Summary
Goal: Immune checkpoint inhibitors (ICIs) have demonstrated substantial efficacy in sufferers with superior non-small cell lung most cancers (NSCLC). Nevertheless, the optimum period of ICI remedy stays unclear, and restricted real-world knowledge can be found. The purpose of this research was to judge the connection between ICI remedy period and total survival (OS) in sufferers who achieved various finest total response (BOR) throughout ICI remedy, and to check sufferers handled for six to 18 months vs. at the very least 18 months.
Strategies: This retrospective cohort research included grownup sufferers identified with superior NSCLC who acquired ICI remedy on the Zhejiang Most cancers Hospital between 2017 and 2022. Information assortment ended on Could 1, 2024, and statistical evaluation was carried out between Could and June 2024.
Outcomes: Utilizing strict entry standards, we screened 487 sufferers with superior NSCLC and recognized 134 eligible sufferers. Amongst these sufferers, the median durations of immunotherapy and follow-up have been 24.57 months and 43.60 months, respectively. The target response charge (ORR) was 58.2%, and the median progression-free survival (PFS) was 10.6 months. Median OS was not reached. On the final follow-up, 54 sufferers had no illness development, and 118 sufferers remained alive. Sufferers handled with ICI remedy for ≥ 18 months had superior survival to these handled for six to 18 months (P = 0.039). Additional evaluation revealed that the survival profit was related to BOR throughout ICI remedy. Particularly, sufferers reaching full response/partial response (CR/PR) who acquired ≥ 18 months of ICI remedy had a development towards longer median OS than these handled for six to 18 months, however the distinction didn’t attain statistical significance (P = 0.177). Sufferers with steady illness (SD) who acquired ≥ 18 months of ICI remedy had a statistically longer median OS than these handled for six to 18 months (P = 0.019). Amongst sufferers handled with ICIs for ≥ 18 months, 24 continued with ICI-based remedy and achieved a median PFS2 of 6.67 months, an ORR of 33.3%, and a illness management charge (DCR) of 83.3%.
Conclusions: This research supplies real-world proof and novel insights into the necessity for persevering with ICI remedy past 18 months in sufferers with superior NSCLC who don’t exhibit progressive illness. For sufferers reaching SD throughout ICI remedy, a remedy period of at the very least 18 months seems applicable. For sufferers reaching CR/PR, remedy selections must be individualized in response to patient-specific circumstances. Nevertheless, owing to the retrospective research design, potential choice bias and confounding components might need influenced the outcomes. Due to this fact, our findings require additional validation in potential scientific research.
key phrases
Introduction
In sufferers with superior non-small cell lung most cancers (NSCLC) missing recognized oncogenic driver mutations, immune checkpoint inhibitors (ICIs) focusing on programmed loss of life protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) have change into a gorgeous and extensively used remedy choice, due to their sturdy responses and customarily manageable toxicity profiles with respect to these of platinum-based doublet chemotherapy1,2. Nevertheless, the optimum period of ICI monotherapy stays undefined, and remedy usually extends till illness development, insupportable opposed occasions, or as many as 2 years3.
The CheckMate 153 trial prospectively evaluated the period of ICI remedy in sufferers with superior NSCLC by evaluating steady nivolumab till development vs. a hard and fast 12-month course. Continued remedy was related to superior progression-free survival (PFS) and total survival (OS), thus suggesting that, for responsive sufferers, ICI remedy ought to prolong past 1 yr4. 5-year follow-up knowledge from the Keynote-010 and Keynote-024 trials indicated that 83% and 82% of sufferers, respectively, who accomplished 2 years of pembrolizumab remained alive 3 years post-treatment, and 48% and 46%, respectively, didn’t present illness development or obtain subsequent remedy5,6. Nonetheless, scientific trial populations are extremely chosen and won’t mirror real-world outcomes.
