Abstract
Introduction
Recent studies have suggested enhanced therapeutic effects of subsequent chemotherapy after immune checkpoint inhibitor (ICI) treatment, highlighting the importance of subsequent treatment selection. Nanoparticle albumin-bound paclitaxel (nab-PTX) is commonly used in subsequent chemotherapies; however, its efficacy as a subsequent treatment after ICI treatment has not been reported.
Methods
We retrospectively evaluated the efficacy and safety of nab-PTX using two prospective studies that we previously reported. The first study evaluated the efficacy and safety of nab-PTX as a second-line treatment after the failure of the first-line cytotoxic chemotherapy, excluding ICI (study 1; n = 32), and the other as a subsequent treatment after failure of ICI treatment, regardless of treatment line (study 2; n = 29).
Results
The objective response rate was significantly higher in study 2 {55.2% (95% confidence interval [CI]: 28.1–79.6)} than in study 1 (28.1% [95% CI: 13.7–46.7]) (p = 0.04). Although the disease control rate was slightly higher in study 2 (86.2% [95% CI: 65.9–97.0]) than in study 1 (71.9% [95% CI: 53.3–86.3]), there was no significant difference (p = 0.2). The median progression-free survival was significantly longer in study 2 than in study 1 (3.9 months [95% CI: 2.0–5.5] in study 1 vs. 5.6 months [95% CI: 3.0–12.8] in study 2; hazard ratio [HR]: 0.46 [95% CI: 0.27–0.81], p = 0.006). The median overall survival was slightly longer in study 2 despite the greater number of patients who received nab-PTX in late treatment line, but there was no significant difference between study 1 and study 2 (10.9 months [95% CI: 5.1–16.8] in study 1 vs. 11.9 months [95% CI: 7.6–24.8] in study 2; HR: 0.77 [95% CI: 0.46–1.31], p = 0.34). Safety profiles did not differ between the patients in studies 1 and 2.
Conclusion
Nab-PTX monotherapy may be an effective subsequent treatment option after ICI treatment.
Keywords: Non-small cell lung cancer, Immune checkpoint inhibitor, Nanoparticle albumin-bound paclitaxel, Subsequent treatment
Introduction
Immune checkpoint inhibitors (ICIs), such as anti-programmed cell death 1 (PD-1), anti-programmed cell death ligand 1 (PD-L1), and anti-cytotoxic T-lymphocyte-associated antigen antibodies, are widely used as standard treatments for various malignancies, including non-small cell lung cancer (NSCLC). Treatment with ICI dramatically improves the prognosis of patients with advanced NSCLC compared to conventional cytotoxic chemotherapies [1, 2]. Furthermore, several studies have demonstrated that cytotoxic chemotherapy after ICI treatment has a higher objective response rate (ORR) than chemotherapy without prior ICI treatment in recent years [3–6]. This synergistic antitumor effect on subsequent treatments, as well as the therapeutic effect of the ICI themselves, may explain why ICI treatments improve the prognosis of patients with advanced NSCLC. Recently, most patients with advanced NSCLC have received ICI(s) with or without cytotoxic chemotherapy as the first-line treatment; therefore, selecting a subsequent treatment after ICI treatment is extremely important.
However, the evidence regarding the selection of subsequent treatments after ICI treatment is limited. The anticancer agents that are commonly used as subsequent treatments include docetaxel ± ramucirumab, pemetrexed, gemcitabine, and nanoparticle albumin-bound paclitaxel (nab-PTX). Notably, nab-PTX has been demonstrated to have a significantly higher ORR, longer progression-free survival (PFS), and lower incidence of febrile neutropenia (FN) than docetaxel in patients with previously treated advanced NSCLC [7]. These findings indicate that nab-PTX is a promising anticancer agent. If the efficacy of nab-PTX as a subsequent treatment after ICI treatment is demonstrated, it may be extremely important evidence in clinical practice.
