Most patients with advanced NSCLC without driver mutations will get pembrolizumab (high expressers) or PD1-/PD-L1-inhibition with chemotherapy or perhaps combined PD-1/CTLA4-inhibition in first-line. If there is a response, most patients will still get a recurrence or progress. But what can we offer to them then?
With PD-1/PD-L1-inhibition in 2nd-line we got a good evidence-based treatment option. Moving this in first-line we have to find alternatives. Until now almost no relevant data exist. We suggest following scenarios: a) after first-line pembrolizumab alone a classical chemotherapy doublet should be given. In case of mono/oligo-progression local therapies can be added. Alternatively addition of a further immune modulator can be examined in clinical trials. b) after first-line immune-checkpoint-inhibition and chemotherapy classical second-line chemotherapy is reasonable. If not yet given, pemetrexed could be applied in non-squamous NSCLC. Else usually docetaxel will be chosen. In early progression / recurrence antiangiogenetic drugs can be added. Of course a further immune modulating drug can be tested in prospective clinical trials and in mono/oligo-progression local treatment is possible. c) after first-line PD-1- and CTLA4-inhibition classical doublet chemotherapy is probably the preferred option. Alternatively prospective clinical trials can examine further immune modulating agents. In case of mono/oligo-progression local treatments can be evaluated. For the situation of 2nd recurrence only individualized treatment decisions can be offered.
Overall there is no good evidence how to proceed after disease progression after treatment with immune-checkpoint-inhibitors. Prospective clinical trials in order to select good sequence options for advanced NSCLC without driver mutations are urgently needed.