In a latest retrospective evaluation, solely roughly 20% of sufferers discontinued immunotherapy after 2 years, whereas 80% continued upkeep remedy. Nevertheless, when analyzed at a brand new baseline of two years, the distinction in OS charges between sufferers who discontinued vs. continued remedy was not statistically important (79% vs. 81%, P = 0.36)7. Indefinite ICI remedy additionally has inherent drawbacks, akin to elevated threat of medical and financial toxicity. Whereas immune-related opposed occasions (irAEs) usually happen inside the first 3 months, their frequency will increase with longer remedy durations8. Due to this fact, figuring out the optimum remedy period is essential to steadiness efficacy with toxicity.
Herein, we report the differential survival advantages of 6 to 18 months vs. greater than 18 months of ICI remedy in sufferers with superior NSCLC. We chosen an 18-month cutoff level on the idea of current proof and extra validation. To justify this alternative, we performed survival analyses with different cutoff factors, together with 19–24 months, and current the outcomes for the 24-month evaluation herein. The CheckMate 153 research has supported remedy continuation past 1 yr, and demonstrated important enhancements in PFS and a development towards extended OS4. In distinction, retrospective research have advised no extra survival profit from persevering with immunotherapy past 2 years7,9.
Supplies and strategies
Sufferers
This population-based retrospective cohort research included grownup sufferers identified with superior NSCLC between 2017 and 2022 in our scientific database. Information have been censored as of Could 1, 2024, and evaluation was performed from Could to June 2024 (Figure 1).
Flowchart of the research inhabitants.
The inclusion standards have been (1) age 18 years or older; (2) analysis of stage IV NSCLC in response to the 2019 American Joint Committee on Most cancers (AJCC) TNM staging system for lung most cancers; (3) receipt of single-agent or mixture ICI remedy; (4) PFS exceeding 6 months; and (5) Japanese Cooperative Oncology Group efficiency standing (ECOG-PS) rating of 0–4 (with larger scores indicating better incapacity).
The exclusion standards have been (1) incomplete scientific knowledge or lacking data on remedy efficacy evaluation; (2) historical past of major malignancies in different organs; (3) concurrent extreme systemic illnesses; and (4) positivity for epidermal development issue receptor (EGFR), anaplastic lymphoma kinase (ALK), and c-ros oncogene 1 (ROS-1) mutations.
The research was performed with the knowledgeable consent of the sufferers and the approval of the Ethics Committee of Zhejiang Most cancers Hospital, in accordance with the rules of the Declaration of Helsinki (IRB No. 2023-510).
Normal data assortment
Sufferers acquired ICIs in response to the label after Meals and Drug Administration approval. The next clinicopathologic traits have been collected for all sufferers: age, gender, ECOG-PS rating, smoking historical past, histology, mind metastasis, EGFR/ALK/ROS-1 mutation standing, PD-L1 immunohistochemistry standing, kind of ICI, remedy line of ICI, remedy for irAEs, and causes for ICI discontinuation. All sufferers have been evaluated radiologically for the scientific outcomes of goal response charge (ORR), PFS, and OS in response to Response Analysis Standards in Strong Tumors (RECIST, v1.1) by way of computed tomography or magnetic resonance imaging. AEs have been graded in response to the Nationwide Most cancers Institute’s Frequent Terminology Standards for Opposed Occasions (model 4.03).
Efficacy evaluation and follow-up
The first endpoint was OS, outlined because the time from initiation of first-line remedy to loss of life, the final follow-up, or the information cutoff (Could 31, 2024). PFS was outlined because the time from the beginning of the final ICI cycle to the date of illness development or loss of life. Sufferers with out illness development throughout follow-up have been censored on the final contact date or knowledge cutoff, whichever occurred first. PFS2 was outlined because the time from ICI rechallenge to subsequent development or loss of life.
Statistical evaluation
Information assortment and research inhabitants
Information assortment was censored as of Could 31, 2024. The research inhabitants consisted of sufferers identified with superior NSCLC who acquired ICI remedy. Affected person and tumor traits have been summarized with descriptive statistics.
Survival analyses have been carried out with the Kaplan-Meier technique, and variations in survival curves have been assessed with the log-rank take a look at. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) have been estimated with the Cox proportional hazards (PH) mannequin.