Fortunately, we have previously reported two prospective multicenter studies evaluating the efficacy and safety of nab-PTX in patients with previously treated advanced NSCLC, although the study periods were different. The first one, in which patients were enrolled between June 2013 and October 2015, is a study to evaluate efficacy and safety of nab-PTX as a second-line treatment after failure of first-line cytotoxic chemotherapy except ICI (hereinafter, this is called “Study 1”) [8], and the other one, in which patients were enrolled between February 2018 and December 2020, is as a subsequent treatment after failure of ICI treatment regardless of treatment line (hereinafter, this is called “Study 2”) [9]. In Japan, nivolumab, an anti-PD-1 antibody, was approved in December 2015 for the treatment of patients with advanced NSCLC who were previously treated. Moreover, pembrolizumab, which is another anti-PD-1 antibody, was also approved for administration as a first-line treatment in patients with advanced NSCLC with PD-L1 tumor proportion score (TPS) on at least 50% in December 2016. In other words, study 1 was conducted at a time when ICIs were not commonly administered in early line treatment, while study 2 was conducted at a time when ICIs were becoming more commonly administered in early line treatment. With this historical background, comparing and analyzing updated clinical data from these two studies can yield important evidence of the efficacy and safety of nab-PTX as a subsequent treatment after ICI treatment, as both studies had similar participating institutes, study designs, treatment schedules, and assessments. Therefore, we conducted this retrospective study to evaluate whether the efficacy of nab-PTX could be improved by ICI treatment.
Methods
Study Design and Patients
This was a retrospective study comparing the updated results of two multicenter, open-label, phase 2 studies that we have previously reported [8, 9] and was approved by the Ethics Committee of the Faculty of Medical Sciences, University of Fukui (Reference Number 20220117, approved on October 11, 2022). As we previously described [8, 9], the common eligibility criteria for two studies included age of 20 years or higher, Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0–2, having normal organ functions, histologically or cytologically proven unresectable advanced or recurrent NSCLC, and at least one measurable lesion by Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1 [10]. The key difference between the two studies was that eligible patients in study 1 were treated with nab-PTX as a second-line chemotherapy after failure of the first-line cytotoxic chemotherapy except ICI, whereas those in study 2 were treated with nab-PTX after failure of ICI treatments regardless of treatment line.
Treatment and Assessment
As previously described [8, 9], the treatment schedule, dosing criteria, and dose reduction criteria were the same in both studies. Briefly, nab-PTX (Abraxane®, Taiho Pharmaceutical Co., Ltd., Tokyo, Japan) was administered intravenously at a dose of 100 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Treatment was continued until progressive disease (PD) or unacceptable adverse events were confirmed. Treatment response using RECIST version 1.1 was assessed using computed tomography or magnetic resonance imaging at intervals of 8 weeks until PD. Dose reduction was allowed with a reduction of 20 mg/m2 to a minimum dose of 60 mg/m2 when the following criteria were met during the treatment: grade 4 neutropenia, grade 3 or higher neutropenia that delayed the start of each cycle, grade 3 or higher thrombocytopenia, FN, or grade 3 or higher non-hematologic toxicities with the exception of alopecia according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 [11].
Statistical Analysis
Fisher’s exact test was used to analyze the differences in patient characteristics, ORR, disease control rate, and adverse events, and the Mann-Whitney U test was used to analyze the differences in median age and number of treatment cycles between study 1 and study 2. PFS was defined as the time from the date of initiation of treatment with nab-PTX to the date of disease progression or death from any cause. Overall survival (OS) was defined as the time from the date of initiation of treatment with nab-PTX to the date of death from any cause. OS and PFS were estimated using the Kaplan-Meier method, and their 95% confidence intervals (CIs) were calculated. The log-rank test was used to analyze the differences in event-time distributions. A Cox proportional hazards model using a stepwise method was used to identify the prognostic factors. A probability value (p value) of <0.05 was considered statistically significant. The data cut-off date was August 31, 2023. Statistical analyses were performed using EZR statistical software, version 1.55 (Y. Kanda, 2021).
Results
Patient Characteristics
Patient characteristics are shown in Table 1. A total 32 patients were enrolled in study 1 between June 2013 and October 2015. Thirty patients were enrolled in study 2 between February 2018 and December 2020, and 29 were included in the analysis. The patient characteristics at baseline were balanced between studies 1 and 2, but the number of cases in which nab-PTX was administered as a third- or later-line treatment was significantly higher in study 2 (postoperative adjuvant chemotherapy and treatment with tyrosine kinase inhibitors were not counted as a treatment line in this study). Furthermore, the number of squamous cell carcinoma cases was higher in study 2, although the difference was not statistically significant. In study 1, 5 patients (15.6%) tested positive for epidermal growth factor receptor (EGFR) mutations, while in study 2, 3 patients (10.3%) were positive (p = 0.71). Additionally, only 1 patient (3.1%) had a positive echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene (p = 1.00). All patients with either EGFR mutations or ALK fusion gene had previously received treatment with tyrosine kinase inhibitors (TKIs) before enrollment for each studies (18.8% [95% CI: 7.2–36.4] in study 1 vs. 10.3% [95% CI: 2.2–27.4] in study 2, p = 0.48). Comparisons of PD-L1 TPS could not be made because PD-L1 analysis was not available in study 1. Therefore, most patients had an unknown PD-L1 TPS, and PD-L1 TPS was evaluated using archival tumor specimens in only 4 patients in study 1. Ten out of 32 (31.3%) patients in study 1 received ICI treatments after nab-PTX treatment.
