It is known that nutritional status and inflammation have an important role in treatment response and long-term outcome in various malignancy including lung cancer. In this study, we investigated the prognostic significance of PNI and mGPS, which are important parameters in the evaluation of inflammation and nutrition together, in patients with targetable mutations. In EGFR and ALK mutant patients, both PNI and mGPS were found to be a prognostic marker for PFS. High PNI and mGPS scores were associated with prolonged survival in both EGFR and ALK mutant patients. Similarly, both PNI and mGPS were found to be independent prognostic markers in multivariate analyses.

PNI has been used as a prognostic factor for various malignancy for a long time. PNI can reflect both nutritional and inflammatory conditions together rather than the other parameters which are reflected nutritional or inflammatory condition alone. Therefore, PNI has been considered as an important prognostic marker for malignant diseases. It can be calculated easily using simple, objective, and inexpensive laboratory parameters. In previous studies, PNI was found as a significant prognostic index for advanced or early-stage NSCLC. In these trials, high PNI level was found related to increased survival (Sheng et al. 2016; Xu et al. 2017, Seo et al. 2019). On the other hand, there is only one trial that investigated prognostic effect of PNI on advanced NSCLC with targetable mutation. Sheng et al. showed that high PNI was related to increased overall survival in patients with EGFR mutation. However, in subgroup analyses of this study, PNI was found as a significant prognostic marker for exon 21 L858R mutation but not exon 19 deletion. An important problem for investigation of PNI as a prognostic marker is the determination of the threshold level for PNI. The widespread consensus about the optimal threshold level of PNI has not been reached yet. In previous studies, PNI level for threshold varied from 45 to 52 (Qiu et al. 2015; Li et al. 2018; Wang et al. 2020). ROC curve analysis was performed to determine the cut-off value for PNI and the ideal result was not obtained. For this reason, we accepted that the threshold level was 50 as a median PNI level of our population and the patients were stratified as high (≥ 50) or low PNI (< 50).

In our trial, we found that high PNI level was related with significant longer PFS in the whole group and EGFR exon 21 L858R subgroup but not in EGFR exon 19del subgroup. These results were consistent with previous trial as mentioned above. The possible reasons for not reaching statistical significance in EGFR exon 19 del subgroup may be relatively low patient count or patients clinical features. On the other hand, we cannot explain the exact mechanism. To the best of our knowledge, this is the first study that investigates the prognostic value of PNI in both EGFR and ALK mutated patients treated with targeted agents. As mentioned above, both poor nutritional status and increased inflammation had a negative effect on survival due to various mechanisms. Our results found consistent with previous knowledge about the relationship between nutritional or inflammation and survival outcomes.

Modified GPS is another index that can reflect both inflammatory and nutritional conditions, and it can be calculated easily using serum albumin and CRP level. There are many studies and meta-analysis concerning mGPS and prognosis in various malignancies including gastric, colorectal, and also lung cancer without driver mutation (Woo et al. 2015; Zhang et al. 2015; Jin et al. 2017). All of these data showed that mGPS had a significant prognostic value in these malignancies. Additionally, survival has been significantly worsened from score 0 to 2. In a meta-analysis, the relative risk of death increased 1.77 times in lung cancer patients with high mGPS (Jin et al. 2017). To the best our knowledge, despite there are many studies that investigated mGPS in advanced lung cancer, there are no previous studies about advanced lung cancer that treated with targeted agents. Therefore, this is the first study that investigated prognostic value of mGPS in advanced lung cancer patients who had the targetable mutation and received targeted therapy. In our study, the results were consistent with previous trials that made in lung cancer without driver mutation. The survival worsened in patients with high mGPS in both EGFR and ALK-positive subgroup. Unlike PNI, the prognostic significance of mGPS showed in both EGFR exon 19 del and exon 21L858R subgroups. Additionally, the relative risks for progression or death were 2.5 and 2.7 times higher in mGPS ≥ 1 than 0 in EGFR and ALK mutated patients, respectively. As a result, mGPS can be accepted as a reliable, inexpensive, and easily applicable marker for EGFR and ALK mutated patients who were treated with targeted therapy.

The retrospective design of the study is the major limitation of our study and it may be related to selection bias of the patients. However, the number of patients may be sufficient for these rare subgroups of advanced lung cancer. Although the comorbidities that can directly affect albumin, CRP and CBC parameters are excluded in this study, and the unpredictable comorbidities can affect blood parameters indirectly. Another limitation of our study is the patients with the other targetable mutations, such as ROS-1, BRAF, and MET, not included in this study.

In conclusion, this is the first study that showed prognostic importance of PNI and mGPS as markers that reflect the inflammatory and nutritional conditions in advanced lung cancer with targetable mutation. Nowadays, the absence of reliable and easily applicable markers is an important problem for the management of patients with the targetable mutation. As a result of this study, PNI and mGPS as a reliable, inexpensive, and easily applicable prognostic marker can fill this gap. Additionally, these indexes may be guided to treatment selection in future. Therefore, further prospective studies are needed to demonstrate the possible effect of both PNI and mGPS on treatment selection.