Do we have any data on sequencing of up front therapies for patients with high PD-L1 and targeted mutations?

Patients with EGFR and BRAF mutations or ALK and ROS1 fusions should receive 1st line approved TKI therapy and second line approved TKI therapy for EGFR and ALK. Checkpoint inhibitors should be used only after TKIs even if PD-L1 expression is high. For patients with PD-L1 expression >50%, it is not clear whether checkpoint inhibitor alone or combined with chemotherapy would be superior. 

@Dr. First Last makes a very important point. I have seen at least 2 cases where patients were started on pembrolizumab because the tumor PD-L1 was high and then subsequently tumor was found to be EGFR mutation positive. 

As far as sequence of therapy, yes Osimertinib followed by chemotherapy (platinum/pemetrexed combo), unless a specific genetic alteration is identified in the tumor following progression on Osimertinib. After Osimertinib and platinum based chemo, equal consideration could be made for PD-1/PD-L1 inhibitors or docetaxel though I would lean towards docetaxel. 

Two other issues-

1. Impower 150 demonstrated signficantly improved PFS with the combination of carboplatin/palitaxel/bevacizumab/atezolizumab compared to carboplatin/paclitaxel and bevacizumab in EGFR and ALK positive NSCLC patients. Further information and regulatory authority approval is needed before such combinations can be integrated into routine practice. 

2. We have reported on 2 patients who received osimertinib after having received erlotinib and PD-1 inhibitor on a clinical trial and subsequently developed pneumonitis. Since the half life of antibodies is long, toxicities from the interaction with osimertinib may occur even after the PD-1/PD-L1 inhibitor has been discontinued. 

One clarification on my previous comment- In IMPOWER150 patients with EGFR and ALK NSCLCs were only enrolled after treatment with TKIs.