Discussion
NSCLC, death, toxicity, tumours, tumour, PD‐L1
TUMOURS, TUMOUR, STAGE IV NSCLC, NSCLC
The ComIT‐1 trial investigated primarily the toxicity, secondarily the systemic responses and exploratively the ctDNA responses in metastatic NSCLC patients treated with atezolizumab and stereotactic body radiotherapy. In accordance with previous studies [Due to a small sample size, it is not possible to draw solid conclusions from our study, and we have chosen a descriptive approach. The objective response rate in our trial was similar to those reported with PD‐1/PD‐L1 inhibitors as monotherapy for pretreated patients with advanced NSCLC [In our study, the majority of participating patients had PD‐L1 negative tumours, and a substantial number of these experienced a durable clinical utility. Out of the 15 PD‐L1 negative patients, 6 (40%) underwent treatment with atezolizumab for more than 12 months and 10 (67%) were alive more than 18 months after the start of the study treatment. These numbers are encouraging, considering subgroup analysis from the phase III OAK trial which showed that atezolizumab was superior to docetaxel in previously treated NSCLC patients [Nevertheless, a significant proportion of our patients did not respond to the study treatment. One reason might be that the SBRT schedule was not ideal. The optimal radiation dose, fractionation and timing to generate an immune response and enhance the effect of combining radiotherapy with immunotherapy remain to be defined. Preclinical models suggest that prior radiotherapy upregulates PD‐L1 expression and thus facilitates later administration of ICIs [In our trial, radiotherapy was given as SBRT, but with significantly lower doses than standard curative stereotactic radiotherapy. This radiotherapy dosing was chosen to induce immunogenic cell death while being well tolerated and was in accordance with other studies testing the combination of immunotherapy and radiation [Multisite SBRT represents another interesting approach to optimize the combined treatment of radiotherapy and immune checkpoint inhibitors [In advanced NSCLC, there is a need for new predictive biomarkers to better identify patients who will benefit from immune checkpoint blockade and to help monitor the treatment effect. A promising tool in this setting is ctDNA. Previous studies have demonstrated a strong correlation between longitudinal ctDNA changes, radiographic responses and clinical outcomes in stage IV NSCLC patients treated with ICIs [A potential advantage of ctDNA is its rapid kinetics. Several studies have reported that the ctDNA response considerably precedes the radiological response in NSCLC patients treated with immunotherapy [Some studies have reported a transient flare‐up of AF within the first 14 days after the start of immunotherapy in a subgroup of patients, possibly due to the increased release of DNA from dying tumour cells [The subtype of mutation detected in blood seemed to impact the response to atezolizumab in our trial. In accordance with previous reports, we found that patients with a targetable driver mutation (A major limitation is the small and heterogeneous study population and the non‐randomized design, which makes it difficult to draw firm conclusions. To capture the role of SBRT in the combined approach with respect to improving PFS and response rates, a larger trial containing a comparison group receiving ICI alone is needed. Furthermore, pre‐treatment ctDNA was detected in only 11 of the 21 enrolled patients and due to incomplete tissue genotyping data, we were not able to confirm the concordance between mutations detected in plasma and mutations in tissue for all patients. In theory, mutations identified in plasma could represent contamination from germline variants and clonal hematopoietic mutations and not be attributed to tumour cells. We could have reduced this risk by doing paired peripheral blood mononuclear cell NGS or by excluding mutations with AF > 20% in all patient samples [