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Clinical outcomes for immune checkpoint inhibitors plus chemotherapy in non-small-cell lung cancer patients with uncommon driver gene alterations

BMC Cancer volume 24, Article number: 952 (2024) Cite this article

Abstract

Background

Limited data exists on the efficacy of immune checkpoint inhibitor (ICI) combinations in non-small-cell lung cancer (NSCLC) with uncommon driver alterations in genes such as ERBB2, BRAF, RET, and MET. This study retrospectively assessed ICI-combination therapy outcomes in this molecular subset of NSCLC.

Methods

We retrospectively analyzed patients with advanced NSCLC confirmed with driver alterations in genes including ERBB2, BRAF, RET or MET, and received ICI combined with chemotherapy (ICI + chemo) and/or targeted therapy (ICI + chemo/TT) as first-line (1L) or second- or third-line (≥ 2L) treatment at Hunan Cancer Hospital between January 2018 and May 2024.

Results

Of the 181 patients included in the study, 131 patients received 1L-ICI + chemo (ERBB2, n = 64; BRAF, n = 34; RET, n = 23; and MET, n = 10), and 50 patients received ≥ 2L-ICI + chemo/TT (ERBB2, n = 16; BRAF, n = 7; RET, n = 14; MET, n = 13). The full cohort had an overall response rate (ORR) of 45.9% and disease control rate of 84.0%. Among patients who received 1L-ICI + chemo, ORR ranged between 51.6% and 60.0%, with the median progression-free survival (mPFS) and overall survival (mOS) of 8.2 and 21.0 months for those with ERBB2-altered tumors, 10.0 and 15.0 months for BRAF-altered tumors, 12.1 months and OS not reached for RET-altered tumors, and 6.2 and 28.0 months for MET-altered tumors, respectively. Additionally, ORR ranged between 14.3% and 30.8% for ≥ 2L-ICI + chemo/TT; mPFS and mOS were 5.4 and 16.2 months for patients with ERBB2-altered tumors, 2.7 and 5.0 months for BRAF-altered tumors, 6.2 and 14.3 months for RET-altered tumors, and 5.7 and 11.5 months for MET-altered tumors, respectively.

Conclusion

ICI-based combination therapies, regardless of treatment line, were effective in treating patients with advanced NSCLC harboring driver alterations in ERBB2, BRAF, RET, or MET. This suggests their potential as alternative treatment options in this patient population.

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Introduction

Lung cancer is the second most commonly diagnosed cancer worldwide. In 2022, lung cancer is projected to account for an estimated 236,740 new diagnoses in the United States, and is expected to lead to approximately 130,180 fatalities, maintaining its position as the leading cause of cancer-related deaths in the United States [1]. Non-small-cell lung cancer (NSCLC), accounting for approximately 84% of all lung cancer diagnoses, presents a significant challenge in oncology [2, 3]. Advances in molecular profiling have driven the integration of chemotherapy, targeted therapy, and immunotherapy, notably improving 5-year survival rates to approximately 15–50% in patients diagnosed with NSCLC harboring driver alterations [4,5,6,7]. The mutation prevalence for ERBB2, BRAF, RET, and MET highlights the rarity and complexity of these genetic alterations, emphasizing the importance of personalized medicine. ERBB2 alterations are found in 1.5% to 5.6% of NSCLC cases, with additional cases harboring amplifications [8, 9]. RET alterations, though less quantified, are recognized alongside other uncommon alterations [10]. BRAF alterations, while uncommon, have become one of the actionable targets due to the availability of targeted inhibitors [11]. MET alterations, detected in approximately 1–5% of cases, are notable for their role in resistance mechanisms post-EGFR tyrosine kinase inhibitor (TKI) treatment [12]. Historically, NSCLC treatment was confined to chemotherapy and targeted therapy for specific genetic alterations. The emergence of immunotherapy, particularly the immune checkpoint inhibitors (ICIs), has significantly expanded the treatment horizon and heralded a new era in the management of NSCLC.

