Resistance is the biggest challenge across the landscape of different compounds such as the new RET or MET inhibitors. I think it is promising to look at the story of EGFR-activating mutations, as initially we had gefitinib and erlotinib but were unaware of how they actually worked until the mutation data evolved. Subsequently, more potent compounds were created that continue to extend the time of patients on these treatments through improved medicinal chemistry and superior target binding.

Retrospective analyses have demonstrated limited activity of immune checkpoint inhibitors (CPIs) in patients with actionable oncogenic driver mutations. In similar vein, the ran­domized controlled IMpower150 and IMpower130 studies revealed no survival benefit of adding CPIs to platinum doublets in patients who harbored EGFR and ALK aberrations.

Based on the randomized, phase III CheckMate 9LA study, the first-line regimen of nivolumab plus ipilimumab and two cycles of chemotherapy has been approved in the indication of meta­static NSCLC without EGFR or ALK aberrations in many countries. CheckMate 9LA included approximately 360 patients with stage IV or recurrent disease in each arm and demonstrated significant OS, PFS, and ORR improvements with the immunotherapy-based regimen compared to four cycles of standard chemotherapy.

Approximately 13 % of patients with ade­nocarcinoma of the lung harbor the KRASG12C mutation. To date, no agent targeting this oncogenic driver has been licensed, although there is a need to improve outcomes in this population after progression on first-line treatment encompassing immune checkpoint inhibitors. The first-in-class, irreversible, selective KRASG12C inhibitor sotorasib has demonstrated durable clinical benefit in pretreated patients with KRASG12C-mutated, locally advanced or metastatic NSCLC in the single-arm phase II CodeBreaK100 trial.

EGFR tyrosine kinase inhibitors (TKIs) are the established first-line option in patients with EGFR-mutated NSCLC, although resistance inevitably develops in the long run. A wide variety of genomic alterations has been identified in the context of EGFR TKI resistance. HER3, which is expressed in 83 % of NSCLC tumors, is not known to confer resistance to EGFR TKI therapy in EGFR-mutant disease.

Despite established strategies such as platinum-based chemotherapy and EGFR-targeted agents, there is a high unmet need for improved adjuvant treatment in the setting of completely resected early-stage NSCLC (stage IB-IIIA). Therefore, the global phase III IMpower010 trial tested the anti-PD-L1 antibody atezolizumab 1,200 mg every 21 days for 16 cycles compared to best supportive care (BSC) in patients with stage IB-IIIA lung cancer who had undergone lobectomy or pneumonectomy followed by 1-4 cycles of chemotherapy.