Would you consider checkpoint inhibitor therapy alone in a patient with metastatic NSCLC with PDL-1 < 1% who is otherwise refusing chemotherapy?

I would not personally recommend a checkpoint inhibitor in the first line setting of a PDL1 negative metastatic NSCLC. I think genomic analysis would help guide that decision as well. For example, the presence of an STK11 mutation would make me even more hesitant to recommend a single agent checkpoint inhibitor. Based on Checkmate 227, if a patient is completely against chemotherapy in combination with immunotherapy, one could consider nivolumab with ipilimumab if TMB is high.

I would not do single agent IO.

I would consider ipilumumab+nivolumab based on Checkmate-227, where PDL1<1% and TMB-low subgroups showed benefit.

I agree with @Dr. First Last's answer. I would generally try to understand why the patient is refusing chemo (ie chemo + pembro), and reassure them about 4 cycles of chemo, then maintenance pembro; however, if after thoughtful consideration they still refuse chemo, I'd think about nivo/ipi given the CheckMate 227 showing benefit in the greater and less than 1% population. I would like to see the study of Keynote 189/407 vs CheckMate 227 (ie chemo + pembro vs nivo/ipi). I agree that currently we have no strong data supporting single agent pembro (and even less for single agent nivo).

With the available keynote data, I would not recommend pembro for PD-L1 <1%. If they have good functional status and no overt autoimmune diseases, ipi+Nivo is an option for TMB high expressers. I would also get full NGS testing, either tissue or liquid if not enough tissue is available.