The superior efficacy of ICIs, such as anti-programmed cell death protein (PD) 1/PD-ligand 1 (PD-L1) monoclonal antibodies, alone or in combination with chemotherapy and/or other regimens were demonstrated in the KEYNOTE-189 and KEYNOTE-407 studies [12, 13]. Based on these findings, ICI-based combinatorial strategies have become the standard first-line therapy for NSCLCs without EGFR or ALK alterations [12, 13]. However, the real-world effectiveness of these ICI-based regimens in patients with NSCLC harboring less common driver alterations remains underexplored. Although case reports suggest the potential of ICI combination therapies in patients with non-EGFR driver gene alterations, comprehensive studies synthesizing real-world data on these uncommon alterations are scarce [14, 15].

Targeted therapy is the standard first-line treatment in NSCLCs with alterations in ERBB2, BRAF, RET, and MET [16,17,18,19]. Nevertheless, patients often develop resistance to subsequent lines of targeted agents. Retrospective studies indicate that ICI monotherapy exhibits limited activity in patients with NSCLC who harbor driver gene alterations [20]. In this context, ICI-based combination strategies present as a viable alternative, potentially expanding the benefits of ICI to a broader patient demographic. Notably, the IMpower150 study highlighted the improved outcomes with first-line atezolizumab plus bevacizumab and chemotherapy, primarily in patients with EGFR mutations [21]. However, the efficacy of ICI combination strategies in NSCLC with other driver alterations remains to be confirmed.

This retrospective study primarily investigates the outcomes and tolerability of ICI-based combination therapies in patients with NSCLC harboring uncommon driver gene alterations. The findings from this study may potentially serve to enrich clinical decision-making with practical insights.

Methods

Study design and patients

This retrospective study reviewed the data of 8,505 patients with NSCLC who received treatment from Hunan Cancer Hospital between January 2018 and May 2024. Patients selected for this analysis had pathologically confirmed stage IIIB-IV NSCLC, harbored uncommon driver gene alterations identified by next-generation sequencing (NGS) [17] on blood or tissue biopsy samples, and had undergone at least one cycle of ICI-based combination therapy. Exclusion criteria: 1) the absence of driver gene alterations in BRAF, ERBB2, MET, and RET; 2) patients detected with alterations in genes including EGFR, ALK, ROS1 or KRAS; and 3) patients who did not receive ICI-based combination or monotherapy. The focus of this study was on the following uncommon alterations: ERBB2 alterations (exon 20 insertion/duplication, amplification), BRAF mutations (V600E and non-V600E), RET fusion, and MET alterations (amplification and exon14 skipping). NTRK fusion was initially included but ultimately excluded as patients with this alteration did not undergo immunotherapy. This study received approval from the Hunan Cancer Hospital Institutional Review Board Committee, with informed consent waived (approval number 2020-YYB-SSQ-012). All procedures in our study were performed in accordance with the ethical standards of the institutional and national research committees and the 2013 revision of the Declaration of Helsinki.

Data collection and definitions

Data were collected from patients’ medical records, with progression-free survival (PFS) defined as the duration from the first ICI-combined therapy dose to disease progression, last follow-up, or death. Evaluation of treatment response and progression followed the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. Objective response rate (ORR) encompassed complete and partial response cases. Disease control rate (DCR) included complete response, partial response, and stable disease cases. Treatment-related adverse events (TRAEs) were documented in the medical records in strict accordance with the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, from the U.S. National Cancer Institute. Tumor tissues underwent fixation, embedding, and histological processing, with PD-L1 expression assessed in a minimum of 100 tumor cells per sample using 22C3 antibody (Dako, Agilent, CA, USA). PD-L1 positivity was recorded as tumor proportion score (TPS) when membranous staining was observed on ≥ 1% of tumor cells.