Table 1.
Patient characteristics and treatment outcomes
| Study 1 (n = 32) | Study 2 (n = 29) | p value | |
|---|---|---|---|
| Median age, years (range) | 67.5 (45–79) | 69 (43–82) | 0.22 |
| Sex | |||
| Male | 24 | 22 | 1.00 |
| Female | 8 | 7 | |
| ECOG-PS | |||
| 0–1 | 32 | 28 | 0.48 |
| 2 | 0 | 1 | |
| Smoking status | |||
| Never | 4 | 4 | 1.00 |
| Past/Current | 28 | 25 | |
| Histology | |||
| Squamous cell carcinoma | 5 | 11 | 0.08 |
| Adenocarcinoma | 25 | 14 | |
| Large cell carcinoma | 1 | 0 | |
| Not otherwise specified | 1 | 4 | |
| Clinical stage | |||
| III | 6 | 8 | 0.55 |
| IV | 25 | 18 | |
| Recurrent | 1 | 3 | |
| Driver oncogenes | |||
| EGFR mutation positive | 5 | 3 | 0.71 |
| EML4-ALK fusion gene positive | 1 | 0 | 1.00 |
| Others | |||
| KRAS G12C mutation positive | – | 2 | |
| PD-L1 tumor proportion score | |||
| <1% | 2 | 13 | – |
| 1–49% | 1 | 5 | |
| ≥50% | 1 | 9 | |
| Unknown | 28 | 2 | |
| CNS metastasis | |||
| Yes | 6 | 5 | 1.00 |
| No | 26 | 24 | |
| No. of previous regimens* | |||
| 1 | 32 | 6 | <0.001 |
| 2 | – | 18 | |
| ≥3 | – | 5 | |
| 1st line chemotherapy* | |||
| Platinum-based chemotherapy (without ICI) | 31 | 22 | – |
| Single-agent cytotoxic chemotherapy | 1 | 1 | |
| ICI monotherapy | 0 | 4 | |
| ICI + platinum-based chemotherapy | 0 | 2 | |
| Type of previous ICI | |||
| PD-1 antibody + chemotherapy | – | 2 | – |
| PD-1 antibody | – | 23 | |
| PD-L1 antibody | – | 4 | |
| ICI after nab-PTX | |||
| Yes | 10 | – | – |
| No | 22 | – | |
| Best overall response | |||
| Complete response | 1 | 1 | – |
| Partial response | 8 | 15 | |
| Stable disease | 14 | 9 | |
| Progressive disease | 9 | 4 | |
| Objective response rate, % (95% CI) | 28.1 (13.7–46.7) | 55.2 (28.1–79.6) | 0.04 |
| Disease control rate, % (95% CI) | 71.9 (53.3–86.3) | 86.2 (65.9–97.0) | 0.22 |
| Median treatment cycles (range) | 3 (1–9) | 6 (1–64) | 0.002 |
| Dose reduction, n (%) | 14 (43.8) | 8 (27.6) | 0.29 |
| One-stage reduction | 9 (28.1) | 4 (13.8) | 0.22 |
| Two-stage reduction | 5 (15.6) | 4 (13.8) | 1.00 |
| Discontinuation | 2 (6.3) | 4 (13.8) | 0.41 |
ECOG, Eastern Cooperative Oncology Group; PS, performance status; EGFR, epidermal growth factor receptor; EML4, echinoderm microtubule-associated protein-like 4; ALK, anaplastic lymphoma kinase; KRAS, Kirsten rat sarcoma viral oncogene homolog; PD-(L)1, programmed death (ligand) 1; CNS, central nervous system; ICI, immune checkpoint inhibitor; nab-PTX, nanoparticle albumin-bound paclitaxel; CI, confidence interval.
*Postoperative adjuvant chemotherapy and treatment with tyrosine kinase inhibitors were not counted as a previous regimen.
