Comparison of different maintenance regimens following first-line immunochemotherapy for advanced non-small cell lung cancer

Introduction

Immunochemotherapy is the standard first-line treatment for EGFR/ALK (epidermal growth factor receptor/anaplastic lymphoma kinase) wild-type advanced non-small cell lung cancer (NSCLC) (1). However, there is no consensus in clinical guidelines with respect to the combination regimen, duration, or the best maintenance strategy.

The successful discovery that programmed cell death 1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors are superior to chemotherapy leads to PD-1/PD-L1 inhibitors as a single agent treatment in advanced NSCLC patients without targetable driver mutations (2-4). The chemo-free regimen as first-line and maintenance treatment appears to be promising. However, single-agent immune checkpoint inhibitors (ICIs) may be less effective and result in treatment failure for patients with PD-L1 <1%. An indirect comparison showed that when compared to ICIs monotherapy, ICIs plus chemotherapy regimen is beneficial both in overall survival (OS) and progression-free survival (PFS), even in patients with PD-L1 expression ≥50% (5). A completely chemo-free regimen may not be an optimal selection. Combined with chemotherapy is necessary in advanced NSCLC treated with ICIs.

However, in the eras of immunotherapy, it is unclear whether long-term use of chemotherapy is needed as recommended in the 2021 Chinese Society of Clinical Oncology (CSCO) guidelines. Before the ICIs were approved, pemetrexed and bevacizumab played important roles in the first-line and maintenance treatment. The AVAPERL and ECOG 5508 studies showed that for advanced nonsquamous NSCLC, bevacizumab plus pemetrexed maintenance was associated with a significant PFS benefit compared with single-agent bevacizumab or pemetrexed (6,7). However, the cumulative toxicity of long-term chemotherapy, particularly in terms of neurotoxicity, nephrotoxicity, and myelotoxicity, impairs the quality of life and increases chemotherapy-associated mortality (8,9). Moreover, many older patients with advanced NSCLC have comorbid conditions and functional impairments that make long-term cytotoxic chemotherapy difficult (10).

To date, the optimal treatment in the induction and maintenance phase for advanced NSCLC has not been established. Successful induction therapy could bring a high response rate. Effective maintenance therapy could play an important role in prolonging the remission interval in the post-consolidation setting. In the Keynote-407, four cycles of pembrolizumab plus chemotherapy were used in the induction phase, and single pembrolizumab was used in maintenance phase. Patients had significantly longer OS and PFS compared to those treated with chemotherapy (11). In the Keynote-189 study, after four cycles of pembrolizumab plus pemetrexed and platinum induction, and followed by pembrolizumab plus pemetrexed maintenance, OS and PFS were improved substantially in patients with NSCLC (12). As reported in Checkmate 9LA, there remains a need for chemotherapy (but more short-course) during the first few weeks of dual immunotherapy to enhance clinical benefit. Dual immunotherapy maintenance is another choice (13). In the IMpower 150 study, adding bevacizumab to the combination strategy in the induction and maintenance phase showed a significant benefit in PFS and OS (14). There have been no head-to-head clinical trials to demonstrate the optimal regimen of the induction and maintenance phase.

In this study, we compared the clinical efficacy of four first-line induction and maintenance regimens for non-EGFR/ALK-driven advanced NSCLC, and developed a chemo-holiday regimen that minimizes the use of chemotherapy drugs without compromising efficacy. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-489/rc).

Methods

Patients

We retrospectively evaluated 1,510 EGFR/ALK wild-type NSCLC patients who received immunotherapy in the First Affiliated Hospital of Guangzhou Medical University (Guangzhou, China) from January 2019 to September 2021 (Figure 1). This retrospective study was approved by the Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University (No. ES-2023-020-01). The requirement for informed consent was waived for this retrospective analysis. The study was conducted in accordance with the ethical standards of the Helsinki Declaration (as revised in 2013) and the applicable regulatory requirements.

Figure 1 Flow chart of selecting eligible patients. EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; NSCLC, non-small cell lung cancer; PD, progressive disease; CR, complete response; PR, partial response; SD, stable disease.

