As PD-L1 expression is not sufficient for determining whether a patient’s disease will respond to PD-1/PD-L1 inhibition, smoking history and tumor mutation burden may help to inform treatment decision-making, according to Dr Gainor.
Some cancers that are associated with particular carcinogens, as lung cancer is with tobacco exposure, tend to have more mutations.
“If a cancer accumulates enough mutations, it begins to look foreign to the immune system,” Dr Gainor said. “Research is beginning to show that if you look at tumor mutation burden, there does seem to be an association with response to immunotherapy.”
A recent study published in The New England Journal of Medicine compared nivolumab with chemotherapy among patients with PD-L1 expression of at least 5%.5 The primary efficacy outcomes were similar between the 2 treatment groups, though the researchers identified a subgroup of patients with both high tumor mutation burden and high PD-L1 expression that had a significant benefit from nivolumab.
An exploratory analysis of 312 patients with high mutation burden showed a higher response rate in the nivolumab group compared with the chemotherapy group (48% vs 28%, respectively) and had a longer progression-free survival (9.7 months vs 5.8 months). Patients with a high tumor mutation burden and PD-L1 expression of 50% or greater had a response rate of 75% compared with 32% in patients with 1 one of these 2 traits.
A retrospective study published in Molecular Cancer Therapeutics reviewed data from 1638 patients with a variety of cancers who underwent genomic profiling and had tumor mutation burden assessment.6 Data from 151 patients treated with immunotherapy were analyzed, and those with a high mutation burden (20 or more mutations/Mb) had a response rate of 58% compared with 20% in patient with low to intermediate tumor mutation burden. Median progression-free survival and overall survival were also significantly improved in patients with a high mutation burden.
- Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:1627-39.
- Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicenter randomized controlled trial. Lancet. 2016;389:255-65.
- Reck M, Rodrıguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375:1823-33.
- Garassino MC, Cho BC, Kim JH, et al. Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study. Lancet Oncol. 2018 Mar 12. doi: 10.1016/S1470-2045(18)30144-X [Epub ahead of print]
- Carbone DP, Reck M, Paz-Ares L, et al. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med. 2017;376:2415-26.
- Goodman AM, Kato S, Bazhenova L, et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther. 2017;16:2598-608.