Efficacy of second- and third-line chemotherapy after chemotherapy with platinum doublet and immunotherapy in non-small cell lung cancer: a descriptive study

Introduction

Phase III studies have demonstrated the efficacy of second-line chemotherapy in non-small after prior retreatment with a platinum doublet in non-small cell lung cancer (NSCLC) (1-3). Shepherd et al. demonstrated a significantly longer overall survival (OS) in patients treated with second-line docetaxel vs. placebo (2). Fossella et al. then demonstrated a higher efficacy of docetaxel in the second-line of treatment compared to vinorelbine and ifosfamide (1). Finally, Hanna et al. demonstrated similar efficacy of pemetrexed compared to docetaxel in second-line treatment (3). However, all these studies were conducted before the era of immunotherapy and therefore do not answer the question of whether the effectiveness of second-line chemotherapy is similar even after pretreatment with chemoimmunotherapy.

A few retrospective studies have been published showing the effectiveness of the combination of docetaxel + nintedanib/ramucirumab (4-8). However, these treatment combinations are not covered by health insurance in a number of countries (including the Czech Republic), which is why monochemotherapy is the usual standard in this situation. However, data for the effectiveness of monochemotherapy after previous chemoimmunotherapy are very limited (9,10). Therefore, the first aim of this study was to retrospectively evaluate data from the Czech multicenter Lung Cancer Focus (LUCAS) registry to evaluate the effectiveness of second-line chemotherapy after previous use of platinum doublet chemotherapy and immunotherapy.

To the best of our knowledge, there are no data evaluating the efficacy of third-line chemotherapy in patients diluted with chemotherapy + immunotherapy and second-line chemotherapy. The second aim of this study was therefore to retrospectively evaluate the data from the aforementioned LUCAS registry in patients treated with this third-line of chemotherapy. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2555/rc).

Methods

The LUCAS project is a clinical registry for newly diagnosed patients with lung cancer since 1 June 2018. All centers mentioned in this study are involved in this project. The project is registered on ClinicalTrials.gov under registration number NCT04228237. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Ethics Committee of University Hospital Olomouc, Faculty of Medicine and Dentistry, Palacky University (No. 63/18 MEK 13) and individual consent for this retrospective analysis was waived. The other institutions in this project were also informed and approved this study. In the LUCAS project, basic demographic and clinical characteristics, performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG), morphological, immunohistochemical, immunochemical and molecular genetic characteristics, data about pharmacotherapy (including types, combinations and sequences), data about the interventions (including surgery, radiotherapy etc.) are recorded.

Patients

All patients from the LUCAS registry with completed characteristics of chemotherapy and corresponding to the necessary entry—i.e., patients pre-treated with chemoimmunotherapy, possibly chemotherapy (containing a platinum doublet) followed by immunotherapy, and then with the use of second- or third-line chemotherapy were included in this retrospective study. Stage III patients after chemoradiotherapy were included only if they progressed early and investigators evaluated next therapy as a subsequent line of treatment.

Statistical methods

OS was defined as time from start of the treatment to death for any cause. Time on treatment (ToT) was defined as time from the start of the treatment to the end of treatment form any cause. Kaplan-Meier method was used to estimate the OS and ToT. The date of death was obtained from the Czech Statistical Office as of 30 September 2023. These data were supplemented with death information from “Reimbursement payment (K-batch)” and from the CLADE information system for manual data entry into the LUCAS registry. Living patients were censored at the last date they were known to be alive. Median follow-up was determined using the reverse Kaplan-Meier method. Basic statistics such as the proportion of patients with a recorded event, median OS and ToT with a 95% CI were presented. To capture the spread of the survival data beyond the median, the 25th (Q1) and 75th (Q3) percentiles with 95% CIs were also estimated using the Kaplan-Meier curves. The analysis was performed using IBM SPSS Statistics 29, and R software was utilized to plot the survival curves.

Results

Patient characteristics

A total of 114 patients were included in the evaluation of the effectiveness of chemotherapy after previous chemoimmunotherapy (or chemotherapy followed by immunotherapy)—i.e., second-line chemotherapy. Median age was 67 (range, 41–87) years. Other baseline characteristics are shown in Table 1. Median follow-up was 14.2 (95% CI: 11.4–24.9) months.

A total of 22 patients were included in the analysis of the efficacy of third-line chemotherapy. Median age was 64 (range, 41–87) years. Other baseline characteristics are shown in Table 2. Median follow-up was 7.8 months [95% CI: 3.9–not available (NA)] months.

ToT

The median ToT for second-line chemotherapy was 2.9 (95% CI: 2.4–4.7) months. The 25th percentile (Q1) was 0.9 (95% CI: 0.2–1.6) months and the 75th percentile (Q3) was 5.3 (95% CI: 4.7–NA) months. Kaplan-Meier curve for ToT for second-line chemotherapy is shown on Figure 1.

Figure 1 Kaplan-Meier curve for ToT of patients treated with second-line chemotherapy. ToT, time on treatment.