Statistical analysis

Statistical analysis was conducted using SPSS Statistics (version 27, IBM Corp., Armonk, New York, USA). The Kaplan–Meier method estimated the group-specific PFS, with the 95% confidence interval (CI) for PFS calculated via the Cox proportional hazard model. Two-sided P < 0.05 was considered as statistical significance.

Results

Patient characteristics

From a total of 8,505 patients with NSCLC who had NGS-based genomic data, our initial screening identified no driver gene alterations in 43.2% (n = 3,676) of patients. Additionally, 50.0% (n = 4,255) of patients were detected with at least one common driver gene alteration, including EGFR alterations (35.3%, n = 3,004), ALK rearrangement (5.3%, n = 450), ROS1 rearrangement (1.4%, n = 121), and KRAS alterations (8.0%, n = 680). These patients were excluded from further analysis. Subsequently, we identified 574 patients harboring uncommon driver gene alterations, including ERBB2 alterations (2.2%, n = 191), BRAF alterations (1.2%, n = 102), RET rearrangement (1.7%, n = 141), MET alterations (1.5%, n = 130), and NTRK alterations (0.1%, n = 10) (Fig. 1).

Fig. 1
figure 1

Flow diagram of the study design

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Among the 574 patients with uncommon alterations, 181 patients received at least one line of ICI-based combination therapy. Of which, 131 treatment-naïve patients received first-line ICI combined with chemotherapy, wherein 64 patients were detected with ERBB2 alterations, 34 had BRAF alterations, 23 had RET alterations, and 10 had MET alterations. Additionally, 50 previously treated patients received ICI-based combination therapies as second- or third-line treatments. Of them, 16 patients were detected with ERBB2 alterations, 7 with BRAF alterations, 14 with RET alterations, and 13 with MET alterations (Fig. 1). Detailed information on the somatic alterations detected from the patients are presented in Figure S1.

Among 131 patients who received first-line and 50 patients who received later-line ICI-based treatment, pembrolizumab and sintilimab were the most preferred ICI regimens, administered to 68% (123/181) of patients in the first-line setting and to 25.4% (46/181) in the second- or third-line settings. The choice of second- or third-line combination strategies was tailored based on each patient’s physical condition. A majority (72.0%, 36/50) received ICI plus chemotherapy, 12 patients (24.0%, 12/50) were given ICI in combination with chemotherapy and bevacizumab, and two patients (4.0%, 2/50) received ICI plus anlotinib (Tables 1 and 2).

Table 1 Baseline clinical characteristics and the treatment details of the cohort who received first-line ICI plus chemotherapy
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Table 2 Baseline clinical characteristics and the treatment details of the cohort who received second-line or third-line ICI-based combination strategies
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Clinical outcomes with ICI and chemotherapy combination in the first-line setting

In the first-line setting, ICI plus chemotherapy demonstrated an ORR of 54.2% and a DCR of 87.0%. Notably, the highest ORR observed was 60.0% in the MET-altered group. The ORR was closely comparable across other alteration groups, with patients harboring ERBB2 alterations showing a 51.6% objective response, patients harboring BRAF alterations with 58.8%, and those with RET alterations having a 52.2% objective response (Table S1 and Fig. 4).

Regarding the median PFS, the ERBB2-altered group had 8.2 months (95% CI: 6.4–10.0), the BRAF-altered group had 10.0 months (95% CI: 4.2–15.8), the RET-altered group achieved 12.1 months (95% CI: 9.3–14.9), and the MET-altered group recorded 6.2 months (95% CI: 2.1–9.9) (Fig. 2A). The median OS was 21.0 months (95% CI: 12.2–29.8) for the ERBB2-altered group, 15.0 months (95% CI: 7.2–22.8) for the BRAF-altered group, 28.0 months (95% CI: 0.0–66.7) for the MET-altered group, and was not reached (NR) among the patients with RET-altered NSCLC (Fig. 2B). As of the data cut-off date (May 26, 2024), 52% (12/23) of the patients with RET-altered NSCLC received RET-TKIs after disease progression with first-line ICI plus chemotherapy. Compared with patients with RET-altered NSCLC who did not receive RET-TKIs, those who received RET-TKIs have a trend of OS difference, but the difference did not reach statistical significance (NR vs 35 months, p = 0.128; Figure S2). Additionally, analyses further demonstrated the clinical characteristics and radiographic evaluations of efficacy among the 64 patients with ERBB2-altered NSCLC, 34 patients with BRAF-altered tumors, 23 patients with RET-altered tumors, and 10 patients with MET-altered tumors in the first-line treatment group (Fig. 3A-C). Table S2 tabulates the analysis on the impact of molecular factors, such as various uncommon gene alteration subtypes or the degree of PD-L1 expression, on mPFS with first-line therapy.

