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.

REFERENCE

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.