Impact of Tumor Burden on Survival for Patients with EGFR-Mutant NSCLC Treated with Osimertinib

The number of visceral tumors and metastatic disease sites impacts survival in patients with stage IV EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC) treated with osimertinib monotherapy, according to a Cleveland Clinic study recently presented at the American Society of Clinical Oncology 2024 annual meeting.

“Traditionally, we’ve given osimertinib as monotherapy for these patients,” says Nathan Pennell, MD, PhD, co-director of the Cleveland Clinic Lung Cancer Program and Vice Chair of Clinical Research for Cleveland Clinic Cancer Center. “But recent trial data from FLAURA2 demonstrated a significant progression-free survival benefit to combination therapy with platinum-pemetrexed chemotherapy. Unfortunately, it also demonstrated a clear increase in adverse events, so it’s not a clear-cut decision. Our analysis offers an additional data point when considering this clinical decision.”

Tumor burden and survival

Acquired resistance to the tyrosine kinase inhibitor (TKI) osimertinib has remained a challenge for treating patients with EGFRm NSCLC. Some studies have indicated a potential association between tumor burden and the risk of developing resistant clones to TKI monotherapy, but none have explored an association with clinical outcomes.

The research team, including first author Lukas Delasos, DO, a fellow at Cleveland Clinic Cancer Center, reviewed the records of stage IV EGFRm NSCLC patients who received osimertinib between 2018 and 2023. Patients who discontinued use for reasons other than disease progression were excluded. The 325 patients had a median follow-up time of 22.7 months (0.6 – 85.6 months). Median progression-free survival (PFS) for the group was 16.3 months (95% CI; 13.7 – 18.9), and median overall survival (OS) was 31.1 months (95% CI; 27.4 – 39.3).

The team used the total number of visceral tumors (TTn, 1-4, 5-9, ≥10) and the total number of sites of metastatic disease (MDn, 1-2, 3-4, ≥5) to characterize tumor burden at baseline. Patients with 1-2 metastatic disease sites had better median PFS and OS compared with those with higher MDn of 3-4 and ≥5 (median PFS: 21.5 vs 11.4 vs 9.0 months, respectively [P < 0.0001]; median OS: 44.3 vs 20.8 vs 22.4, respectively [P < 0.0001]. A similar correlation was observed with the total number of visceral tumors; patients with 1-4 visceral tumors had significantly higher median PFS compared with patients with 5-9 and ≥10 visceral tumors (median PFS: 21.5 vs 16.3 vs 13.4 months, respectively P = 0.001). Patients with 10 or more visceral tumors had significantly worse median OS compared with those with 1-4 or 5-9 tumors (23.7 vs 35.1 vs 57.7 months, respectively; P < 0.0001). Location of metastases impacted survival as well, as patients with bone and liver metastases had worse median PFS and OS, and those with brain and lung metastases only had worse median OS.

Combination therapy or osimertinib alone?

In this cohort, the extent of a patient’s baseline tumor burden impacted both PFS and OS in patients with stage IV EGFRm NSCLC who have been treated with osimertinib monotherapy. Patients with lower tumor burden, as characterized by TTn and MDn, appear to fare better than those with intermediate or higher tumor burden, and the risk of adverse events may outweigh the benefits of combination therapy in this population.

“Ultimately, this topic needs further study, including prospective trials,” says Dr. Pennell, “but for a clinician deciding whether to treat with TKI or combination therapy, it may be a good idea to include tumor burden when weighing risks and benefits for these patients.”