To make sure the validity of the Cox PH mannequin, we performed a number of steps to confirm and deal with the PH assumption:
We used the Schoenfeld residuals take a look at to evaluate the PH assumption for every covariate within the Cox mannequin. The null speculation of the Schoenfeld residuals take a look at was that the hazard ratio was fixed over time. A P-value under 0.05 signifies a violation of the PH assumption. Moreover, we visually inspected the log-minus-log (LML) plots to confirm any crossing of survival curves, which may additionally recommend a violation of the PH assumption. For covariates that violated the PH assumption, we launched time-dependent covariates into the Cox mannequin. Particularly, we included interplay phrases between the covariates and time. For instance, for remedy period T, we included the interplay time period X1 × t within the mannequin.
the place X1 represents remedy period, X2 represents different covariates, and β3 represents the coefficient for the interplay time period. After incorporating time-dependent covariates, we re-evaluated the PH assumption with the identical strategies (Schoenfeld residuals take a look at and LML plots) to make sure that the modified mannequin glad the PH assumption.
We carried out univariate evaluation to display screen variables, then chosen these with statistically important P-values for inclusion within the subsequent multivariate Cox regression mannequin.
All P-values have been two-sided, and the edge statistical significance was set at P
Outcomes
Affected person traits
Table 1 summarizes the baseline traits of the sufferers included within the research.
Baseline cohort traits
For the 34 sufferers handled with ICIs for six to 18 months, the median age was 63 years (vary: 38–85 years), 88% have been males, and 76.5% had a smoking historical past. At the beginning of ICI remedy, 91.2% had an ECOG PS rating of 0–1. Pathologically, 47.1% had adenocarcinoma, and 32.3% had squamous cell carcinoma. A complete of 26.5% of sufferers had mind metastases, whereas 23.5% had liver metastases. Moreover, 47.1% of sufferers acquired ICIs as a first-line remedy, and 76.5% underwent mixture remedy. Among the many 24 people in whom PD-L1 expression might be assessed, 16 confirmed positivity. Fifty p.c of sufferers skilled irAEs, primarily affecting the endocrine system (41.2%), lungs (29.4%), pores and skin (17.6%), and gastrointestinal tract (17.6%). One of the best total response (BOR) was full response (CR) or partial response (PR) in 18 sufferers (52.9%) and steady illness (SD) in 16 sufferers (47.1%). For the 100 sufferers handled with ICIs for 18 months or extra, the median age was 65 years (vary: 36–87 years), 85% have been males, and 80% had a smoking historical past. At the beginning of ICI remedy, 89% had an ECOG PS rating of 0–1. Pathologically, 42% of sufferers had adenocarcinoma, and 30.6% had squamous cell carcinoma. A complete of 23% of sufferers had mind metastases, whereas 20% had liver metastases. Moreover, 42% of sufferers acquired ICIs as a first-line remedy, and 68% underwent mixture remedy. Amongst 51 people in whom PD-L1 expression might be assessed, 38 confirmed positivity. Forty-eight p.c of sufferers skilled irAEs, primarily involving the pores and skin (29.2%), endocrine system (27.1%), lungs (22.9%), and gastrointestinal tract (12.5%). Notably, 18 sufferers discontinued remedy due to irAEs. No variations in baseline traits have been noticed amongst subgroups (P > 0.05) (Table 1, Tables S1–S3).
Total efficacy
Among the many 134 sufferers receiving ICI remedy, the median period of immunotherapy and follow-up was 24.57 months and 43.60 months, respectively. The BOR was CR in 3 sufferers (2.24%), PR in 75 sufferers (55.97%), and SD in 56 sufferers (41.79%). The ORR was 58.2%, and the median PFS was 10.6 months. The median OS was not reached. The two-year OS charge was 98.5%, and the 4-year OS charge was 37.3%. On the time of information evaluation, 118 sufferers (88.06%) remained alive, whereas 70 sufferers (52.24%) skilled illness development. Websites of illness development included the lungs (42.86%), lymph nodes (27.14%), bone (12.86%), stomach (12.86%), mind (12.86%), and pleura (10%).
