A real-world study of single-agent immune checkpoint inhibitors in driver-mutated non–small cell lung cancer (NSCLC) has demonstrated significant variation in progression-free survival between mutation subtypes, according to data presented during the International Association for the Study of Lung Cancer (IASLC) 2020 North America Conference on Lung Cancer.1
Although the large, retrospective analysis confirmed a poor progression-free survival for patients with EGFR- and ALK-positive tumors, investigators identified a small subset of patients in whom single-agent immunotherapy demonstrated a benefit. Data showed that 8% and 11% of patients with EGFR- and ALK-mutated disease, respectively, were progression-free at 12 months.
“Further research characterizing this subset of patients to determine the potential clinical and molecular features associated with extended progression-free survival is of great interest,” said lead study author, J. Nicholas Bodor, MD, PhD, MPH, Assistant Professor of Thoracic Oncology at Fox Chase Cancer Center in Philadelphia.
“PD-L1 positivity was correlated with progression-free survival only in KRAS-mutated tumors.”— J. Nicholas Bodor, MD, PhD, MPH
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Results also showed a limited correlation between PD-L1 positivity and progression-free survival. In particular, said Dr. Bodor, there was no indication that PD-L1 positivity was predictive of longer survival in EGFR-mutated tumors.
“PD-L1 positivity was correlated with progression-free survival in KRAS-mutated tumors alone,” said Dr. Bodor. “Ultimately, PD-L1 expression may not be a useful biomarker for other mutation subtypes.”
Background and Study Design
As Dr. Bodor explained, immunotherapy has medically changed the treatment landscape of advanced NSCLC, but only a subset of patients have durable responses. Although results from second-line immunotherapy clinical trials have shown that tumors with oncogenic mutations in EGFR or ALK have an increased resistance to single-agent checkpoint inhibitors, said Dr. Bodor, few studies have examined immunotherapy outcomes in driver-mutated NSCLC using large, real-world patient cohorts. It is also unclear whether PD-L1 expression and smoking history are predictive of response in driver-mutated tumors.
For this study, Dr. Bodor and colleagues used a nationwide, de-identified database from Flatiron Health to analyze patients with advanced NSCLC possessing driver-mutated tumors treated with single-agent immunotherapy. Real-world progression-free survival was defined as the time from immunotherapy initiation to the date of real-world disease progression or death. Dates of real-world progression events were ascertained using clinician documentation of growth or worsening of disease in electronic health records. Median progression-free survival was determined for EGFR, ALK, BRAF, and KRAS mutation subtypes, and survival was correlated to PD-L1 expression and smoking history.
PD-L1 Expression Not Predictive of Outcome
As Dr. Bodor reported, the study cohort included 1,746 patients with driver-mutated tumors who were treated with single-agent immunotherapy between April 2014 and February 2019. Of these patients, 458 had EGFR-mutated tumors, 65 had ALK-mutated tumors, 146 had BRAF-mutated tumors, and 1,077 had KRAS-mutated tumors. PD-L1 expression data were available for 795 patients.
The majority of patients were female, including two-thirds of patients with EGFR-mutated lung cancer. In addition, most tumors were nonsquamous in histology, and, as expected, history of smoking varied considerably by mutation subtype.
“The large majority of patients with KRAS- or BRAF-mutated tumors had a history of smoking, whereas a larger percentage of those with EGFR- or ALK-mutated tumors had no smoking history.”— J. Nicholas Bodor, MD, PhD, MPH
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“The large majority of patients with KRAS- or BRAF-mutated tumors had a history of smoking, whereas a larger percentage of those with EGFR- or ALK-mutated tumors had no smoking history,” said Dr. Bodor. “However, it is interesting to note that approximately half of the patients in the EGFR- and ALK-positive group had some smoking history.” Dr. Bodor also reported that approximately 75% of tumors were PD-L1–positive (> 1% PD-L1 expression), which was the case for all mutation subtypes.
Results showed that median progression-free survival varied significantly by tumor-mutation subtypes. Patients with KRAS- and BRAF-mutated tumors had longer progression-free survival compared to patients with EGFR or ALK mutations, Dr. Bodor reported.
Although EGFR- and ALK-positive tumors were associated with relatively short progression-free survival (approximately 2.5 months), Dr. Bodor and colleagues identified a small subset of patients with extended progression-free survival. For EGFR-mutated tumors, 8% of patients were progression-free at 12 months, and for ALK-mutated tumors, 11% of patients were progression-free at 12 months.
Of note, progression-free survival did not vary significantly by PD-L1 expression for EGFR, ALK, and BRAF tumors, said Dr. Bodor. Only in patients with KRAS-mutated tumors did progression-free survival vary by PD-L1 expression. Those with PD-L1–positive KRAS tumors had significantly longer progression-free survival compared with those who had PD-L1–negative tumors (4.2 vs 3.0 months).
Although PD-L1 expression did not appear to be predictive of outcomes for most tumor-mutation subtypes, the authors noted that smoking may be a predictive marker. “There was a suggestion that having a smoking history resulted in a modest improvement in median progression-free survival for EGFR- and ALK-mutated tumors,” Dr. Bodor concluded.
DISCLOSURE: Dr. Bodor reported no conflicts of interest.
1. Bodor JN, Bauman JR, Handorf EA, et al: Real-world progression-free survival in oncogenic driver-mutated non-small cell lung cancer treated with single-agent immunotherapy. 2020 North America Conference on Lung Cancer. Oral Abstract Session 2. Presented October 17, 2020.
Invited discussant of the abstract, Joel W. Neal, MD, PhD, Associate Professor of Medicine at Stanford University, called this real-world analysis novel,1 given the decreasing number of patients treated with single-agent immunotherapy.
“I think we’re unlikely to have a larger prospective study [in ...