PD-(L)1 inhibitors plus bevacizumab and chemotherapy as first-line therapy in PD-L1-negative metastatic lung adenocarcinoma: a real-world data

The demographic and clinicopathological information for all patients were recorded, which include age, sex, smoking history, metastatic sites, gene mutations, PD-L1 expression, treatment regimens and duration, salvage radiotherapy, and adverse events. Tumor response and progression were assessed using the Response Evaluation Criteria in Solid Tumors v1.1, determined as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). At least one lesion could be evaluated. CR was considered that all target lesions are gone and the short axis of any pathological lymph node must decrease to < 10 mm. PR was defined that the sum of the maximum diameter of the tumor target lesions has decreased by ≥ 30%. PD was defined that the sum of the maximum diameters of the tumor target lesions increases more than 20%, or new lesions appear. SD was defined that the sum of the maximum diameters of the tumor target lesions does not decrease to PR, or increases without reaching PD. Overall response rate (ORR) was defined as the percentage of patients who achieved CR and PR in all patients evaluated. Disease control rate (DCR) was defined as the sum of CR, PR, and SD rates. PFS was defined as the period from the initial first-line treatment administration to the date of disease progression or death from any cause. OS was defined as the duration from the initial first-line treatment administration to death because of any cause. The post-progression survival time was defined as the duration starting from the first radiological progression to the last follow-up or the time of death.

Patients received 4–6 cycles of IBC, IC or BC treatment at the induction stage. The platinum-based chemotherapy schemes include paclitaxel plus cisplatinum/carboplatin, or pemetrexed plus cisplatinum/carboplatin. Following the induction phase, patients receiving IBC or BC continued bevacizumab until unmanageable toxicity or disease progression, and patients receiving IBC or IC continued PD-(L)1 inhibitors until loss of clinical benefit. PD-(L)1 inhibitors included pembrolizumab, atezolizumab, sintilimab, camrelizumab, and triplimab.

Adverse events were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v5.0. The evaluation criteria are displayed in supplement Table.

SPSS v25.0 and GraphPad Prism 8 were used for statistical analyses. Descriptive statistics using counts (percentages) for categorical variables or medians for continuous variables were used to summarize the baseline characteristics of the patients. For categorical variables, Chi-square test or Fisher’s exact test was used to compare categorical variables. For continuous variables, one-way ANOVA test was conducted. We also used the Kaplan–Meier survival curve and log-rank test to compare the survival difference between two treatment groups. The Cox proportional hazards regression model was applied to assess the hazard ratio (HR) and corresponding 95% CI. P < 0.05 was considered statistically significant. Considering multiple testing, the Benjamini/Hochberg (B/H) was employed to regulate two-sided p values to control the false discovery rate (FDR). A correlation was deemed to be statistically significant, if its p value was < 0.05, corresponding to an FDR of 5%.

A total of 205 patients were enrolled in this study—62 in the IBC group, 83 in the BC group, and 60 in the IC group. The median age for all patients was 60 years (range: 31–79). The proportion of female was 31.7%. 46.8% of patients had smoking history. The baseline characteristics of the three groups were broadly balanced. A detailed summary of the clinical characteristics of patients is shown in Table 1.

Of 62 patients in the IBC group, 27 achieved PR and 35 SD, with an ORR of 43.5% and a DCR of 100%. In BC group, 32 patients obtained PR, 44 SD, and 3 PD. The ORR and DCR were 40.5% and 96.2%, respectively. Of 60 patients receiving IC treatment, 23 patients attained PR, 25 SD, and 9 PD. ORR and DCR for IC group were 40.4% and 84.2%, respectively. Patients receiving BC (P = 0.015) or IBC (P = 0.001) treatment showed the significantly improved DCR compared with those receiving IC. In addition, the IBC group had the numerically highest ORR among three groups although no significant difference was discovered (p = 0.919). Detailed information is presented in Table 2.

Patients receiving IBC treatment displayed the longest PFS among three groups (p = 0.005) (Fig. 1A). However, the medium OS were not significantly different (mOS: IBC vs. IC vs. BC:18.86 months vs. 17.02 months vs. 18.53 months; p = 0.48) (Fig. 1B). Then we conducted a pairwise comparison among three groups. We found that IBC treatment obtained a superior PFS benefit compared with either IC (medium: 9.53 months vs. 6.74 months; HR: 0.606; Fig. 1C) or BC treatment (medium: 9.53 months vs. 8.28 months; HR: 0.555; Fig. 1D). However, no PFS difference was observed between BC and IC groups (Fig. 1E).

To further explore the features labeling potential beneficiary population, we conducted subgroup analyses based on different clinical characteristics including age, sex, smoking history, gene mutation subtypes, and different metastatic sites. We found patients with male gender, smoking history, TP53 mutation, wild-type genes, liver or adrenal metastases were more likely to obtain PFS benefit from IBC treatment compared with IC treatment (Fig. 2A). In addition, compared with BC, IBC treatment showed beneficial PFS in patients with male gender, smoking history, wild-type genes, adrenal metastasis, lung metastasis, and brain metastasis (Fig. 2B). However, compared with IC, BC treatment showed PFS benefit only in patients with liver metastasis (Fig. 2C). In terms of OS, no significant difference was observed in either subgroup among three treatments (Fig. 3A–C). However, we found that IBC treatment displayed a tendency of OS benefit compared with BC in male and in patients without gene mutations (Fig. 3B).

We collected the variations of first-line treatments and follow-up treatments due to the absence of difference in overall survival. In the first-line therapies, treatment discontinuation in IBC group (21.0%) was more common than those in BC (6.0%) and IC (11.7%) groups (p = 0.024). At data cutoff, 171 patients achieved progression in total: 47 in IBC group, 76 in BC group, and 48 in IC group. The follow-up treatments included immunotherapy, anti-angiogenic therapy, TKI, and chemotherapy. We observed higher frequency of patients receiving immunotherapy (46%) or TKIs (9.2%) in BC group than those in IC (37.5%, 4.2%) and IBC (34%, 4.3%) groups. More importantly, patients who received immunotherapy in later lines showed numerically superior post-progression survival than those not (10.28 month vs. 6.89 month). In addition, we found more patients received ≥ 3rd-line treatment in BC (6.6%) and IC (8.3%) groups compared with IBC (4.3%) group. All information is summarized in Table 3.

In generally, the occurrence of adverse events in the three groups is comparable, with a total rate of 45%, 39.8%, and 30.6% (p = 0.254), and grade III–IV adverse events of 13.3%, 20.4%, and 11.3% in IC, BC, and IBC groups, respectively (p = 0.271). Transaminases increase was the most frequent grade I–II adverse event in IC treatment group (23.3%), while the most frequent event was nausea/vomiting in IBC (29.0%) and BC (25.3%) groups. Neutropenia was the predominant grade III–IV adverse event across the three groups. The IBC treatment commonly led to grade I–II nausea/vomiting and grade III–IV neutropenia (8.1%), similar to those in the BC (11.0%) and IC (5.0%) groups. Moreover, the ratio of grade I–II dermal toxicity (6.7%) and pneumonitis (10.0%) in the IC group was higher than that in the IBC group, whereas the frequency of grade I–II hypothyroidism (3.2%) and RCCEP (reactive cutaneous capillary endothelial proliferation) (6.4%) in the IBC group was higher than that in the IC group. Moreover, infusion-related reactions occurred only in the IBC group. Grade I–II bleeding was observed in the BC group alone. All adverse events are listed in Table 4.