Efficacy by remedy period
Within the group handled with ICIs for six to 18 months, 18 sufferers had a BOR of CR/PR, and 16 had a BOR of SD (Tables S2 and S3). Within the group handled for 18 months or extra, 60 sufferers had a BOR of CR/PR, and 40 had a BOR of SD (Tables S2 and S3). No important variations in median PFS have been noticed between teams (10.50 months vs. 10.60 months; P = 0.640); nonetheless, the group handled for ≥ 18 months had a considerably longer median OS (not reached vs. not reached; P = 0.039) (Figure 2).
Kaplan-Meier curves of progression-free survival (PFS) and total survival (OS) by remedy period. (A) PFS in sufferers handled with ICI for six to 18 months vs. 18 months or extra. (B) OS in sufferers handled with ICI for six to 18 months vs. 18 months or extra. (C) PFS in sufferers handled with ICI for six to vs. 24 months or extra. (D) OS in sufferers handled with ICI for six to vs. 24 months or extra.
Comparability of the teams handled for six to vs. ≥ 24 months indicated no important distinction in median PFS (10.50 months vs. 10.60 months; P = 0.970). Though the median OS was longer within the group handled for twenty-four months or extra (not reached vs. not reached; P = 0.390), the distinction was not important (Figure 2).
For sufferers reaching CR/PR, the median OS was longer within the group handled for ≥ 18 months moderately than lower than 18 months (not reached vs. not reached; P = 0.177), however the distinction was not statistically important. For sufferers with SD, the median OS was considerably longer within the group handled for ≥ 18 months moderately than lower than 18 months (not reached vs. not reached; P = 0.019) (Figure 3).
Kaplan-Meier curves of total survival (OS) by remedy period in sufferers reaching full or partial response (CR/PR) and steady illness (SD). (A) Kaplan-Meier curve displaying total survival (OS) for sufferers reaching full or partial response (CR/PR), stratified by remedy period (≥ 18 months vs. 6 to 18 months). (B) Kaplan-Meier curve displaying total survival (OS) for sufferers with steady illness (SD), stratified by remedy period (≥ 18 months vs. 6 to 18 months).
Rechallenge with ICIs
Of the 100 sufferers handled for 18 months or extra, 38 sufferers have been rechallenged with ICIs after illness development and at the very least 30 days with out remedy: 24 acquired ICIs alone or together with chemotherapy, whereas 14 acquired chemotherapy or chemotherapy mixed with antiangiogenic remedy. The median PFS2 was 6.47 months. The BOR was PR in 26.3%, SD in 55.3%, and PD in 18.4% of sufferers. The ORR was 26.3%, and the DCR was 78.9%. Among the many 24 sufferers receiving ICIs alone or together with chemotherapy (Figure 4), the median PFS2 was 6.67 months; 12 sufferers achieved SD, 8 sufferers achieved PR, and 4 sufferers achieved PD. The ORR was 33.3%, and the DCR was 83.3%. Among the many 14 sufferers receiving chemotherapy or chemotherapy mixed with antiangiogenic remedy, the median PFS2 was 6.12 months; 8 sufferers achieved SD, 2 sufferers achieved PR, and 4 sufferers achieved PD. The ORR was 14.3%, and the DCR was 71.4%. Twenty sufferers have been alive on the knowledge cut-off.
Therapy discontinuation over time and ICI rechallenge. Swimmer plot of sufferers handled with ICI for ≥ 18 months rechallenged with ICI-based remedy. ICI, immune checkpoint inhibitor; PD, progressive illness; PR, partial response; SD, steady illness.
IrAEs
Sixty-five sufferers skilled irAEs, together with 20 circumstances of endocrine reactions, 17 circumstances of rash, 16 circumstances of pneumonitis, and three circumstances of gastrointestinal reactions. Furthermore, 37 sufferers stopped remedy due to illness development: 18 due to irAEs, and seven due to pandemic-related causes.
