Frontline Treatment of Metastatic NSCLC Without Actionable Mutations

Mark Awad, MD, PhD Memorial Sloan Kettering Cancer Center

Key Points

• Always confirm the absence of actionable mutations with tissue-based next-generation sequencing, as liquid biopsy alone may miss low-shedding tumors.

• PD-L1 expression guides frontline strategy—50% or greater favors single-agent immunotherapy, whereas 1% to 49% often suggests greater benefit with chemo-immunotherapy.

• Dual immunotherapy with CTLA-4 inhibitors lacks a clear survival benefit in high PD-L1 cases and remains underused due to unclear patient selection.

• With no major efficacy differences among PD-1/PD-L1 inhibitors, choice depends on access, toxicity, and trial data.

• Stay alert for targetable mutations even in currently nonactionable non-small cell lung cancer—KRAS G12C and HER2 may inform second-line options.

The Oncology Brothers—Rahul Gosain, MD, MS, and Rohit Gosain, MD—spoke with Mark Awad, MD, PhD, of Memorial Sloan Kettering Cancer Center, about frontline treatment strategies for patients with metastatic non–small cell lung cancer (NSCLC) without actionable mutations.

To start, Dr. Awad noted that next-generation sequencing is key for ruling out the growing list of actionable mutations. Although liquid biopsy sequencing is an important diagnostic tool, he added, many cancers don’t release enough DNA for these mutations to appear on liquid next-generation sequencing, underscoring the importance of tissue-based sampling.

Selecting Treatment Based on PD-L1 TPS

A primary marker for metastatic lung cancer is PD-L1 tumor proportion score (TPS), which is divided into 3 categories based on PD-L1 expression: negative (less than 1%), low-positive (1-49%), and high (50% or greater). Generally, PD-L1 levels nearing 100% correspond with better response to immune checkpoint inhibition.

For patients with high PD-L1 expression, single-agent immunotherapy with a PD-1 inhibitor is preferred; however, Dr. Awad added the caveat that some molecular subsets of lung cancer, such as EGFR, ALK, and ROS1, have high PD-L1 expression but don’t respond to immunotherapy.

Randomized trial data show that dual immunotherapy with a concurrent CTLA-4 inhibitor did not improve survival in patients with high PD-L1 expression, although combining single-agent immunotherapy with chemotherapy may be appropriate for some who also have a high burden of disease or central nervous system metastases.

While some single-agent immunotherapies are for patients with a low-positive PD-L1 TPS, chemotherapy plus immunotherapy appears to be more effective based on pooled US Food and Drug Administration analyses and data from KEYNOTE-189 and KEYNOTE-407, Dr. Awad stated.

For Dr. Awad, a major issue for thoracic oncologists centers on when to use dual immunotherapy with CTLA-4 inhibitors. He identified an unmet need for trials comparing chemotherapy plus either a PD-1 inhibitor or a PD-1 and CTLA-4 inhibitor.

Generally, most patients who have metastatic NSCLC without actionable mutations aren’t receiving a CTLA-4 inhibitor, Dr. Awad said. “That speaks to the importance of biomarker discovery and development in this space,” he continued. “We’ve had CTLA-4 approved for many years, but we just don’t know the right patient population that benefits from CTLA-4 today.”

Choosing Immunotherapy for Metastatic NSCLC

There’s no evidence of significant differences in efficacy between the approved PD-1 or PD-L1 inhibitors, such as pembrolizumab, cemiplimab, and tislelizumab, so all are reasonable options for patients with high PD-L1 expression, Dr. Awad said.

The consensus is less clear when comparing dual immunotherapy options. The POSEIDON study evaluated durvalumab plus tremelimumab and included 4 cycles of chemotherapy; CheckMate 9La investigated nivolumab plus ipilimumab but limited chemotherapy to 2 cycles. Dr. Awad suggested that each patient’s performance status, high-risk features, and toxicity goals should inform the choice of regimen and overall treatment intensity.

Though the discussion focused on frontline treatment selection for NSCLC without actionable mutations, Dr. Rahul Gosain noted that oncologists still need to be aware of actionable mutations with approved second-line therapies, such as KRAS G12C or HER2-positive disease.