The median ToT for third-line chemotherapy was 5.1 (95% CI: 1.4–NA) months. The 25th percentile (Q1) was 0.5 (95% CI: 0.3–NA) months and the 75th percentile (Q3) was 6.4 (95% CI: 5.1–NA) months. Kaplan-Meier curve for ToT for third-line chemotherapy is shown on Figure 2.

Figure 2 Kaplan-Meier curve for ToT of patients treated with third-line chemotherapy. ToT, time on treatment.

OS

The median OS for second-line chemotherapy was 7.2 (95% CI: 6.1–11.2) months. The 25th percentile (Q1) was 2.5 (95% CI: 1.8–4.5) months and the 75th percentile (Q3) was 19.3 (95% CI: 12.7–26.7) months. Kaplan-Meier curve for OS for second-line chemotherapy is shown on Figure 3.

Figure 3 Kaplan-Meier curve for OS of patients treated with second-line chemotherapy. OS, overall survival.

The median OS for third-line chemotherapy was 13.8 (95% CI: 6.1–NA) months. The 25th percentile (Q1) was 5.5 (95% CI: 0.8–NA) months and the 75th percentile (Q3) was 18.5 (95% CI: 13.8–NA) months. Kaplan-Meier curve for OS for third-line chemotherapy is shown on Figure 4.

Figure 4 Kaplan-Meier curve for OS of patients treated with third-line chemotherapy. OS, overall survival.

ToT and OS for specific drugs

To enable comparison of individual drugs in second-line chemotherapy (third-line chemotherapy contains too few patients to divide the patient group), we also present ToT and OS separately for docetaxel, paclitaxel, pemetrexed and vinorelbine in Tables 3,4.

Discussion

In our group of patients, we demonstrated both the effectiveness of second-line chemotherapy and the possible effect of third-line chemotherapy (in highly selected patients) in patients pretreated with a platinum doublet and immunotherapy (either together with chemotherapy or sequentially).

Our data for second-line chemotherapy are comparable to earlier second-line data from phase III trials for docetaxel/pemetrexed (after a previous platinum doublet) (1-3). The ToT in our study (2.9 months) is comparable to the study by Fossella et al., where the median number of docetaxel cycles administered was 3 (i.e., median ToT 2.1 months) (1). As well as our median for OS (7.2 months) is comparable to the aforementioned studies—median OS reached 5.7 months (Fossella et al.), 7.5 months (Shepherd et al.) and 8.3 (pemetrexed) vs. 7.9 (docetaxel) months (Hanna et al.) (1-3).

Even in the more recent phase III trials with the docetaxel + nintedanib/ramucirumab combination, where docetaxel was used as a comparator, our ToT results were comparable to the duration of treatment data for docetaxel (11,12). In study by Reck et al. median ToT for docetaxel reached 2.8 months and in study by Garon et al. was median ToT for docetaxel 3.0 moths (11,12). Median OS was a bit higher in these studies—9.1 months in both studies (11,12). These studies were conducted before the era of immunotherapy and, unlike our group of patients, the patients were not pretreated with immunotherapy. In summary, it can be said that the inclusion of immunotherapy in the treatment algorithm probably does not significantly reduce the effectiveness of subsequent chemotherapy.

In new studies with second-line immunotherapy and sotorasib, where docetaxel was used as a comparator, the ToT for docetaxel is not known in immunotherapy studies and reached higher values (4 months) in study trial with sotorasib (13-15). However, patients with a worse PS were not included, and there was also further selected population (only patients KRAS G12C mutation) in trial with sotorasib vs. docetaxel. The OS data from these studies are completely incomparable with our study—some patients in the docetaxel arm subsequently received immunotherapy (in our study immunotherapy was used before second-line chemotherapy) or sotorasib (it was NA for our patients at the time).

Most of the publications examining the effect of treatment after chemotherapy and immunotherapy dealt with the combination of docetaxel with nintedanib/ramucirumab (4-6,8,16,17). These retrospective studies (with the exception of the study by Reck et al., where it was a subanalysis from a prospective study) demonstrate the effectiveness of these combinations (8,16,17). Median OS was 8.4–11.6 months and in the Japanese study by Katayama et al. even 22.6 months (8,16,17). A meta-analysis by Garon et al. then reports a median OS of 13.5 months for the combination of docetaxel + ramucirumab after chemoimmunotherapy (18). These results would suggest a better efficacy of combination therapy with docetaxel when compared with our data.

Data for chemotherapy alone after using a platinum doublet and immunotherapy are very limited. Assi et al. published a study with 21 patients treated with docetaxel with median progression-free survival (PFS) of 3 months, ToT or OS are not published (9). Auclin et al. then in 57 patients treated with taxane monotherapy or other chemotherapy they achieved a median OS of 6.4 vs. 6.7 months (10). In this respect, our data do not deviate from the range of results of this study. Conversely, Ishida et al. published better results with docetaxel treatment with a median OS of 17.6 months (6). However, their data contained only 15 patients and was base just on Japanese patients. Thus, population differences could also play a role (e.g., the different representation of mutations in the Asian vs. European population) (19). The largest published set of patients comes from the United States (however, this is only published as an abstract, the full article has not been published to the best of our knowledge) (20). One hundred and sixty-six patients treated with taxanes in monotherapy were included in this study, with a median OS of 9.0 months. This slightly better outcome compared to our data can be partially due to a certain selection of patients for this analysis, when only ECOG PS 0–1 patients without laboratory limitations and administration of more than one cycle of immunotherapy were included.