Prognostic evaluation
Univariate and multivariate analyses have been performed to evaluate scientific parameters affecting PFS and OS in sufferers with superior NSCLC (Tables 2 and 3). We carried out univariate evaluation to display screen variables, then chosen these with statistically important P-values (P P = 0.008], first-line use of immunotherapy [HR: 0.543 (95% CI: 0.333–0.884), P = 0.014], and incidence of irAEs throughout immunotherapy [HR: 0.437 (95% CI: 0.295–1.028), P = 0.038] have been impartial prognostic components for PFS. Univariate evaluation additionally indicated that smoking historical past and liver metastases correlated with poorer OS, whereas reaching CR/PR throughout immunotherapy correlated with extended OS. Multivariate evaluation recognized liver metastases [HR: 5.421 (95% CI: 1.932–15.208), P = 0.001] and reaching CR/PR throughout immunotherapy [HR: 0.293 (95% CI: 0.104–0.823), P = 0.020] as impartial prognostic components for OS.
Univariate and multivariate evaluation of progression-free survival
Univariate and multivariate evaluation of total survival
Dialogue
This retrospective cohort research investigated the connection between the period of immunotherapy with ICIs and OS in sufferers with superior NSCLC. Our findings revealed important variations in OS between sufferers handled with ICIs for six–18 months vs. 18 months or longer. Notably, probably the most important results on survival occurred inside the 18–24 months remedy window, and restricted extra advantages have been achieved past 24 months. By introducing time-dependent covariates into the Cox PH mannequin, we have been in a position to seize the evolving results of remedy on survival. Particularly, we examine the accuracy of information illustration between totally different remedy durations. We validated the PH assumption with Schoenfeld residual checks, which revealed no important time dependence. Though early crossover was noticed, the survival curves indicated steady separation within the later section, in settlement with the PH assumption below steady long-term threat situations.
ICIs have been demonstrated to realize clinically significant enhancements in outcomes for sufferers with superior NSCLC missing driver mutations. Nevertheless, figuring out the optimum period of remedy stays difficult10. Clinically, ICI remedy is often continued till illness development or unacceptable toxicity happens, with the purpose of maximizing therapeutic advantages. Nonetheless, the sturdy results of ICIs and the chance of irAEs recommend that defining a particular remedy period is likely to be extra prudent. On the one hand, from a pharmacological perspective, PD-1 receptor occupancy on circulating T cells can persist for months and promote adaptive immune responses by way of the formation of reminiscence T cells11. However, extended ICI remedy might result in overactivation of the immune system, thus rising the chance of immune exhaustion12. Moreover, prolonged remedy durations are related to larger charges of irAEs. For instance, the CheckMate-153 trial indicated a better incidence of irAEs with steady nivolumab remedy than a hard and fast 1-year course (48% vs. 26%)4. Lastly, long-term use of ICIs poses substantial financial burdens on each sufferers and healthcare techniques. Due to this fact, we sought to steadiness the advantages and dangers of remedy by figuring out the suitable remedy period, and we examined real-world circumstances to search out solutions. On the idea of current proof, a remedy interval of 12–24 months appeared excellent. Our outcomes additional refined this timeframe, particularly demonstrating no important distinction in median PFS between the 6 to 18 months group and the ≥ 18 months group (10.67 months vs. 12.67 months; P = 0.463), however a considerably longer median OS within the ≥ 18 months group (not reached vs. not reached; P = 0.039). Comparability of the ≥ 24 months vs. 6 to 18 months teams indicated no important variations in mPFS (10.67 months vs. 11.23 months; P = 0.672), though the median OS was nonsignificantly longer within the ≥ 24 months group (not reached vs. not reached; P = 0.392).