The included criteria were as follows: (I) patients who were diagnosed with advanced or metastatic NSCLC by cytological and histological examination and confirmed without EGFR/ALK mutation by the tissue-based gene test; (II) patients treated with 2–6 cycles of first-line ICIs plus platinum-based doublet chemotherapy with or without anti-angiogenesis, and then followed by chemo-on or chemo-free maintenance. All patients had no chemotherapy or anti-angiogenesis drugs contraindications before treatment. The excluded criteria were as follows: (I) patients with neo-adjuvant/adjuvant immunotherapy; (II) patients who had disease progression or died after first-few weeks of immunochemotherapy, with no maintenance period; (III) ICIs monotherapy without chemotherapy or anti-angiogenesis; (IV) patients treated with second-line immunotherapy; (V) patients without complete clinical or imaging data.

Groups

There were four common regimens, as show in Figure 1: (I) chemo-on maintenance regimens: after 2–6 cycles of initial ICIs plus platinum-based doublet chemotherapy with or without anti-angiogenesis (bevacizumab/anlotinib), patients were followed by ICIs plus platinum-free chemotherapy (pemetrexed/gemcitabine) with (group 1, I+C+A) or without anti-angiogenesis maintenance (group 2, I+C); (II) chemo-free maintenance regimens: after 2–6 cycles induction of ICIs plus platinum-based doublet chemotherapy with or without anti-angiogenesis, patients were followed by single-agent ICIs maintenance (group 3, I), or ICIs plus anti-angiogenesis maintenance (group 4, I+A).

Outcomes

Clinical response was assessed by immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). The primary outcome was first-line therapy PFS. For groups 1 and 2, PFS was defined as the time from the beginning of treatment until the first disease progression. For groups 3 and 4, a rechallenge with initial chemo-agents was added upon the first unconfirmed progressive disease (iuPD), those achieving controlled disease might be repeatedly followed by another chemo-free maintenance period. Notably, for groups 3 and 4, PFS was defined as the time between treatment initiation and failure of rechallenge [last progressive disease (PD)]. After the first progression, whether the patients rechallenged the initial immunochemotherapy with or without anti-angiogenesis regimen was determined by the clinician based on the patient’s condition and consent.

Statistical analysis

To summarize the baseline patient characteristics, means with standard deviation and medians with interquartile range (IQR) were used for normally and non-normally continuous distributed variables, respectively. Numbers reported with percentages were used for categorical variables. In order to evaluate the baseline characteristics and assess the comparability of the four groups, continuous variables were analyzed using one-way analysis of variance (ANOVA) when they were normally distributed, or the Kruskal-Wallis test for data not meeting the assumptions of normality. Categorical variables were analyzed using the Chi-square test or Fisher’s exact test. Kaplan-Meier curve was used to describe the PFS, and the differences between groups were tested by log-rank method. All statistical tests were two-sided and all tests were considered significant for P values below 0.05. In addition, subgroup analyses were performed to explore hazard ratio (HR) in different groups stratified by age, sex, and smoking status, Eastern Cooperative Oncology Group (ECOG) performance status, stage, induction cycles, histologic features and PD-L1 expression. The statistical analyses in this study were performed with R software (version 4.1.0) and SPSS statistics version 23.0 (IBM Corp., Armonk, NY, USA).

Results

Patients’ characteristics

The baseline characteristics of the included cases are summarized in Table 1. After 2–6 cycles of induction, a total of 140 patients were followed by continued maintenance treatment. There were 20 (14.3%), 40 (28.6%), 42 (30.0%) and 38 (27.1%) patients in group 1 to 4, respectively. The enrolled patients ranged in age from 33 to 78. One hundred and fifteen (82.1%) were male, 76 (54.3%) were smokers, 118 (84.3%) were ECOG 1, 92 (65.7%) had distant metastasis, 18 (12.9%) had negative PD-L1 expression, and 22 (15.7%) had PD-L1expression ≥50%. The majority of baseline characteristics among participants in all four groups were similar, with the exception of histologic features and PD-L1 expression.

