Longer Survival with Four-Drug Treatment in EGFR- or ALK-Mutated Lung Cancer

EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma kinase) mutations are common genetic alterations in non-small cell lung cancer (NSCLC) that can profoundly affect treatment. Advanced lung cancers with these alterations are now initially treated with targeted medicines. EGFR tyrosine kinase inhibitors (TKIs) are prominent first-line options in EGFR-positive disease, while oral ALK inhibitors are preferred for ALK-mutated cancers. Some patients, however, develop resistance over time. Subsequent treatment depends on genetics, clinical characteristics, stage and other potential mutations. New strategies and combinations are continually investigated to overcome resistance and improve outcomes.

Promising phase III ATTLAS results presented at ESMO Congress 2023 in Madrid on October 20-24 suggest a potential new approach for patients whose cancer progresses despite TKIs.

In patients with TKI-resistant NSCLC, ATTLAS tested atezolizumab, bevacizumab and cisplatin–pemetrexed (ABCP). As the first randomized phase III study of this regimen, it met its primary endpoint. Patients receiving ABCP had significantly longer median progression-free survival (PFS) than those receiving chemotherapy alone: 8.5 versus 5.6 months (hazard ratio [HR] 0.62; 95% confidence interval 0.45-0.86; p=0.004).

ATTLAS continues research into new treatments after progression on TKIs, confirming preliminary evidence from IMpower150 subgroup analyses. IMpower150 showed a favorable survival effect from combining a PD-L1 inhibitor with a VEGF inhibitor in EGFR-mutated patients previously treated with TKIs.

Consistent with the PFS benefit, objective response rates were higher with ABCP than chemotherapy alone (69.5% versus 41.9%; p<0.001). No additional safety signals were reported. The study enrolled 228 patients with EGFR mutations or ALK translocations who had progressed on previous TKI treatment.

The PFS (disease-free survival) effect appeared related to PD-L1 expression. At PD-L1 expression levels of 1% or higher, 10% or higher and 50% or higher, HRs were 0.47, 0.41 and 0.24, respectively. This is noteworthy because earlier studies found no direct relationship between PD-L1 expression and checkpoint inhibitor response in patients with driver mutations. Further studies are needed to validate and fully understand this observation.

TKIs have become standard treatment in driver-mutated lung cancer, but many patients eventually develop resistance. ATTLAS is the first prospective study showing that this four-drug regimen may offer advantages over chemotherapy.

Several interesting studies are underway in driver-mutated, TKI-resistant disease, including fourth-generation EGFR inhibitors, HER3- and TROP2-directed antibody–drug conjugates, and combinations with c-MET inhibitors. Typical NSCLC response rates range from 30%-50%, making it important to develop biomarkers that direct treatment to those most likely to respond. The risk of adverse events also makes the interval between TKIs and immunotherapy combinations important. Careful consideration of when to stop TKIs is therefore needed to optimize treatment benefit.