Disease progression in non-small cell lung cancer on immune-checkpoint inhibition, what are the options?

Most patients with advanced non-small cell lung cancer (NSCLC) and without driver mutations get or will get in the near future pembrolizumab (high expressers of PD-L1) or a combination of PD-1-/PD-L1- with chemotherapy or perhaps a combination of PD-1- and CTLA4-inhibition. In stage III after chemoradiotherapy consolidation with durvalumab is in use. If there is a response to first-line therapy, most patients will still get a recurrence or progress. The question is what kind of therapy we can offer to these patients. With the introduction of PD-1- and PD-L1-inhibition in the recurrent disease situation we got a good treatment option with solid evidence from randomized trials. As these immune-checkpoint-inhibitors are moving in first-line we have to find alternatives for recurrent or refractory tumours. Until now almost no relevant data exist what the best options are. Extrapolating from the knowledge we have from earlier situations we can suggest the following scenarios, but they have to be confirmed by prospective clinical trials: (I) if in first-line pembrolizumab alone was given, probably a classical chemotherapy doublet should be given. In the case of mono/oligo-progression local therapies can be added. Alternatively the addition of a further immune modulating drug can be examined in clinical trials; (II) if in first-line a combination of immune-checkpoint-inhibition and chemotherapy was applied, probably classical second-line chemotherapy is reasonable. If in first-line pemetrexed was not given, it could be applied in non-squamous NSCLC for second-line. Else usually docetaxel will be chosen. The question of rapid recurrence/progression leads to the option of adding antiangiogenetic drugs in early progression/recurrence. Of course a further immune modulating drug can be tested in prospective clinical trials and in mono/oligo-progression local treatment can be discussed; (III) if in first-line a combination of PD-1- and CTLA4-inhibition was used, 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 at the moment only individualized treatment decisions can be offered. Overall there is unfortunately no good evidence until now how to proceed after disease progression after treatment with immune-checkpoint-inhibitors. Prospective clinical trials in order to select good sequence options for the treatment of advance NSCLC without driver mutations are urgently needed.