For patients with metastatic non–small cell lung cancer (NSCLC) lacking an actionable driver mutation, the choice between immune checkpoint inhibitor (ICI) monotherapy and combination therapy increasingly turns on a PD-L1 threshold, tumor histology, and adverse effect (AE) profile, rather than efficacy alone, according to faculty at an OncLive® Scientific Interchange and Workshop
“The data [are] very compelling for PD-L1 [expression level of] over 80% to generally go with monotherapy,” Sandip P. Patel, MD, of UC San Diego Health Moores Cancer Center, said during the workshop.1
Faculty worked through 2 illustrative cases, including one squamous with high PD-L1 expression and another with nonsquamous, PD-L1–negative, TP53-mutated disease. Discussion spanned where to set the PD-L1 expression levels cutoff for monotherapy, how PD-1 and PD-L1 inhibitors compare on rash and other AEs, whether STK11 and KEAP1 co-mutations should steer patients toward CTLA-4 inhibitor–based combinations, the growing use of subcutaneous formulations in maintenance, and the gaps that remain for patients with KEAP1-mutated disease and for never-smokers without actionable alterations.
Top takeaways from an OncLive workshop on ICI selection in mNSCLC
- Faculty generally favored ICI monotherapy at PD-L1 tumor proportion score (TPS) ≥80%, citing a desire to avoid taxane-based chemotherapy when the data support it.
- Cemiplimab's lower reported rates of rash (1.1%) and pneumonitis, plus supportive data in patients with hepatitis B, hepatitis C, or HIV, made it faculty's preferred PD-1 inhibitor for high-PD-L1 and squamous disease.
- For PD-L1–negative disease, faculty favored CTLA-4 inhibitor–based regimens (CheckMate 227, CheckMate 9LA) but cautioned that STK11 and KEAP1 remain prognostic, not validated predictive, biomarkers.
- KEAP1-mutated tumors were described as platinum resistant with dismal real-world outcomes across regimens, prompting several faculty to limit chemotherapy intensity in this subgroup.
- Subcutaneous ICI formulations are being adopted quickly in the maintenance phase, driven by shorter chair time and formulary/pathway integration.
- Faculty called for faster KEAP1 testing turnaround (currently about 3 weeks) and more effective options for KEAP1-mutated and non-smoking, biomarker-negative disease.
What PD-L1 expression threshold should guide ICI monotherapy in squamous NSCLC?
Presented with a 68-year-old man with squamous metastatic NSCLC and a PD-L1 tumor proportion score (TPS) of 95%, faculty largely favored PD-1 monotherapy. Six-year follow-up of the phase 3 EMPOWER-Lung 1 trial (NCT03088540) reinforced that preference: cemiplimab-rwlc (Libtayo) monotherapy produced a median overall survival (OS) of 26.1 months (squamous, 22.7; nonsquamous, 28.7), with 23.8% of patients alive at 6 years. Notably, 1.1% of patients experienced any-grade rash, vs 11% with pembrolizumab (Keytruda) in the phase 3 KEYNOTE-024 trial (NCT02142738) and 18.5% with atezolizumab (Tecentriq) in the phase 3 IMpower110 trial (NCT02409342).2
Panelists said the AE profile, not efficacy, is now a deciding factor.1
“It's not really in question at this point that the PD-L1 inhibitors across the board...are just slightly less [in terms of] AEs and slightly less potent [than PD-1 inhibitors],” Eric K. Singhi, MD, of MD Anderson Cancer Center, said.
Patel put his own cutoff at a TPS of 80% to 90%, reasoning that “even dirty biomarkers can still be useful, especially if they're pointing you to a decision between things that are reasonable.”
Julian A. Marin-Acevedo, MD, of Indiana University, cautioned the threshold effect may not hold in squamous disease. Citing a retrospective analysis, he noted “the higher the PD-L1 [level], the better for nonsquamous. As long as it's positive for squamous, the responses don't apparently change that much. PD-L1 might not be always the right biomarker for squamous in particular.”
Faculty also noted that EMPOWER-Lung 1's inclusion of patients with hepatitis B, hepatitis C, or HIV made its data especially relevant to real-world practice.
How do STK11 and KEAP1 mutations shape combination therapy in nonsquamous metastatic NSCLC?
For a 58-year-old never-smoker with PD-L1–negative, TP53-mutated nonsquamous disease with a high tumor mutational burden, faculty converged on CTLA-4 inhibitor–based combinations, the regimens from the phase 3 CheckMate 227 (NCT02477826) or CheckMate 9LA (NCT03215706) trials, regardless of co-mutation status.1
A 5-year genomic analysis of the phase 3 EMPOWER-Lung 3 trial (NCT03409614) showed OS benefit with cemiplimab plus chemotherapy in TP53-mutated (HR, 0.48; 95% CI, 0.29-0.79) and KRAS-mutated (HR, 0.52; 95% CI, 0.26-1.04) subgroups, but not in KEAP1-mutated disease (HR, 1.08; 95% CI, 0.35-3.34).3
Singhi tied these findings to platinum sensitivity. “With KEAP1, you're driving a lot [of resistance],” he said, adding that patients in the community often cannot wait for results because testing “takes 3 weeks. You don't have time.”