ORR and Disease Control Rate
Treatment responses are presented in Table 1. The ORR was significantly higher in study 2 (55.2% [95% CI: 28.1–79.6]) than in study 1 (28.1% [95% CI: 13.7–46.7]) (p = 0.04). Although the disease control rate was slightly higher in study 2 (86.2% [95% CI: 65.9–97.0]) than in study 1 (71.9% [95% CI: 53.3–86.3]), there was no significant difference (p = 0.2).
PFS and OS
At data cut-off, the median follow-up time was 10.9 months (range: 0.9–112.2) for all patients (study 1: 10.9 months [range: 0.9–112.2], study 2: 11.9 months [range: 2.3–67.8]). Thirty-two patients (100%) in study 1 and 27 patients (93.1%) in study 2 had PD, and 31 patients (96.9%) in study 1 and 26 patients (89.7%) in study 2 had died.
The Kaplan-Meier curves for PFS and OS are shown in Figure 1. The median PFS was 3.9 months (95% CI: 2.0–5.5) in study 1 and 5.6 months (95% CI: 3.0–12.8) in study 2, and was significantly longer in study 2 than in study 1 (hazard ratio [HR]: 0.46 [95% CI: 0.27–0.81], p = 0.006). The median OS was 10.9 months (95% CI: 5.1–16.8) in study 1 and 11.9 months (95% CI: 7.6–24.8) in study 2. Although the median OS was slightly longer in study 2 despite the greater number of patients who received nab-PTX in late treatment line, there was no significant difference between study 1 and study 2 (HR: 0.77 [95% CI: 0.46–1.31], p = 0.34).
Fig. 1.
a Kaplan-Meier estimates for PFS stratified between study 1 and study 2. The median PFS was 3.9 months (95% CI: 2.0–5.5) in study 1 and 5.6 months (95% CI: 3.0–12.8) in study 2 and was significantly longer in study 2 than in study 1 (hazard ratio [HR]: 0.46 [95% CI: 0.27–0.81], p = 0.006). b Kaplan-Meier estimates for OS stratified between study 1 and study 2. The median OS was 10.9 months (95% CI: 5.1–16.8) in study 1 and 11.9 months (95% CI: 7.6–24.8) in study 2. There was no significant difference between study 1 and study 2 (hazard ratio [HR]: 0.77 [95% CI: 0.46–1.31], p = 0.34).
Factors Related to PFS
The results of the Cox proportional hazards model for PFS are shown in Table 2. A univariate Cox proportional hazards model shows that ECOG-PS 0 (HR 0.43 [95% CI: 0.23–0.80], p = 0.008) and prior ICI treatment (HR 0.46 [95% CI: 0.27–0.81], p = 0.006) are indicators of longer PFS. Multivariate analysis reveals that ECOG-PS and prior ICI treatment are independent predictors of PFS. Interestingly, a univariate Cox proportional hazards model shows that number of previous regimens of 1 is associated with shorter PFS than of 2 or higher (HR 1.80 [95% CI: 1.02–3.19], p = 0.04). This may be due to the fact that most patients in number of previous regimens of 1 are patients in study 1 and all patients in number of previous regimens of 2 or higher are patients in study 2. Therefore, prior ICI treatment may be a more significant prognostic factor than early treatment lines.
Table 2.
Cox proportional hazards model for PFS
| n | Median PFS | Univariate | Multivariate | |||
|---|---|---|---|---|---|---|
| HR (95% CI) | p value | HR (95% CI) | p value | |||
| Age | ||||||
| <70 | 35 | 5.0 (3.0–8.0) | 0.71 (0.42–1.20) | 0.207 | ||
| ≥70 | 26 | 4.0 (2.7–5.5) | ||||
| Sex | ||||||
| Male | 46 | 4.4 (2.7–5.5) | 1.40 (0.77–2.55) | 0.28 | ||
| Female | 15 | 5.5 (2.4–11.0) | ||||
| ECOG-PS | ||||||
| 0 | 17 | 6.5 (3.7–14.6) | 0.43 (0.23–0.80) | 0.008 | 0.50 (0.26–0.93) | 0.028 |
| 1–2 | 44 | 3.7 (2.4–5.4) | ||||
| Smoking | ||||||
| Never | 8 | 6.8 (1.7–13.0) | 0.86 (0.41–1.83) | 0.70 | ||
| Past/current | 53 | 4.3 (2.9–5.5) | ||||
| Histology | ||||||
| Non-Sq | 45 | 4.3 (3.0–5.6) | 1.11 (0.62–1.99) | 0.72 | ||
| Sq | 16 | 5.2 (1.8–10.0) | ||||
| Stage | ||||||
| III | 13 | 5.4 (0.7–7.8) | 0.83 (0.44–1.55) | 0.55 | ||
| IV/Recurrent | 48 | 4.2 (3.0–5.5) | ||||
| No. of previous regimens* | ||||||
| 1 | 38 | 4.1 (2.4–5.6) | 1.80 (1.02–3.19) | 0.04 | ||
| 2- | 23 | 5.4 (3–10.3) | ||||
| CNS metastasis | ||||||
| Yes | 11 | 5.5 (2.6–6.3) | 0.80 (0.41–1.59) | 0.53 | ||
| No | 50 | 4.1 (2.9–6.0) | ||||
| Prior ICI treatment | ||||||
| Yes | 29 | 5.6 (3.0–12.8) | 0.46 (0.27–0.81) | 0.006 | 0.53 (0.31–0.93) | 0.028 |
| No | 32 | 3.9 (2.0–5.5) | ||||
PFS, progression-free survival; HR, hazard ratio; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; PS, performance status; Sq, squamous cell carcinoma; CNS, central nervous system; ICI, immune checkpoint inhibitor.
