Would you consider using IO alone for lung cancer patients with PD-L1 <1%  but who have high TMB?

The brief answer here is a resounding no. A more extended version might include a statement that this would be a case of not seeing the forest for the trees.

And the tree here is the FDA approval of pembrolizumab in a tissue-agnostic fashion for patients with advanced TMB >10 mutations/Mbase- likely the most controversial FDA approval in the history of King Keytruda, racking up 40+ approvals over the last decade. The approval is based on a small substudy of KEYNOTE-158, including 9 tumor types (actually not including non-small cell lung cancer) and demonstrating a response rate of 29%. When one looks at the actual data, neither the response rate nor the PFS is all that convincing here, but the approval (Marcus et al., PMID 34083238) does ext...

The CheckMate 227 trial showed that patients with a PD-L1 expression of <1% had a better OS with the combination of nivolumab and ipilimumab when compared to chemotherapy, regardless of TMB status. In an unplanned subgroup analysis, in patients with PD-L1 <1%, patients with a TMB >/= 10 muts/mB seemed to derive a larger benefit with combination ipi-nivo (HR for OS: 0.51; 95% CI, 0.3-0.87). On the other hand, patients with TMB <10 muts/MB had an HR- 0.69 (95% CI, 0.46-1.05) with combination IO. Based on these results, combination IO is an option for patients with PD-L1 <1%, regardless of TMB status.

Agree with Dr. @Dr. First Last that treatment with nivolumab plus ipilimumab is reasonable. In CheckMate 227, ipilimumab is given at 1 mg/kg q6 weeks, which is associated with fewer immune-related side effects compared to other doses/schedules. The mOS in patients with PD-L1-positive vs. negative disease was identical. However, nivolumab plus ipilimumab is not approved in patients with PD-L1-negative disease. The FDA limited approval to PD-L1-positive disease because this was the primary endpoint population in CheckMate 227.