Tumour Mutation Burden Predicts Immunotherapy Response in Lung Cancer

PD-1/PD-L1 molecules are blocked to activate the immune system against cancer by immunotherapies, which have transformed outcomes in lung cancer and become standard treatment. However, while some patients respond well to immunotherapy, others do not achieve the desired response. To predict which patients will respond well, intensive “biomarker research” is under way. A notable study was reported on 16 June 2022 in JAMA Oncology. Ricciuti and colleagues found that patients with higher tumour mutation burden (TMB) and advanced non-small cell lung cancer (NSCLC) had better outcomes with immunotherapy than other patients.

Results From 1500 Patients

The study retrospectively analysed 1,552 patients receiving PD-1 or PD-L1 inhibitor immunotherapy without chemotherapy: 714 from Dana-Farber Cancer Institute, 672 from Memorial Sloan Kettering Cancer Center (MSKCC) and 166 from Stand Up To Cancer/Mark Foundation. Clinical, pathological and genomic data were collected between September 2013 and September 2020.

Key Findings

Analysis in the MSKCC cohort defined TMB > 19 mutations per megabase as high TMB and TMB ≤ 19 per megabase as low TMB. High tumour TMB was associated with better objective response rates, progression-free survival and overall survival. These findings were validated in the other two cohorts.

Overall, 161 patients had high TMB and 1,391 had low TMB.

Across all patients, comparing high with low TMB by PD-L1 positivity, objective response rates were:

• For patients with PD-L1 < 1%:
  • 46.7% with high TMB versus 8.7% with low TMB ( P < 0.001)
• For PD-L1 1% to 49%:
  • 50% versus 17.7% ( P < 0.001), and
• For PD-L1 ≥ 50%:
  • 56.5% versus 38.1% ( P  = 0.02).

Comparing high with low TMB by PD-L1 expression, median progression-free survival was:

• For PD-L1 < 1%:
  • 10.7 versus 2.1 months ( P < 0.001)
• For PD-L1 1% to 49%:
  • 13.6 versus 2.9 months, and
• For PD-L1 ≥ 50%:
  • 18.1 versus 5.2 months ( P < 0.001).

Comparing high with low TMB by PD-L1 expression, median overall survival was:

• For PD-L1 < 1%:
  • 23.9 versus 10.4 months ( P = 0.07)
• For PD-L1 1% to 49%:
  • not reached versus 11.3 months ( P < 0.001), and
• For PD-L1 ≥ 50%:
  • 47.7 versus 21.4 months ( P  = 0.02).

Multiplex immunofluorescence and transcriptomic profiling showed that higher TMB levels

• were associated with increased CD8-positive and
• PD-L1-positive T-cell infiltration,
• increased PD-L1 expression in tumour and immune cells, and
• stronger signatures of innate and adaptive immune responses.

These findings reinforce TMB’s position among the most useful biomarkers of immunotherapy response. The study suggests that higher TMB is associated with immune-cell infiltration and an inflammatory T-cell-mediated response, resulting in greater sensitivity to PD-1/PD-L1 blockade in NSCLC across PD-L1 expression subgroups.