*Postoperative adjuvant chemotherapy and treatment with tyrosine kinase inhibitors were not counted as a previous regimen.
One-year PFS rates were 6.3% in study 1 and 34.5% in study 2, respectively, and the rates were significantly higher in study 2 than in study 1 (p = 0.009). Furthermore, 2-year PFS rate was 10.3% in study 2, whereas there were no such patients in study 1.
Delivered Chemotherapy
The median number of treatment cycles was 3 (range: 1–9) in study 1 and 6 (range: 1–64) in study 2, which was significantly higher in study 2 than in study 1 (p = 0.001) (Table 2). Fourteen patients in study 1 (43.8% [95% CI: 26.4–62.3]) and 8 patients in study 2 (27.6% [95% CI: 12.7–47.2]) were required at least one-stage dose reduction, and 5 patients in study 1 (15.6% [95% CI: 5.3–32.8]) and 4 patients in study 2 (13.8% [95% CI: 3.9–31.7]) were required two-stage dose reduction, respectively, but there were no significant differences between study 1 and study 2 (p = 0.29, 1.00). Treatment was discontinued due to adverse events in 2 patients in study 1 (6.2% [95% CI: 0.8–20.8]) and in 4 patients in study 2 (13.8% [95% CI: 3.8–31.7]), with no significant difference (p = 0.41).
Safety
Table 3 presents the toxicity profiles, which align with previous studies [8, 9]. No new adverse events were identified. No significant differences were observed in the incidence of hematologic adverse events. Specifically, FN occurred in only 1 patient in study 1 (3.1% [95% CI: 0.1–16.2] in study 1 vs. 0% [95% CI: 0–11.9] in study 2, p = 1.00). In non-hematologic adverse events, the incidence of myalgia was significantly higher in study 1 than in study 2 (21.9% [95% CI: 9.3–40.0] in study 1 vs. 0% [95% CI: 0–11.9] in study 2, p = 0.01), and that of alopecia was significantly lower in study 1 than study 2 (18.8% [95% CI: 7.2–36.4] in study 1 vs. 58.6% [95% CI: 38.9–76.5] in study 2, p = 0.02). Liver dysfunction (9.4% [95% CI: 2.0–25.0] in study 1 vs. 17.2% [95% CI: 5.8–35.8] in study 2, p = 0.46) and pneumonitis (6.3% [95% CI: 0.8–20.8] in study 1 vs. 10.3% [95% CI: 2.2–27.4] in study 2, p = 0.66) were slightly more frequent in study 2 than in study 1, although the differences were not statistically significant. Limited to severe adverse events of grade 3 or 4, there were no significant differences between the groups. No treatment-related deaths occurred in either groups.
Table 3.
