When Standard Therapy Is Not Feasible in Stage III Non–Small Cell Lung Cancer
Edgardo Santos, MD, The Oncology Institute, Hollywood, Florida, discusses the management of a patient with unresectable stage III KRAS G12C–mutated, PD-L1–high non–small cell lung cancer (NSCLC) to illustrate how clinical and molecular factors influence treatment selection.
He reviews the evidence supporting concurrent chemoradiotherapy followed by durvalumab as the standard of care while explaining how treatment tolerance, radiation feasibility, and comprehensive biomarker testing informed an alternative therapeutic approach. He also highlights the evolving role of molecular profiling, PD-L1 expression, and circulating tumor DNA in guiding personalized treatment decisions and assessing response.
Transcript:
Hi, everyone. My name is Dr Edgardo Santos. I’m the medical director for the Oncology Institute of Hope and Innovation, the physician lead for the TOI Lung Cancer Center of Excellence, and a clinical associate professor at Florida Atlantic University. I’m also currently the president of FLASCO here in the state of Florida. Thank you again to the Oncology Learning Network for inviting me to present this case, which represents a very common scenario in our clinical practice.
This is a 65-year-old Caucasian woman whom I saw several months ago. She initially presented with shortness of breath and weight loss. Her symptoms began early in 2025. She had experienced both influenza and COVID infection and initially believed that her persistent cough represented residual symptoms from those infections. However, her shortness of breath continued to worsen, so she sought medical attention in July. A chest X-ray demonstrated a lesion in the right middle lobe, which was confirmed on CT imaging.
She underwent biopsy of the right middle lobe lesion, which demonstrated poorly differentiated adenocarcinoma with extensive necrosis. Unfortunately, there was only limited diagnostic material available, making it difficult to perform the molecular testing and immunohistochemistry that we routinely obtain today to guide treatment decisions. The tumor stained positive for TTF-1, Napsin A, and CK7, and negative for p63, p40, and GATA3, consistent with a primary lung adenocarcinoma. For staging, MRI of the brain showed no brain metastases. PET/CT demonstrated extensive disease involving the right middle lobe primary tumor, right hilar lymph nodes, bilateral mediastinal lymph nodes, bilateral supraclavicular lymph nodes, and a small ipsilateral pulmonary nodule. Clinically, she had T4N3M0 stage IIIC adenocarcinoma of the lung according to the AJCC staging system.
Her past medical history included inflammatory bowel disease. She was a light smoker, approximately five cigarettes daily for about 40 years, and had quit nine years previously. There was no significant alcohol or illicit drug use. Her family history included colon cancer in her mother and prostate cancer in her brother. Physical examination was unremarkable, and laboratory studies demonstrated only mild normocytic anemia with otherwise normal biochemistry.
When I first saw the patient, attempts had already been made to perform tissue next-generation sequencing, but there was insufficient tissue, and PD-L1 testing could not be completed. Therefore, I ordered a liquid biopsy, which identified KRAS G12C and TP53 mutations. I then discussed with the patient the importance of obtaining another tissue biopsy for comprehensive molecular profiling and PD-L1 testing, and she agreed. The repeat biopsy again confirmed KRAS G12C and demonstrated a PD-L1 tumor proportion score of 98%.
The clinical question becomes: how should we treat a patient with T4N3M0 stage IIIC adenocarcinoma of the lung, excellent performance status, KRAS G12C mutation, and PD-L1 expression of 98%?
Possible treatment options include concurrent chemoradiotherapy followed by consolidation immunotherapy, induction chemotherapy followed by concurrent chemoradiotherapy and consolidation immunotherapy, single-agent immunotherapy, or chemoimmunotherapy. Based on current guidelines and available evidence, the standard approach for unresectable stage 3 disease is concurrent chemoradiotherapy followed by 1 year of durvalumab. This recommendation comes from the PACIFIC trial.
As we remember, PACIFIC enrolled patients with unresectable stage IIIA, IIIB, or IIIC non–small cell lung cancer who had not progressed following platinum-based concurrent chemoradiotherapy. Patients were randomized to durvalumab 10 mg/kg every 2 weeks for 1 year or placebo. The coprimary end points were progression-free survival and overall survival. The trial was positive for both end points. Median progression-free survival improved from 5.6 months with placebo to 16.9 months with durvalumab. Subsequent overall survival analyses also demonstrated a significant benefit. Median overall survival reached 47.5 months with durvalumab, substantially improving upon the historical outcomes of concurrent chemoradiotherapy alone, which had generally been around 28 to 30 months. We also know from subgroup analyses that patients with PD-L1 expression derive particularly meaningful benefit, whereas patients without PD-L1 expression appeared to derive less benefit.
Returning to our patient, she was evaluated by radiation oncology. Because of the very large treatment volume, the radiation oncologist recommended induction chemotherapy in an attempt to reduce tumor burden before proceeding with concurrent chemoradiotherapy. She therefore received 2 cycles of cisplatin plus pemetrexed. Unfortunately, she tolerated treatment poorly and developed pancytopenia after both cycles. Following repeat volumetric assessment, radiation oncology concluded that the radiation field remained too large and that proceeding with definitive thoracic radiation would place her at very high risk for severe radiation pneumonitis. At that point, we reconsidered her overall treatment strategy.
Importantly, we now had complete molecular information, including the KRAS G12C mutation and the very high PD-L1 expression of 98%. Given her inability to tolerate chemotherapy and the inability to safely deliver thoracic radiation, we elected to proceed with single agent pembrolizumab. This decision was supported by the KEYNOTE-024 trial, which enrolled patients with advanced non–small cell lung cancer and PD-L1 expression of at least 50%. In that study, pembrolizumab significantly improved overall survival compared with chemotherapy, with median overall survival of 26.3 months versus 13.4 months. Long-term follow-up from KEYNOTE-024 further established pembrolizumab monotherapy as a standard treatment in this population.
We also know from the EMPOWER-Lung 1 study evaluating cemiplimab that patients with very high PD-L1 expression, particularly above 90%, appear to have especially favorable outcomes, with median overall survival exceeding 30 months. This reinforces the concept that not all PD-L1–high tumors behave identically. Patients with PD-L1 expression above 90% may derive even greater benefit from immune checkpoint inhibitor monotherapy.
This case illustrates a common but challenging clinical scenario. Although concurrent chemoradiotherapy followed by durvalumab remains the standard of care for unresectable stage 3 disease, individual patient factors—including disease volume, radiation feasibility, treatment tolerance, and molecular profile—must all be considered.
In our patient's case, despite induction chemotherapy, radiation remained unsafe because of the treatment volume and the patient's poor tolerance to systemic therapy. Given her PD-L1 expression of 98%, we proceeded with pembrolizumab monotherapy. After only 3 cycles of pembrolizumab, PET/CT demonstrated a complete metabolic response. In addition, circulating tumor DNA, which had initially shown a tumor fraction of 1.89%, became undetectable after three cycles of treatment. So radiographically and molecularly, the patient is currently in clinical remission. With that, I conclude this presentation. I hope to have the opportunity to present another interesting case in the near future.