Fig. 2
figure 2

Progression-free survival of the study cohort. Kaplan–Meier curves are shown for progression-free survival (PFS) (A, C) and overall survival (OS) (B, D) for each gene alteration group for first-line treatment with immune checkpoint inhibitor (ICI) plus chemotherapy (A, B) for second-line or third-line treatment with ICI-based combination strategy with chemotherapy and/or targeted therapy (C, D). The sequential order of the groups is ERBB2-altered NSCLC, BRAF-altered NSCLC, RET-altered NSCLC, and MET-altered NSCLC

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Fig. 3
figure 3

Waterfall plots showing the best objective response of each patient harboring ERBB2 alteration (A) BRAF alteration (B) RET rearrangements and MET alterations (C) to first-line treatment with immune checkpoint inhibitor (ICI) plus chemotherapy and second-line or third-line treatment with ICI-based combination strategy with chemotherapy and/or targeted therapy. Each patient’s clinical characteristics were annotated accordingly

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In terms of smoking history, patients who received first-line ICI plus chemotherapy who were smokers had comparable PFS and OS as those who were never smokers (PFS: 8.5 months vs 9.3 months, p = 0.759; OS: 28.0 vs 29.2, p = 0.445; Figure S3). We stratified 131 patients who received first-line ICI plus chemotherapy based on PD-L1 expression level into PD-L1 TPS ≥ 90% subgroup (n = 16) and TPS < 90% subgroup (n = 88). The remaining 27 patients had no PD-L1 expression data and were not included in this analysis. Patients with PD-L1 TPS ≥ 90% were observed to have a trend of longer PFS and significantly longer OS outcomes than those with TPS < 90% (PFS: 14.0 months vs 8.0 months, p = 0.094; OS: NR vs. 19.0 months, p = 0.014). Patients with TPS ≥ 90% had numerically higher ORR but did not reach a statistical difference (81.3% vs 52.3%, p = 0.052; Figure S4). In addition, we compared the survival outcomes of the 131 patients who received first-line ICI plus chemotherapy based on the chemotherapy regimen they received (ie, pemetrexed-based vs paclitaxel-based ICI combination). Over 80% of patients (109/131) received first-line ICI plus pemetrexed. We found no statistical difference in PFS and OS between patients who received pemetrexed-based ICI regimen and those who received paclitaxel-based ICI regimen (PFS: 8.8 months vs 8.5 months, p = 0.811; OS: 28.0 months vs. 37.0 months, p = 0.385; Figure S5).

Clinical outcomes with ICI-based combination therapy in the second- or third-line setting

The study also evaluated the effectiveness of second- or third-line ICI-based combination therapies in patients whose disease had progressed after previous chemotherapy and/or targeted therapy. Table S3 summarizes the treatment regimens these patients received prior to receiving the ICI-based combination therapy. In this cohort, the median PFS varied across the different alteration groups. Specifically, the median PFS was 5.4 months (95% CI: 4.4–6.4) for the ERBB2-altered group, 2.7 months (95% CI: 0.9–4.5) for the BRAF-altered group, 6.2 months (95% CI: 1.1–11.3) for the RET-altered group, and 5.7 months (95% CI: 3.1–8.3) for the MET-altered group (Fig. 2C). The median OS was 16.2 months (95% CI: 1.1–31.3) for the ERBB2-altered group, 5.0 months (95% CI: 2.4–7.6) for the BRAF-altered group, 14.3 months (95% CI: 0.0–44.0) for the RET-altered group, and 11.5 months (95% CI: 2.1–20.9) for the MET-altered group (Fig. 2D).

