New Frontiers in Targeted Therapy for Rare Lung Cancer Alterations

Bruna Pellini, MD, chief of Thoracic Oncology at Baptist Health Miami Cancer Institute, highlights a period of unprecedented progress in the treatment of rare genomic subtypes of non–small cell lung cancer (NSCLC). Reflecting on the evolution of the field, Pellini notes that only a few years ago, thoracic oncologists lacked the highly effective targeted options available to their colleagues in breast cancer. Today, that landscape has shifted dramatically, particularly for patients with HER2-mutant and ROS1-positive disease.

The HER2 Revolution in Lung Cancer

For years, HER2 mutations in lung cancer lacked specific, effective therapies. However, Pellini points to three recently approved drugs that have redefined the standard of care:

• Trastuzumab deruxtecan (T-DXd; Enhertu): An antibody-drug conjugate that has shown significant efficacy in this patient population.
• Zongertinib (Hernexeos): A highly potent HER2-targeted therapy approved in August 2025, offering a much more tolerable toxicity profile than previous attempts at targeting this mutation.
• Sevabertinib (Hyrnuo): Another critical addition to the arsenal, approved in late 2025, further expanding options for patients who previously had few.

Advancements in ROS1 and ALK-Positive Care

Pellini is particularly enthusiastic about taletrectinib (Ibtrozi), which was approved in the summer of 2025 for ROS1-positive NSCLC. This drug addresses a major quality-of-life hurdle: the central nervous system (CNS) toxicities—such as chronic dizziness and fall risks—common with older-generation ROS1 inhibitors.

"Taletrectinib not only provides high response rates and shrinks tumors effectively in the brain, but it does so without the debilitating dizziness that plagues many patients," Pellini explains.

Furthermore, she underscores the "fascinating" results of the CROWN trial regarding lorlatinib (Lorbrena) for ALK-positive NSCLC. The data demonstrated a five-year median progression-free survival (PFS) that had not yet been reached—a result previously unheard of in stage IV lung cancer. This landmark data has fundamentally changed her clinical practice, making lorlatinib a preferred first-line treatment.

The Nuance of Personalized Selection

Despite the surge in targeted pills, Pellini emphasizes that "the correct therapy for the correct patient" sometimes involves traditional methods. Recent research published in 2025 suggests that for certain subgroups, such as those with BRAF mutations or MET exon 14 skipping mutations, a combination of chemotherapy and immunotherapy might actually yield better survival outcomes than targeted therapy alone. Navigating these nuances is now the central challenge of modern thoracic oncology.

Watch the first part of the interview with Dr Pellini here.