsets of lung cancer, including STK11/KEAP1-mutated tumors, SMARCA4-deficient undifferentiated tumors, and NUT carcinoma. He emphasized that these entities share characteristics of biological aggressiveness, limited responsiveness to standard therapies, and the need for early recognition to guide management and referral to appropriate clinical trials.

Herzberg noted thatSTK11 and KEAP1 mutations, particularly when co-occurring with KRAS mutations, have long been associated with poor prognosis across treatment modalities, including chemotherapy, immunotherapy, and radiation. Their presence signals a higher likelihood of resistance to immune checkpoint blockade and suboptimal benefit from cytotoxic therapy. For this reason, he explained that identifying these mutations early raises a heightened level of concern, as conventional treatment strategies often yield limited and short-lived responses. Molecular profiling at diagnosis is therefore essential to identify these alterations and inform discussions about clinical trials evaluating novel targeted or combination regimens.

Turning to NUT carcinoma, Herzberg stressed the importance of suspicion when a lung tumor appears poorly differentiated or atypical and lacks definitive lineage markers on pathology. NUT carcinoma frequently affects younger patients and never-smokers, and diagnosis relies on identifying NUTM1 rearrangements through immunohistochemistry or molecular testing. Prognosis is typically poor due to rapid disease progression, and standard non–small cell lung cancer (NSCLC) regimens generally offer minimal benefit. Early identification is critical, as these patients may be candidates for investigational therapies, including bromodomain and extraterminal domain inhibitors, or other epigenetically targeted strategies.

Regarding SMARCA4-deficient undifferentiated tumors, Herzberg explained that these malignancies may evolve from underlying NSCLC but demonstrate even more aggressive biology. The therapeutic landscape remains uncertain, as responses to immunotherapy are variable and no established standard exists. Management typically includes platinum-based chemotherapy or immunotherapy, but outcomes remain poor. Ongoing research efforts are focused on understanding the molecular underpinnings of SMARCA4 loss and identifying potential targeted or synthetic lethal strategies.

Herzberg concluded that these aggressive tumor subsets require heightened diagnostic vigilance, early comprehensive molecular testing, and timely referral for clinical trials. Improved biological understanding and therapeutic innovation will be essential to improving outcomes for patients with these high-risk forms of lung cancer.