The clinical characteristics and the radiographic evaluations of the efficacy for these patients were further detailed through post-hoc analyses. This included evaluations of 16 patients with ERBB2 alterations, 7 with BRAF alterations, 14 with RET alterations, and 13 with MET alterations who received second- or third-line treatments (Fig. 3A-C). In terms of response rates, the ORR for the entire group was 24.0%, and the DCR was 76.0%. Breaking it down by alteration type, the ORR was 25.0% for patients harboring ERBB2 alterations, 14.3% for those with BRAF alterations, 21.4% for those with RET alterations, and 30.8% for those with MET alterations (Table S1 and Fig. 4). This analysis provides a comprehensive view of the therapeutic outcomes for patients harboring these uncommon alterations in later-line treatment settings.

Fig. 4
figure 4

The bar and pie charts show the percentage of best response to treatment with first-line immune checkpoint inhibitor (ICI) plus chemotherapy and second-line or third-line treatment with ICI-based combination strategy with chemotherapy and/or targeted therapy

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Safety profile

In the context of TRAEs, the study reported notable findings. In the group receiving first-line ICI plus chemotherapy, 61.1% (80/131) of patients experienced TRAEs. Among these, Grade 3/4 TRAEs occurred in 15.3% of patients (n = 20). Treatment discontinuation due to TRAEs was necessary for 5.3% (n = 7). Four patients in the ERBB2-altered group discontinued treatment due to the following reported adverse events: Grade 3 vomiting, pneumonitis, immune-related hepatitis, and Grade 2 immune-related thrombocytopenia. Two patients in the BRAF-altered group discontinued treatment due to Grade 2 immune-related nephritis and skin rash. A patient in the RET-altered group discontinued treatment due to Grade 3 hyperglycemia. No fatalities were attributed to TRAEs (Table 3). The most common TRAEs occurring in over 10% of patients included leukopenia, neutropenia, anemia, and elevated alanine and aspartate aminotransferase levels. Grade 3/4 TRAEs primarily comprised neutropenia, thrombocytopenia, elevated alanine aminotransferase, and immune-related hepatitis. Additionally, immune-related adverse events (irAEs) of any grade were observed in 35.1% (n = 46), with Grade 3/4 irAEs in 6.9% (n = 9), including hypothyroidism, skin rash, pneumonitis, and immune-related hepatitis.

Table 3 Summary of treatment-related adverse events (TRAEs) for all patients who received ICI plus chemotherapy as first-line treatment
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In the second-/third-line treatment group, 46.0% (23/50) reported TRAEs, with 8.0% (n = 4) experiencing Grade 3/4 TRAEs. Treatment was discontinued due to TRAEs in 6.0% (n = 3): one patient in the BRAF-altered group had Grade 4 immune-related hepatitis and each of the two patients in the RET-altered group had Grade 3 immune-related nephritis and Grade 2 immune-related thrombocytopenia, respectively. Again, no deaths due to TRAEs were reported (Table 4). Common TRAEs included leukopenia, neutropenia, anemia, and hypothyroidism. The reported Grade 3/4 TRAEs were less frequent, with leukopenia, neutropenia, thrombocytopenia, and increased alanine aminotransferase levels. Moreover, any-grade irAEs were noted in 30.0% (n = 15), and Grade 3/4 irAEs in 6.0% (n = 3), encompassing hypothyroidism, hyperthyroidism, skin rash, and immune-related hepatitis.