Treatment-related adverse events
| Study 1 (n = 32) | Study 2 (n = 29) | p value | ||||
|---|---|---|---|---|---|---|
| all grade, n (%) | grade 3 or 4, n (%) | all grade, n (%) | grade 3 or 4, n (%) | all grade | grade 3 or 4 | |
| Hematologic | ||||||
| Neutropenia | 17 (53.1) | 11 (34.4) | 16 (55.2) | 9 (31.0) | 1.00 | 1.00 |
| Leukocytopenia | 14 (43.8) | 8 (25.0) | 15 (51.7) | 8 (27.6) | 0.61 | 1.00 |
| Thrombocytopenia | 0 | 0 | 2 (6.9) | 0 | 0.22 | 1.00 |
| Anemia | 10 (31.3) | 3 (9.4) | 16 (55.2) | 0 | 0.07 | 0.24 |
| Febrile neutropenia | 1 (3.1) | 1 (3.1) | 0 | 0 | 1.00 | 1.00 |
| Non-hematologic | ||||||
| Peripheral sensory neuropathy | 14 (43.8) | 2 (6.3) | 14 (48.3) | 2 (6.9) | 0.80 | 1.00 |
| Myalgia | 7 (21.9) | 1 (3.1) | 0 | 0 | 0.01 | 1.00 |
| Arthralgia | 6 (18.8) | 0 | 2 (6.9) | 0 | 0.26 | 1.00 |
| Liver dysfunction | 3 (9.4) | 0 | 5 (17.2) | 1 (3.4) | 0.46 | 1.00 |
| Nausea/Anorexia | 9 | 1 (3.1) | 10 (34.5) | 1 (3.4) | 0.78 | 1.00 |
| Diarrhea | 0 | 0 | 1 (3.4) | 0 | 0.48 | 1.00 |
| Pneumonitis | 2 (6.3) | 2 (6.3) | 3 (10.3) | 1 (3.4) | 0.66 | 1.00 |
| Alopecia | 9 (28.1) | 0 | 17 (58.6) | 0 | 0.02 | 1.00 |
| Rash | 0 | 0 | 2 (6.9) | 0 | 0.22 | 1.00 |
| Fever | 3 (9.4) | 0 | 1 (3.4) | 0 | 0.61 | 1.00 |
| Fatigue | 3 (9.4) | 3 (9.4) | 1 (3.4) | 0 | 0.61 | 0.24 |
Discussion
To the best of our knowledge, this is the first study to demonstrate that the efficacy of nab-PTX is improved when administered as a subsequent treatment after failure of ICI treatment, relative to its administration as a second-line treatment after failure of the first-line cytotoxic chemotherapy except for ICI. Furthermore, prior ICI treatment was an independent predictor of PFS using the Cox proportional hazards model. Specifically, we demonstrated that ORR was significantly higher and PFS was significantly longer in patients who received nab-PTX as a subsequent treatment after failure of ICI treatment than in those who received nab-PTX as a second-line chemotherapy after failure of the first-line cytotoxic chemotherapy, despite a significantly higher proportion of patients receiving nab-PTX as a late-line treatment and a high proportion of squamous cell carcinoma. In general, late-line cytotoxic chemotherapy is less effective than early line chemotherapy [12], and the prognosis of squamous cell lung cancer is typically poorer than that of non-squamous cell carcinoma [7, 13]. Considering these findings, more patients in study 2 were expected to have poorer prognoses than those in study 1. Therefore, the results of the present study strongly support the efficacy of nab-PTX as a subsequent treatment after failure of ICI treatment.
The strength of the present study is that it was a comparative study limited to nab-PTX monotherapy with long-term follow-up with a sufficient number of events and demonstrated that ORR and PFS were improved when nab-PTX was administered as a subsequent treatment after ICI treatment. Previous studies [3–6] have indicated that chemotherapy, when administered subsequent to ICI treatment, yields a higher ORR than cytotoxic chemotherapy without prior ICI treatment. However, the existing literature lacks reports demonstrating the advantages of PFS or OS. For example, in a large-scale retrospective study, Kato et al. [5] concluded that the ORR of chemotherapy after PD-1 inhibitor treatment was higher than that after cytotoxic chemotherapy without prior ICI treatment. However, the results did not translate into an advantage in terms of PFS or OS. Similarly, Park et al. [6] reported that the ORR was higher when chemotherapy was administered after ICI treatment and PFS was similar to the last cytotoxic chemotherapy before ICI treatment in their retrospective study. Another retrospective study by Shiono et al. [3], which was limited to docetaxel plus ramucirumab after ICI treatment, showed that the ORR was higher than that reported in previous clinical studies. However, the benefit for PFS or OS was unclear. The results of the present study provide important evidence that nab-PTX monotherapy is extremely effective after failure of ICI treatment. Recently, Yoneshima et al. [7] showed that nab-PTX resulted in a significantly higher ORR and longer PFS than docetaxel in patients with previously treated advanced NSCLC in a randomized, open-label phase 3 trial. Interestingly, in this study, OS did not differ between the nab-PTX and docetaxel groups in the absence of prior ICI treatment, whereas nab-PTX contributed to longer OS than docetaxel in the presence of prior ICI treatment. Therefore, nab-PTX may be a more effective and reasonable subsequent treatment option than docetaxel, particularly after ICI treatment.