Data for third-line treatment are rare. Unique phase III study tested the efficacy of eribulin vs. investigator-administered treatment in higher lines of treatment (21). The median PFS for eribulin was 3.0 months and the median OS was 9.5 months. Other studies addressing systemic third-line treatment are essentially retrospective and were published before the era of immunotherapy (22-27). The number of patients in these studies was quite variable, from several dozen to 230 patients in the Japanese study, where, however, a significant proportion of patients (38%) were treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in the third-line (22-27). Patients who were treated with EGFR TKI in the second-line treatment are often also included in other mentioned studies. In this respect, to the best of our knowledge, our study is unique because it shows a cohort of patients pretreated with a platinum doublet + immunotherapy and second-line chemotherapy. In our study, third-line chemotherapy was used in 22 of 141 (i.e., 19%) patients who had previously been treated with second-line chemotherapy. This number is lower than previously published studies before the era of immunotherapy, when third-line treatment was used in 21–40% of patients (22-24,26). More frequent use of EGFR-TKIs even in patients without a known EGFR mutation in previous era may play a role. Patients treated with potential EGFR-TKIs were not included in the third-line in our cohort in contrary with some other mentioned studies. Retrospective data on the efficacy of third-line therapy are quite heterogeneous, with only a few studies reporting median ToT/PFS, with typically median 2–3 months (22,26,27). Again, only some studies published data for OS, where the median OS ranged from 5.8 to 12 months (22,24,25). In our patient cohort, ToT reached 5.8 months and median OS reached 13.8 months, albeit with a rather wide interval of values due to the low number of enrolled patients. Overall, published and our data point to the theoretical effectiveness of third-line treatment in highly selected patients. However, it is important to take into account that, at least in our case, the data are based on only a small group of highly selected patients. The need for selecting the right group of patients is also indicated by previous data, where third-line treatment is significantly more effective in patients in good PS and in patients with a response to previous chemotherapy (22-25). The fact that this is a selected group of patients is also evident in our patient group—only a relatively small proportion of patients reached the third-line of chemotherapy and at the same time had a good PS (only ECOG PS 0–1) and the most of the patients had adenocarcinomas. The range of values for treatment efficacy of third-line therapy may also be due to the different proportion of individual treatment modalities, for example, in our study the most commonly used drug was vinorelbine, while in the study by Girard et al., it was gemcitabine, in Asahina et al. docetaxel and in Tatli et al. pemetrexed (22,24,25). However, it is not clear which drug would be the most appropriate in this context, although preclinical data indicate possible cross-resistance between paclitaxel, docetaxel and vinorelbine, and after their possible previous use, the use of gemcitabine or pemetrexed could probably be more appropriate (28).

The limitation of our study is mainly its retrospective design, which, among other things, led to a wider spectrum of used chemotherapy without knowledge of the indication of a specific type of treatment. Another limitation is the small number of patients treated in third-line chemotherapy, which may lead to a bias in the median for ToT and OS. There was also very likely a certain selection bias (especially in the third-line of treatment), when it is not clear on the basis of which criteria the next line of treatment was or was not indicated. This selection bias is more pronounced in the third-line chemotherapy, which included only patients with good ECOG PS and adenocarcinomas were dominated. Therefore, these data must be interpreted with caution, taking this selection bias into account. Last but not least, this study does not include a control group, as the LUCAS registry was created at a time when at least second-line immunotherapy was already the standard of treatment and it is not possible to reliably determine data from the registry for patients in whom a symptomatic procedure was chosen after previous chemotherapy and immunotherapy (there is some uncertainty as to whether a symptomatic procedure was really chosen or whether the relevant line of treatment was simply not entered into the registry, for example due to the administration of this treatment at another institution that was not part of the registry).

Conclusions

The efficacy of second-line chemotherapy in our group of patients (pretreated with chemotherapy and immunotherapy) was comparable with registration studies for second-line chemotherapy. As our data suggest, third-line treatment is chosen in highly selected patients (especially very good PS) where it could be effective. In this regard, it would be worthwhile to conduct a prospective study with a clear definition of the selection of these patients.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2555/rc

Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2555/dss

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2555/prf

Funding: This work was supported by the grant of Ministry of Health of the Czech Republic-Conceptual Development of Research Organization (Faculty Hospital in Pilsen-FNPl, 00669806) and by the Cooperatio Programme, research area.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2555/coif). P.D. receives consulting fees and payment or honoraria from LUCAS Project, and is an employee of OAKS Consulting s.r.o. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Ethics Committee of University Hospital Olomouc, Faculty of Medicine and Dentistry, Palacky University (No. 63/18 MEK 13) and individual consent for this retrospective analysis was waived. The other institutions in this project were also informed and approved this study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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