Table 4 Summary of treatment-related adverse events (TRAEs) for all patients who received ICI-based combination therapy as second-/third-line treatment
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Discussion

In this study, we evaluated the real-world effectiveness and safety of ICI-based combination therapies in patients with uncommon alterations in ERBB2, BRAF, RET, and MET. The analysis involved 181 patients and identified favorable outcomes with ICI-based combination therapy, especially in the first-line treatment, with varied median PFS across alteration types. The study also highlighted the modest effectiveness of later treatment lines and a manageable safety profile, underlining the potential of personalized ICI-based therapies as an alternative treatment option in the molecular subset of NSCLC with uncommon genetic alterations.

To the best of our knowledge, this retrospective study is the first to comprehensively evaluate the effectiveness and safety of ICI-based combination therapy in a large cohort of patients with advanced NSCLC harboring uncommon driver gene alterations. Traditionally, patients with NSCLC that harbor common alterations like EGFR mutations, ALK rearrangements, or ROS1 rearrangements are often excluded from registered prospective clinical studies focusing on ICI-based strategies. Moreover, detailed statistics regarding individual gene alteration types, especially for those with low-occurrence alterations like ERBB2, BRAF, RET, and MET, are rarely available. Consequently, clinical data on the efficacy of ICI-based regimens for NSCLC with these uncommon driver gene alterations remain inconclusive.

The outcomes in this study surpass those reported in major phase III clinical trials like KEYNOTE-189, KEYNOTE-407, ORIENT-11, and ORIENT-12, where ORRs ranged from 40 to 50% and PFSs extended from 8.0 to 9.0 months [12, 13, 22, 23]. We hypothesize that the superior clinical outcomes observed in our study might be attributed to the real-world setting and the substantial sample size. Additionally, a significant portion of our patients had tumors that expressed PD-L1, which potentially influenced the tumors’ response to ICI plus chemotherapy (43.7% with PD-L1 TPS > 1%). Our findings suggest that these genetic alterations may be associated with a favorable tumor immune microenvironment for ICI treatment, a hypothesis that warrants confirmation through larger studies and further experimental research. Based on mutational subtypes, clinical outcomes for first-line ICI combination therapy were not significantly different between ERBB2 exon 20 insertion versus duplication, BRAF V600E versus non-V600E, and RET KIF5B versus non-KIF5B. This analysis was not performed on patients with MET-altered NSCLC due to sample size limitations. The influence of molecular subtypes of these driver genes on the effectiveness of ICI or targeted therapies has been underexplored, and our analysis contributes valuable insights into this research area. Nevertheless, the inherent limitations of real-world studies and our sample size call for further validation with larger cohorts.

In this study, the effectiveness of ICI-chemotherapy combinations in the first-line treatment of patients with NSCLC harboring uncommon alterations was evident. ORRs ranged from 51.6% to 60.0%, with median PFS varying between 6.2 and 12.1 months across different alterations. This indicates a promising role of these therapies in specific NSCLC molecular subtypes. Similarly, these drug combinations used in later-line treatment settings showed diverse clinical outcomes, with median PFS ranging from 2.7 to 6.2 months, median OS ranging from 15.0 months to NR, and ORRs between 14.3% and 30.8%. Comparatively, a study on patients with EGFR-mutant advanced NSCLC treated with ICIs reported an ORR of 32.0%, median PFS of 5.0 months, and median OS of 14.4 months [24]. A study evaluating ICI efficacy alone or combined with chemotherapy in patients with NSCLC harboring ERBB2 alterations found that in treatment-naive patients receiving ICI with chemotherapy, the ORR was 52%, median PFS 6.0 months, and 1-year OS rate of 88%. In second-line or subsequent lines of treatment, ICI monotherapy had an ORR of 16%, a median PFS of 4.0 months, and a median OS of 10.0 months [15]. The RET-MAP study, an international multicenter study, showed that some patients with RET-positive NSCLC may benefit from first-line ICI combined with chemotherapy, with median PFS and ORR reaching 9.6 months and 46%, respectively [25]. Data from the LIBRETTO-431 study reported PFS of 14.0 months and ORR of 53.0% of patients with RET fusion-positive NSCLC who received first-line chemotherapy combined with pembrolizumab [26]. The PFS and ORR reported by these published studies were similar to our findings, where we observed a median PFS of 12.1 months and an ORR of 52.2% in patients with RET-rearranged NSCLC who received first-line ICI plus chemotherapy. The above mentioned literature and our findings consistently demonstrate that ICIs, whether as monotherapy or combined with chemotherapy with or without anti-angiogenic therapy, are effective in treating this molecular subset of NSCLC. Another study found that patients with previously treated advanced NSCLC had a significantly higher ORR (35.5% vs. 15.7%), prolonged PFS (median: 5.6 vs. 2.5 months), and OS (median: not estimable vs. 12.6 months) when treated with ICI plus chemotherapy compared to ICI alone [27]. ICI plus chemotherapy demonstrated favorable outcomes even in the subgroup with PD-L1 negative tumors, indicating the better treatment outcomes with ICI plus chemotherapy compared with ICI monotherapy in previously treated patients with advanced NSCLC [27]. Our study’s results are consistent with these findings, contributing to the growing evidence supporting ICI-chemotherapy combinations in diverse NSCLC subtypes.