PFS outcome

As shown in Figure 2A, the median PFS were similar between I+C+A maintenance (22.6 months), I+C maintenance (21.0 months) and I+A maintenance (21.5 months), whereas PFS was relatively inferior in I maintenance alone (13.4 months). When continuous chemotherapy maintenance was given, additional anti-angiogenesis did not show a survival benefit in PFS (I+C+A vs. I+C, HR: 1.03, 95% CI: 0.45–2.39; P=0.95). However, in chemo-free maintenance groups, the addition of anti-angiogenesis was related to a better prognosis, with longer PFS in patients with I+A maintenance compared with those with single-agent ICIs maintenance (I+A vs. I, HR: 0.48, 95% CI: 0.23–0.97; P=0.045). The chemo-free period was at least 13.5 months in patients with I+A maintenance, compared to 6.3 months in those with I maintenance (P=0.038), and the effect of I+A maintenance was comparable to that of the continuous chemotherapy groups (P=0.773) (Figure 2B).

Figure 2 PFS in four groups. (A) Kaplan-Meier estimates of PFS in patients with four different maintenance regimens. (B) Median time in different treatment phase. I, immune-checkpoint inhibitors; C, chemotherapy; A, anti-angiogenesis drugs; PFS, progression-free survival; HR, hazard ratio; CI, confidence interval.

During the maintenance period of group 1 to group 4, 25%, 25%, 19%, and 42% of patients experienced partial response (PR) again, respectively (P=0.131). There were 55%, 65%, 48%, and 61% of patients maintained durable disease control at the end of follow-up, respectively in groups 1 to 4 (P=0.435). For patients with I+A maintenance, 39% of patients received the first iuPD, and initial ICIs plus chemotherapy with anti-angiogenesis regimen was rechallenge. Fifty percent of those patients achieved PR and returned to second chemo-free maintenance phase (Figure 3).

Figure 3 Clinical efficacy evaluation during maintenance period, at the end of follow-up, and after first-line chemo-rechallenge in patient who had PD after I+A maintenance. I, immune-checkpoint inhibitors; C, chemotherapy; A, anti-angiogenesis drugs; PD, progressive disease; CR, complete response; PR, partial response; SD, stable disease.

Subgroup analysis

Median time from the beginning of maintenance to disease progression was comparable among I+C+A, I+C and I+A maintenance groups, and I maintenance alone was relatively inferior (Figure S1). In the subgroup based on age, sex, smoking history, ECOG status, and stage, there was a better PFS in patients with I+A maintenance, compared with those with I maintenance (Figure S2). It seemed that patients with squamous carcinoma benefited more from I+A maintenance (Figure S2). Where stratified by induction cycles, in patients with I+A maintenance, there was a trend that a shorter-course chemo-induction (2–4 cycles) had better clinical outcome than those with 5–6 cycles of chemo-induction (Figure S2). In addition, I+A maintenance was able to improve patient outcome regardless of baseline PD-L1 expression in tumor cells (PD-L1 expression on tumor cells was detected by PD-L1 IHC 22C3 pharmDx) (Figures S2,S3). Even for patients with PD-L1 ≥50%, adding anti-angiogenesis to ICIs was beneficial in PFS. For PD-L1 negative or low expressed population, I+A maintenance still showed an advantage in PFS. Non-statistically significant HRs were found in subgroup analysis between I+A maintenance and I+C±A maintenance.

Chemo-holiday regimen

Based on the results of this study, we proposed a chemo-holiday regimen which minimizes the use of chemotherapy drugs without compromising efficacy. As shown in Figure S4: 2–4 cycles enhanced induction of ICIs plus chemotherapy with anti-angiogenesis, maintenance by ICIs plus anti-angiogenesis, and on-demand chemo-rechallenge upon PD.

Discussion

In this study, we propose a chemo-holiday regimen featured by short-term enhanced induction of ICIs plus chemotherapy with anti-angiogenesis, maintenance by ICIs plus anti-angiogenesis, and on-demand initial chemo-rechallenge, and demonstrated its comparable efficacy to chemo-on maintenance in PFS, thus allowing the minimization of cytotoxic drugs. We highlight that on the basis of immunotherapy, chemotherapy in the maintenance phase is not necessary. ICIs plus anti-angiogenesis is essential during maintenance phase. The efficacy of single-agent ICIs maintenance is suboptimal and adding anti-angiogenesis to ICIs offers extra benefits in PFS. Chemo-holiday regimen provides equivalent efficacy and less toxicity than the continued chemo-on maintenance regimens. On-demand initial chemotherapy rechallenge can delay second-line regimens.

