Advanced non–small cell lung cancer (NSCLC) research includes the exploration of strategies to overcome resistance, such as combinations that can improve long-term responses. Disease-free survival benefits are being reported with the use of targeted therapies in the adjuvant setting, which is likely to shift the targeted therapy landscape in the years to come.

One of the most exciting areas of research in NSCLC is in immune resistance or so-called cold tumors. This is when a tumor has no T-cell infiltrate, and—no matter how much you block PD-1 or PD-L1—there is not going to be a response because there are no T cells there. Figuring out why the T cells are missing and how to better get them inside the tumor is a major goal.

Adagrasib is a KRAS inhibitor that was recently approved by the US Food and Drug Administration for the treatment of patients with KRAS G12C–mutated, locally advanced or metastatic NSCLC after at least 1 prior systemic therapy. Going forward, a challenge lies in figuring out how to pair KRAS-targeted agents with immunotherapy. If progress occurs in this area, it may bring KRAS therapy to the frontline setting.

Improvements in targeted therapies have also come with the development of newer-generation agents that are more selective and have less toxicity and by studying the patterns of resistance. The third-generation EGFR inhibitor osimertinib targets the T790M mutation, which is a mechanism of resistance in 50% of patients with NSCLC.

Additionally, targeted therapies are being studied in patients with earlier disease. For instance, the phase 3 ADAURA trial evaluated adjuvant osimertinib in EGFR-mutated stages IB to IIIA NSCLC after complete tumor resection. This trial showed a significant disease-free survival benefit over placebo, a reduction in local and distant recurrence, and improved central nervous system disease-free survival. We await reports from several ongoing studies on the use of targeted therapies in the neoadjuvant/adjuvant setting and on more uncommon or rare mutations (eg, ALK and ROS), and there is a good deal of interest in early-stage NSCLC harboring actionable mutations.

Whether you are targeting molecular alterations, such as EGFR or ALK, or immune checkpoints, such as PD-1 or PD-L1, one of the challenges relates to how to manage resistance. Most of the research interest is in the use of combinations to overcome resistance. To do that, we are going to use biopsies to choose the right combination of therapeutics. We published data evaluating the combination of ramucirumab, a VEGFR2 inhibitor, plus pembrolizumab in immunotherapy-refractory patients. VEGF is involved in immune resistance, and blocking VEGF appears to be immune activating, improving tumor blood flow, which allows more T cells in. This is a promising strategy for some tumors; however, in lung cancer, it is more difficult. These are not VEGF-driven tumors, and, really, we are only getting a small immune effect. The anti-VEGF tyrosine kinase inhibitors are associated with toxicities. The antibodies might have more promise. The ongoing phase 3 Pragmatica-Lung study is comparing ramucirumab plus pembrolizumab with usual care for the treatment of stage IV or recurrent NSCLC following immunotherapy.