Based on the findings of basic medicine studies, it is presumed that the synergistic effect of nab-PTX after ICI treatment is due to immunological mechanisms. For example, nivolumab has been shown to bind to CD8+ T cells for more than 20 weeks after its last administration [14], suggesting that there may be residual effects on subsequent treatments. Additionally, the residual effects of ICI may be enhanced by subsequent chemotherapy for several reasons. First, paclitaxel increases PD-L1 expression and the number of CD8+ T cells in the tumor microenvironment [15]. Moreover, paclitaxel increases the number of tumor infiltrating lymphocytes [16]. Second, chemotherapy eliminates immunosuppressive cells such as T-regulatory cells or myeloid-derived suppressor cells [17, 18]. Finally, chemotherapy promotes tumor antigen presentation via tumor lysis. An alternative hypothetical mechanism suggests that the tumor microenvironment, modified by ICI may be more conductive to the success of subsequent chemotherapy. For example, interferon-γ produced by T cells induced by ICI plays a role in normalization of tumor blood vessels [19]. The normalization of tumor blood vessels may allow anticancer agents to reach the tumor efficiently. Notably, the present study shows that the long-term efficacy, which is called “durable response,” was more common when nab-PTX was administered as a subsequent treatment after ICI treatment compared to a treatment without prior ICI treatment. This may be caused by these immunological mechanisms and is a characteristic effect of nab-PTX after ICI treatment.
Other clinical studies have suggested the compatibility of ICI with taxane anticancer agents in treating various cancers, including head and neck cancer [20, 21], melanoma [22], and NSCLC [23]. In a retrospective study by Sakai et al. [20], chemotherapy following ICI treatment was highly effective in patients with head and neck cancer. Most patients in this study (over 80%) received a paclitaxel based regimen, achieving a higher ORR compared to the TS-1 regimen. Goldinger et al. [22] reported that in melanoma, the efficacy of chemotherapy following ICI treatment was limited, but single-agent taxanes showed the highest activity. Recently, a phase III, randomized, open-label study (POSEIDON Study) [23] revealed significant improvements in OS and PFS in NSCLC patients. This improvement was observed with a combination of durvalumab (an anti-PD-L1 antibody), tremelimumab (anti-cytotoxic T-lymphocyte-associated antigen-4 antibody), and chemotherapy compared to conventional chemotherapy. According to the study protocol, for patients with squamous cell carcinoma, chemotherapy options compatible with ICIs included gemcitabine or nab-PTX. For patients with non-squamous cell NSCLC, the options were pemetrexed or nab-PTX. Interestingly, subgroup analysis indicated that OS and PFS tended to be longer with nab-PTX, regardless of histology. These clinical studies collectively demonstrate the promising compatibility of ICI with taxane anticancer agents, potentially enhancing the efficacy of nab-PTX following ICI treatment.
The substantial tolerability associated with nab-PTX monotherapy may also account for the notable prolongation of PFS. The present study showed that the safety profiles did not differ between the patients in study 1 and in study 2, although myalgia and alopecia were significantly different. Considering the extended duration of nab-PTX treatment and the increased number of patients receiving it as a late-line treatment in study 2 compared to study 1, nab-PTX monotherapy may have a long-term safety even after ICI treatment. Although docetaxel ± ramucirumab stands as a prevalent treatment for patients with advanced NSCLC with prior treatments, the clinical challenge arises from the high incidence of FN, ranging between 7.1 and 34.2% [7, 13, 24, 25], while nab-PTX monotherapy has generally lower risks of FN with 0–12.9% [7, 26–29], which is similar to our result. Yoneshima et al. [7] demonstrated that the most severe adverse events, including FN, were less common with nab-PTX than with docetaxel and concluded that nab-PTX was a well-tolerated treatment. The long-term high tolerability of nab-PTX may be attributed to the ease of management of adverse events due to the dosing schedule to administer nab-PTX on days 1, 8, and 15 of the 28-day cycle, which we adopted in this study. In our experience, it is easy to select the appropriate dose of nab-PTX for each patient by skipping doses or reducing doses when adverse events occur. This dosing schedule may be more advantageous than that of docetaxel ± ramucirumab. In the present study, most patients were able to continue treatment with nab-PTX after dose reduction, even when adverse events occurred. Therefore, in terms of tolerability and efficacy, nab-PTX might be a reasonable treatment option after ICI treatment.
