Efficacy and safety of alectinib in ALK-positive non-small cell lung cancer and blood markers for prognosis and efficacy: a retrospective cohort study

Abstract

Background: Alectinib is a second generation of ALK-tyrosine kinase inhibitors (ALK-TKIs), which has attracted much attention in the treatment of ALK-positive non-small cell lung cancer (NSCLC). At present, there are few reports on the efficacy and safety of alectinib in Chinese population. Moreover, biomarkers reflecting prognosis and efficacy are exceedingly needed. This study assessed the efficacy of alectinib in patients with ALK-positive NSCLC and analyzed the prognostic factors.

Methods: Patients with ALK-positive NSCLC who were confirmed by histopathology or cytology at the Affiliated Cancer Hospital of Nanjing Medical University between October 2018 and October 2021 were enrolled. All patients were treated with alectinib. The clinical characteristics and circulating tumor biomarkers before and after treatment were collected. Kaplan-Meier test was used to calculate the progression-free survival (PFS). Univariate and multivariate Cox regression analyses were used to explore the influencing factors on PFS. Incidence of adverse events was observed.

Results: Twenty patients progressed after first-line treatment (n=59) with alectinib, and 21 patients progressed following second-line treatment (n=36) with alectinib. The median PFS of first-line treatment patients was not achieved, and the median PFS of patients undergoing second-line treatment was 15.0 months [95% confidence interval (CI): 0.00-32.23]. The most common adverse reactions were liver dysfunction (37.50%), anemia (37.50%), and constipation (20.83%). The incidence of grade III and above adverse reactions was 6.25%. Univariate analysis showed that neutrophil-to-lymphocyte ratio [NLR; hazard ratio (HR) =0.424, P=0.005] carcinoembryonic antigen (CEA; HR =0.482, P=0.029), lactate dehydrogenase (LDH; HR =0.327, P<0.001), carbohydrate antigen (CA)199 (HR =0.313, P=0.002), and circulating cell free DNA (cfDNA; HR =0.229, P=0.008) concentration levels were associated with PFS, and multivariate analysis showed that NLR (HR =3.058, P=0.034) was independent prognostic factor. After three months of treatment, CEA, CA199, NLR, and LDH, could further predict the prognosis of alectinib treatment.

Conclusions: The efficacy and safety of alectinib as a first-line or second-line treatment for ALK-positive NSCLC in keeping with published prospective studies. CEA, CA199, NLR, and LDH within the normal range after three months of treatment were associated with good prognosis. Detection of serum tumor markers can indicate therapeutic success in patients treated with alectinib.

Keywords: ALK-positive; Non-small cell lung cancer (NSCLC); adverse drug reaction (ADR); alectinib; biomarkers.

Figure 1

Flow diagram of the patient selection process. NSCLC, non-small cell lung cancer; IHC, immunohistochemistry; FISH, fluorescence in situ hybridization.

Figure 2

A Kaplan-Meier survival curve of the PFS in 95 patients with ALK-positive NSCLC, who were administered with different lines of treatment. The median PFS of first-line treatment was not reached, and the median PFS of second-line treatment was 15.0 months (95% CI: 0.00–32.23). PFS, progression-free survival; NSCLC, non-small cell lung cancer; CI, confidence interval.

Figure 3

Kaplan-Meier survival curves of PFS in patients with brain metastases. (A) Kaplan-Meier survival curve for PFS of all patients grouped by brain metastasis or not. (B) Kaplan-Meier survival curve for PFS of first-line treatment patients grouped by brain metastasis or not. (C) Kaplan-Meier survival curve for PFS of second-line treatment patients grouped by brain metastasis or not. The median PFS of patients with brain metastasis in second-line treatment was 10.0 months (95% CI: 5.04–14.96). PFS, progression-free survival; CI, confidence interval.

Figure 4

Kaplan-Meier survival curves of PFS grouped by metastatic sites. (A) The median PFS of patients with lymph node metastases was 30.4 months (95% CI: NR). (B) The median PFS of patients with intrapulmonary metastases was 30 months (95% CI: NR). (C) The median PFS of patients with liver metastases was 30.4 months (95% CI: 5.52–54.48). (D) The median PFS of patients with bone metastases was 24.2 months (95% CI: 15.18–33.28). (E) The median PFS of patients with pleural metastases was not achieved. (F) The median PFS of patients with malignant pleural fluid was 30.4 months (95% CI: 14.58–45.42). (G) The median PFS of patients with adrenal metastases was 24.2 months (95% CI: 5.84–42.62). There was no significant correlation between the metastatic sites and PFS. PFS, progression-free survival; CI, confidence interval; NR, not reached.

Figure 5

The ROC curves of the NLR and PLR. ROC, receiver operating characteristic; NLR, neutrophil-lymphocyte ratio; AUC, area under the curve; PLR, platelet-to-lymphocyte ratio.

Figure 6

Kaplan-Meier survival analysis of PFS grouped by blood markers. (A) Kaplan-Meier survival curve for PFS of patients grouped by cfDNA. (B) Kaplan-Meier survival curve for PFS of patients grouped by LDH. (C) Kaplan-Meier survival curve for PFS of patients grouped by CEA. (D) Kaplan-Meier survival curve for PFS of patients grouped by CA199. (E) Kaplan-Meier survival curve of patients with PFS by NLR. Univariate analysis showed that cfDNA, LDH, CEA, CA199, and NLR were associated with PFS. In each subgroup, the PFS of patients with normal indicators was longer than that of patients with abnormal indicators. cfDNA, cell free DNA; LDH, lactate dehydrogenase; CEA, carcinoembryonic antigen; CA, carbohydrate antigen; NLR, neutrophil-lymphocyte ratio; PFS, progression-free survival.

Figure 7

Kaplan-Meier survival curves of LDH, CEA, CA199, and NLR subgroups. (A) Kaplan-Meier survival curves for PFS of patients grouped by LDH. (B) Kaplan-Meier survival curves for PFS of patients grouped by CEA. (C) Kaplan-Meier survival curves for PFS of patients grouped by CA199. (D) Kaplan-Meier survival curves for PFS of patients grouped by NLR. LDH, lactate dehydrogenase; CEA, carcinoembryonic antigen; CA, carbohydrate antigen; NLR, neutrophil-lymphocyte ratio.

Figure 8

Grading of adverse reactions in 96 patients.