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Activating mutations in the epidermal growth factor recep-tor (EGFR) are identified in 15% of Non-Small Cell Lung Cancer. Despite the success of targeted treatment, ac-quired resistance and disease progression inevitably occur. A number of mechanisms of acquired resistance in patients treated with a first-generation EGFR TKI (erlotinib, gefitinib) or second-generation EGFR TKI (afatinib, dacomitinib) have been described with the most common mechanism of resistance being the emergence of the T790M mutation in EGFR in about 50-60% of patients after EGFR TKI failure. The standard treatment in patients harbouring EGFR T790M mutations is osimertinib, a thirdgeneration EGFR TKI. In patients without an EGFR T790M mutation and with acquired resistance to EGFR TKI, or in patients who have progressed after 1st line osimertinib, the standard treatment is platinum based doublet chemotherapy. Atezolizumab is a humanised monoclonal antibody against PD-L1.The randomised phase III IMpower150 trial tested atezolizumab in combination with bevacizumab and carboplatin/paclitaxel (ABCP) versus bevacizumab and carboplatin/paclitaxel alone (BCP) in patients with metastatic NSCLC who had not previously received chemotherapy. Progression-free survival (PFS) for patients without an EGFR or ALK genetic alterations was longer in the ABCP than in the BCP group [8.3 months vs. 6.8 months; HR 0.62; 95% CI 0.52-0.74; P <0.001] Median OS in patients with wild-type genotype was longer in the ABCP group than in the BCP group (19.2 months vs. 14.7 months; HR 0.78; 95% CI, 0.64-0.96; P = 0.02).
The combination of atezolizumab, bevacizumab and chemotherapy was well tolerated and its safety profile was consistent with the safety profile of the individual drugs with no new safety signals reported. In a subgroup analysis of patients with EGFR mutations or ALK translocations, benefit was seen with ABCP versus BCP for PFS (unstrati-fied HR, 0.59; 95% CI, 0.37-0.94) and for OS (unstratified HR 0.54; 95% CI 0.29-1.03). Based on these results, the European Medicines Agency (EMA) has approved ABCP in patients with EGFR/ ALK+ NSCLC after failure of appro-priate targeted therapies. The combination was not ap-proved by Swissmed.
We aim to explore the combination of atezolizumab and bevacizumab in patients with EGFR mutated NSCLC after failure of standard EGFR targeted therapies, by inde-pendently verifying PFS in patients treated with a car-boplatin-paclitaxel combination (Arm A) and also explore PFS with an investigational backbone of pemetrexed mon-otherapy (Arm B). Pemetrexed and bevacizumab without a platinum agent are considered a promising treatment option with potentially low toxicity in patients with advanced nonsquamous NSCLC, since a randomized phase II study in patients with EGFR TKI resistant NSCLC suggested similar outcomes of pemetrexed/cisplatin versus pemetrexed alone with regards to PFS and OS, preserving the ability to use platinum-based therapy as subsequent treatment.