However, the safety concerns should be noted. Liver dysfunction and pneumonitis were slightly more frequent in study 2 than in study 1. For example, a clinical study showed that selpercatinib, which is a selective rearranged during transfection (RET) inhibitor, is prone to cause severe liver dysfunction after ICI treatment [30]. Furthermore, several reports indicated that treatment with EGFR-TKIs after ICI treatment may increase the risk of pneumonitis [31, 32]. In other words, the residual effects of ICI may lead to the development of adverse events in subsequent treatment, which should be noted. Large-scale studies are needed to determine whether nab-PTX after ICI treatment increases the risk of serious adverse events.
This study had several limitations. First, it was a retrospective study with a small sample size. Therefore, the generalizability of this study may be insufficient. Second, the study periods differed between study 1 and study 2; therefore, there were some differences in the patient characteristics. For example, the range of genetic mutations tested varied between the studies. While both studies tested for EGFR mutation and EML4-ALK fusion gene, other mutations like the KRAS G12C mutation were only tested in study 2. Notably, 2 patients in study 2 tested positive for KRAS G12C mutation. These differences in molecular profiling could have introduced a bias in the results. The PD-L1 TPS also could not be analyzed in most cases in study 1 because PD-L1 analysis was not available during study 1 period. Therefore, it was difficult to analyze how the PD-L1 TPS affected the effect of nab-PTX after ICI treatment. Furthermore, there were differences in the rate of ICI use, with 31.3% of patients receiving ICI in study 1 while all patients receiving ICI in study 2, which requires caution when interpreting the treatment outcomes, especially in terms of OS. However, from the opposite point of view, it is possible that the difference in OS compared to PFS may be smaller in patients in study 1 due to the effect of ICI after nab-PTX. Further large-scale prospective comparative clinical studies are required to address these issues. Nevertheless, this OS result may also be valuable, given the higher proportion of patients who received nab-PTX as a late-line treatment and the high proportion of squamous cell carcinoma in study 2 than in study 1. Furthermore, in recent years, it is extremely difficult to collect NSCLC patients who will receive nab-PTX without prior ICI treatments, since most patients receive ICI ± chemotherapy as first-line treatments unless they have difficulty in receiving ICI. Therefore, it is impractical to conduct such prospective comparative studies. The present study is valuable in providing important evidence of the efficacy and safety of nab-PTX as a subsequent treatment after ICI treatment, despite the retrospective nature of the study with small sample sizes.
Conclusion
In conclusion, our study demonstrated a markedly elevated ORR and extended PFS in patients who received nab-PTX as a subsequent treatment after failure of ICI treatment in comparison to those who received nab-PTX as a second-line chemotherapy without prior ICI treatment. Additionally, the toxicity profiles between the two groups did not exhibit significant differences. Thus, we propose that nab-PTX monotherapy merits consideration as a viable treatment option for patients with advanced NSCLC after the failure of ICI treatment.
Acknowledgment
We would like to acknowledge Editage (www.editage.com) for providing English language editing assistance.
Statement of Ethics
This study was approved by the Ethics Committee of the Faculty of Medical Sciences, University of Fukui (Reference Number 20220117, approved on October 11, 2022). Opt-out informed consent protocol was used for use of participant data for research purposes. The opportunity was guaranteed for the research participants to refuse to allow the research to be conducted until the submission of the paper. This consent procedure was reviewed and approved by the Ethics Committee of the Faculty of Medical Sciences, University of Fukui (Reference Number 20220117, approved on October 11, 2022).
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This study was not supported by any sponsor or funder.
Author Contributions
Koki Nakashima, Yukihiro Umeda, Yoshiki Demura, and Tamotsu Ishizuka conceived and designed the study. Koki Nakashima, Yukihiro Umeda, Yoshiki Demura, Tomoaki Sonoda, Toshihiko Tada, Makiko Yamaguchi, Masaki Anzai, Maiko Kadowaki, Masahiro Oi, Chisato Honjo, Miho Mitsui, and Yuko Waseda collected the data. Koki Nakashima and Yukihiro Umeda conducted statistical analyses. Koki Nakashima, Yukihiro Umeda, and Yoshiki Demura contributed to the interpretation of the results. Koki Nakashima drafted the original manuscript. Yukihiro Umeda, Yoshiki Demura, and Tamotsu Ishizuka reviewed the manuscript draft and revised it critically on intellectual content. Tamotsu Ishizuka supervised the project. All authors have read and approved the final manuscript.
Funding Statement
This study was not supported by any sponsor or funder.
Data Availability Statement
All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.