To our knowledge, this is the first study that answers the question of the optimal immune induction and maintenance regimens by comparing different regimens in the real world. The chemo-holiday regimen is effective and well-tolerated. It combines the concepts and advantages of immunochemotherapy in Keynote 189, short-course chemo-induction in Checkmate 9LA, and combined anti-angiogenesis in IMpower 150 (11,13,14). Short-course combined chemotherapy not only plays the sensitization effect on the immune system and avoids the super-progress caused by immune inefficiency, but also reduces the suppression of immune cells caused by excessive chemotherapy. ICIs and anti-angiogenesis exhibit a synergistic antitumor effect in the maintenance period, maximizing the anti-tumor effect, while reducing the side effects from long-term chemotherapy.

Specific immunogenic chemotherapy not only kills tumor cells but also turns “cold” tumors “hot” by inducing immunogenic cell death (ICD), allowing tumor cells sensitization to ICIs (15,16). The chemotherapy, particularly platinum-based drugs, induces tumor cell stress and death that can induce a tumor-special immune response, which leads to the recruitment of dendritic cells (DCs) to the tumor. These DCs engulf dying cancer cells and mature, while PD-L1 and PD-L2 are downregulated, resulting in enhanced tumor-specific T-cell activation (17). The number of CD8⁺ T cells and the expression of PD-L1 in tumor site also increase after chemotherapy (18). There is evidence that chemotherapy-induced proliferation of CD8⁺ T cells, consisting of effector cells expressing coinhibitory checkpoint molecules, offers an appropriate binding site for ICIs (19). Also, activated T cells produce interferon-γ (IFN-γ) to help further eradicate tumor cells. In addition, the combination of ICIs and anti-angiogenesis might further improve the outcome of patients with NSCLC. The use of anti-angiogenesis can normalize and remodel the tortuous tumor vasculature, enabling alleviation of hypoxia and low pH intratumorally (20). Moreover, a normalized vasculature provides a conduit for the efficient immune cells infiltration and delivery of anticancer therapeutics into tumors (21-23). In the induction phase, short-course chemo-anti-angiogenesis induction could alter the immuno-metabolism and tumor microenvironment, and increase immune sensitivity and activation, leading to a synergistic effect with ICIs (17,23-27).

Long-term immunochemotherapy maintenance regimen is not recommended in our study. Hematological, gastrointestinal and skin toxicities are frequently performed in patients with long-term chemotherapy (28,29). Grade 3 or high toxicity rate was 29%, 37%, and 50%, respectively, for bevacizumab, pemetrexed, and their combination maintenance (7). Besides the toxic side effect, long-term chemotherapy is associated with acquired tumor resistance and the emergence of chemo-resistant cancer stem cells (30-33). Cytotoxic chemotherapy also damages the immune system, prompting a suppression of the immune response and reducing the efficacy of immunotherapy (34,35). Patients had a low response rate to subsequent-line therapy once long-term immunochemotherapy had failed. A new maintenance regimen that balances the toxicity and efficacy is needed. In our study, we highlighted that a chemo-free maintenance regimen, ICIs plus anti-angiogenesis maintenance, is feasible and effective. Firstly, compared to long-term immunochemotherapy maintenance, ICI plus anti-angiogenesis maintenance provided equivalent efficacy and at least 13.5-month chemo-free periods. Secondly, it could reduce the toxicities from long-term chemotherapy. Thirdly, it could avoid immune cell suppression caused by excessive chemotherapy and maximize immune efficacy. Fourthly, patients with different histologic subsets of NSCLC can benefit from ICIs plus anti-angiogenesis maintenance. Fifth, chemo-holiday regimen showed significant clinical benefit regardless of PD-L1 expression.