A key query is tips on how to establish sufferers who can safely discontinue remedy whereas minimizing the chance of recurrence. Research addressing the optimum period of ICI remedy in superior NSCLC, significantly contemplating remedy response, are restricted. In NSCLC, the depth of response to ICIs may correlate with longer PFS and OS13. The CheckMate 153 trial has indicated that the good thing about continued nivolumab remedy is pushed primarily by sufferers reaching CR or PR, whereas no OS or PFS profit was noticed for sufferers with SD or PD4. Our knowledge recommend that sufferers reaching CR/PR throughout ICI remedy may profit from continued remedy lasting 18 months (not reached vs. not reached; P = 0.177), though this discovering lacked statistical significance. For sufferers with a finest response of SD, the median OS was considerably longer within the ≥ 18 months than the vs. not reached; P = 0.019). Thus, an ICI remedy period of 18–24 months is likely to be an inexpensive alternative for sufferers reaching SD as their finest response.
Moreover, our findings indicated that sufferers receiving ICI remedy for 18 months or longer may profit from ICI rechallenge after illness development. Amongst a subset of sufferers who underwent ICI rechallenge, the median PFS post-rechallenge was 6.67 months, and 20 sufferers have been alive on the time of information cutoff. These outcomes align with promising observations from randomized scientific trials throughout long-term follow-up intervals relating to ICI rechallenge14.
The incidence of irAEs is related to sustained responses and scientific profit in sufferers with NSCLC receiving ICIs15. In our cohort, 65 sufferers skilled irAEs, together with 20 circumstances of immune-related endocrine reactions, 17 circumstances of immune-related rash, 16 circumstances of immune-related pneumonitis, and three circumstances of immune-related gastrointestinal reactions. Additional evaluation confirmed that the incidence of irAEs throughout immunotherapy [HR: 0.437 (95% CI: 0.295–1.028), P = 0.038] was an impartial prognostic issue for PFS.
In abstract, indefinite continuation of immunotherapy just isn’t a method that persistently yields extra scientific advantages. Our outcomes present a rationale for an ICI remedy period of 18–24 months for sufferers with superior NSCLC whose finest response to ICI remedy is SD. We acknowledge a number of limitations in our research. The non-randomized design and restricted pattern measurement, with solely 134 of 487 initially screened sufferers being eligible, might need launched confounding components and restricted the generalizability of our findings. To deal with these issues, future multi-center research with bigger and extra various affected person populations are required to validate our outcomes and improve exterior validity. The retrospective nature of our research might need launched biases akin to choice bias, incomplete knowledge, or variable adherence to remedy protocols, thereby affecting the accuracy and reliability of the findings. To mitigate these potential biases, we carried out clear inclusion and exclusion standards, excluded circumstances with incomplete knowledge, ensured consistency in remedy protocols, and performed thorough knowledge validation. Moreover, we used multivariate evaluation to manage for confounding components. To additional advance understanding, future analysis ought to discover different covariates, akin to PD-L1 expression ranges, and conduct long-term follow-up research. These efforts might be important to raised perceive the components influencing survival outcomes and to supply extra sturdy proof of scientific follow.
Conclusions
This research elucidated the connection between the period of immunotherapy with ICIs and survival outcomes in sufferers with superior NSCLC. In contrast with sufferers handled with ICIs for six to 18 months, these handled for ≥ 18 months had the same median PFS however a considerably longer median OS. For sufferers reaching CR or PR, the median OS was longer within the group handled with ICIs for ≥ 18 moderately than
Battle of curiosity assertion
No potential conflicts of curiosity are disclosed.
Writer contributions
Conceived and designed the evaluation: Kaibo Ding, Yanjun Xu.
Collected the information: Kaibo Ding, Dujiang Liu, Xinyue Li.
Contributed knowledge or evaluation instruments: Kaibo Ding, Dujiang Liu.
Carried out the evaluation: Kaibo Ding, Zhongsheng Peng, Lin Zhu.
Wrote the paper: Kaibo Ding.
Information availability assertion
The datasets generated and analyzed through the present research can be found from the corresponding creator upon cheap request.
- Acquired October 29, 2024.
- Accepted January 8, 2025.
- Copyright: © 2025 The Authors
