Comparative Efficacy and Safety of Immunotherapy Alone and in Combination With Chemotherapy for Advanced Non-small Cell Lung Cancer

Abstract

There is a lack of direct cross-comparison studies in clinical trials between immunotherapy alone and combination treatment, especially in Non-Small Cell Lung Cancer (NSCLC) patients with high PD-L1 expression. To determine if anti-PD-(L)1 antibody combined with chemotherapy is more efficient than immune checkpoint inhibitor (ICI) monotherapy for advanced NSCLC patients in the real-world data. We retrospectively collected 325 patients with advanced NSCLC treated with ICI alone with or without chemotherapy from 11th July 2016 to 26th May 2020 to investigate which treatment scenario is the most efficient, and how clinical factors impact response. Patients with advanced NSCLC were treated with ICI monotherapy (178/325, 54.8%) or in combination with chemotherapy (147/325, 45.2%). The objective response rate and disease control rate were higher in the combination group than the monotherapy group. Patients (including those with distant metastasis) treated with chemo-immunotherapy were associated with a significantly longer median PFS and OS compared with the monotherapy group, irrespective of the PD-L1 expression level and previous treatment lines. No significant increase in the risk of immune-related adverse events (irAEs) was found after combination with chemotherapy (50.6 vs. 57.8%). IrAEs predicted better PFS of immunotherapy in the monotherapy group, especially for patients with late irAEs (after ≥4 cycles). Collectively, we demonstrated that ICI monotherapy plus chemotherapy might have better anti-tumor activity and an acceptable side-effect profile regardless of PD-L1 level or previous treatment lines. Both regimens were well-tolerated and cost-effective, the more efficient is usually recommended.

Keywords: NSCLC; PD-L1; chemotherapy; immune-related adverse event; immunotherapy.

Figure 1

Outcomes of advanced lung cancer patients treated with ICI alone or in combination with chemotherapy. (A,B) PFS and OS in tumors treated with immunotherapy alone (n = 178) or in combination with chemotherapeutics (n = 147) [HR 0.430, 95% CI 0.319–0.579, log-rank p <1*10⁽⁻⁶⁾]. (C) Reasons for drug withdrawal in tumors from patients received immunotherapy or combination therapy. (D) Tumor burden scores of patients with progressive disease in different group (P = 0.284). (E,F) Metastases before our treatment (E) and recurrent or progressive sites after immunotherapy (F) were shown. Statistical analysis for Kaplan-Meier plots used the log-rank test and statistical analysis for progressive sites used Chi-square test; tumor burden score was tested by Independent samples t-test. PFS, progression-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval. ^aInformation on disease progression in two patients was not available.

Figure 2

Distant metastases before immunotherapy associated with progression-free survival, and overall survival of tumors treated differently. (A,B) PFS (A) and OS (B) in patients with bone metastasis that had ICI monotherapy or in combination with chemotherapy; (C,D) PFS (C) and OS (D) in patients with brain metastasis that received immunotherapy alone or in combination with chemotherapy; (E,F) PFS (E) and OS (F) in patients with adrenal gland metastasis that had anti-PD-(L)1 antibody therapy or in combination with chemotherapeutics; (G,H) PFS (G) and OS (H) in patients with distant lymph node metastasis treated with ICI monotherapy or in combination with chemotherapy; (I,J) PFS (I) and OS (J) in patients with liver metastasis treated differently.

Figure 3

The responses and outcomes of patients with targeted brain metastases received immunotherapy alone or chemo-immunotherapy. (A) Time to brain metastasis response and duration of treatment. Bars represent individual patients who received immunotherapy. (B) Best brain metastasis response in assessable patients. The lower dashed line represents the −30% cut-off that defines an objective response. And the upper dashed line represents 20% cut-off that defines progression disease. CR, complete response; PR partial response; SD, stable disease; PD, progressive disease. ^aOne patient had developed progression of lung tumors and withdrew from immunotherapy despite 100% shrinkage of brain metastasis. ^bOne patient had progressive disease despite <20% enlargement due to the development of new brain metastasis.

Figure 4

Time to onset irAEs and association with outcomes in advanced NSCLC patients treated with ICI monotherapy. (A,B) Kaplan-Meier curves of PFS (A) and OS (B) in patients with early (after 1–3 cycles), late (after four or more cycles) or without irAEs after commencement of ICI therapy. The multivariate HRs, 95% CIs and P-values were analyzed using a stratified Cox proportional hazards model taking into account gender (male, female), age (<65, ≥65), BMI (18) (<18.5, 18.5–22.9, 23–24.9, ≥25), smoking status (non-smoker, smoker), histology (adenocarcinoma, squamous carcinoma, NSCLC, neuroendocrine neoplasm, others), EGFR mutation (wild-type, mutation, unknown), PD-L1 expression level (<25%, ≥25%, unknown) and previous treatment lines (0, 1, ≥2). Log Rank p-values were calculated by log-rank test.