Moreover, when chemotherapy was used as maintenance, additional anti-angiogenesis did not contribute to better PFS, which is similar to the result of the AVEPERL and ECOG-ACRIN 5508 study (6,7). In the AVEPERL and ECOG-ACRIN 5508 study, single-agent pemetrexed or bevacizumab maintenance was recommended for advanced nonsquamous NSCLC, but the combination of pemetrexed and bevacizumab lacked OS benefit and had higher toxicity (6,7). Similar data were obtained in colorectal cancer, the addition of antiangiogenic treatment to standard chemotherapy did not result in an improvement in OS in any of these trials (36-40). In the LEAP-006 clinical trial, pembrolizumab plus pemetrexed with or without lenvatinib were used as maintenance regimen for advanced NSCLC. This trial is still ongoing and we look forward its results to confirm our findings (41).

Single-agent immunotherapy maintenance was also not recommended in our study. Some might view that personalized maintenance regimens should be determined by PD-L1 expression. For patients with PD-L1 expression of at least 50%, Pérol et al. concluded that there is no difference in PFS and OS between ICIs monotherapy and ICIs plus chemotherapy in real world (42). However, only about 30% of advanced NSCLC patients have PD-L1expression ≥50%, and single-agent ICIs maintenance is less effective, especially in patients with low or negative PD-L1 expression. In addition, a large of studies showed that the combination of ICIs and chemotherapy or anti-angiogenesis is significantly better than chemotherapy alone, as well as ICI-monotherapy, regardless of PD-L1 expression. In our study, compared to single ICIs maintenance, adding anti-angiogenesis to ICIs showed significantly longer PFS. In chemo-free maintenance period, anti-angiogenesis is essential, which plays a synergistic role with ICIs and increases the anti-tumor efficacy. The current studies also suggests that anti-angiogenesis treatment was very well tolerated, with low rates of toxicity of grade 3 or high.

In chemo-free maintenance group, initial chemo-regimen were added to rechallenge in the first iuPD. Fifty percent of those received PR and continued to second chemo-free period. We proposed to use chemotherapy on-demand instead of long-term chemotherapy. When the patients meet first PD, on-demand initial chemotherapy can not only control the disease in time, but also delay the time of second-line medication. Initial chemotherapy may play sensitive role again and help kill tumor cells. On the other side, for patients who do not receive diseased control after initial chemo-rechallenge, second-line therapy should be given timely.

We acknowledged some limitations to our study. First, it is a retrospective study and carries the potential disadvantages and bias of a retrospective study. Second, the number of each group is small and future studies with larger sample sizes are needed to strengthen our conclusions. Third, only 71 (50.7%) patients had baseline PD-L1 expression information. We did not perform a PD-L1 subgroup analysis including all patients. Fourth, the toxicities of each group were not recorded in our study. Fifth, the data on OS were immature. Sixth, in I maintenance group, most patients received second-line chemo-agents or gave up treatment at the first progression. Furthermore, some questions remain to be answered. First, it is unclear whether anti-angiogenesis is necessary in induction period. Second, whether anti-angiogenesis contributes a better clinical outcome in patients with dual ICIs maintenance is of doubts. Third, we need novel prognostic markers to identify patients who may benefit more from chemo-holiday regimens. Fourth, there are a number of anti-angiogenesis drugs that have been approved for NSCLC, such as bevacizumab, anlotinib, endostar, ramucirumab. Considering that the targets of these drugs are not the same completely, it is unclear that whether these anti-angiogenesis drugs combined with ICIs have the same efficacy in maintenance period.

Conclusions

For advanced NSCLC patients, we propose a chemo-holiday regimen instead of completely chemo-free or long-term chemotherapy. Chemo-holiday regimen is preferable as first-line treatment with good clinical effect and less side effects, regardless of PD-L1 expression and pathologic types.

Acknowledgments

The Abstract was in part presented on 2022 ESMO conference.

Funding: This study was supported by the China National Science Foundation (grant Nos. 82022048 and 81871893).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-489/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-489/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-489/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-489/coif). W.L. serves as an Associate Editor-in-Chief of Translational Lung Cancer Research from May 2023 to April 2024. 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. This retrospective study was approved by the Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University (No. ES-2023-020-01). The requirement for informed consent was waived for this retrospective analysis. The study was conducted in accordance with the ethical standards of the Helsinki Declaration (as revised in 2013) and the applicable regulatory requirements.

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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