Numerous studies have shown that tumors harboring driver gene mutations are more sensitive to pemetrexed chemotherapy [25, 28, 29]. The PointBreak study showed that pemetrexed-based regimen only slightly delayed the disease progression of advanced non-squamous NSCLC compared with paclitaxel-based therapy (PFS: 6.0 months vs. 5.6 months, p = 0.012); however, there was no impact on OS (12.6 months vs. 13.4 months, p = 0.949) [30]. Our findings showed no statistical difference in PFS and OS between patients who received pemetrexed-based ICI regimen and those who received paclitaxel-based ICI regimen (PFS: 8.8 months vs 8.5 months, p = 0.811; OS: 28.0 months vs. 37.0 months, p = 0.385; Figure S5). This finding suggests that the chemotherapy regimen does not significantly impact the clinical outcomes.

A study by Garassino and colleagues demonstrated a significantly higher ORR with nivolumab therapy in patients with EGFR-mutated NSCLC who are current and former smokers than never-smokers; however, there was no difference in PFS and OS [31]. On the contrary, the meta-analysis by Zhao et al. concluded that ICI therapy provides greater benefit to patients with NSCLC who have a smoking history, as shown by the significantly longer PFS and OS than chemotherapy, but no statistical difference in ORR [32]. Therefore, these contradicting data suggest that we may need to fully integrate other clinical factors when considering a patient’s smoking history in clinical practice. In our study, patients who received first-line ICI plus chemotherapy had comparable PFS and OS between current/former smokers and never-smokers (Figure S3). The following are our two considerations for not including smoking status as one of the key stratification factors: first, the limited sample size of our cohort and the lack of some molecular data for some patients, such as TMB and PD-L1; and second, there is currently no standard for classifying smoking history or the assessment of smoking levels. The assessment of smoking history, particularly in terms of frequency and duration, is fundamentally subjective as it relies on the patient’s personal recollection and estimation. Hence, smoking history may not be the most reliable information for developing treatment plans.

A more reliable biomarker of ICI therapy than smoking status is PD-L1 expression [33, 34]. Patients with PD-L1 TPS ≥ 90% were observed to have numerically higher ORR, a trend of longer PFS, and significantly longer OS outcomes than those with TPS < 90% (Figure S4).

Our study demonstrated that OS outcome was comparable between patients who received RET-TKI and those who did not receive RET-TKI (p = 0.128; Figure S2). Median OS was not reached in the RET-TKI group and was 35.0 months in the Non-TKI group. Considering the limited sample size, this finding requires further validation with a larger patient population. These preliminary findings suggest that the sequential treatment of ICI plus chemotherapy, followed by RET-TKIs could afford clinical benefits to patients. The LIBRETTO-431 study reported a numerically higher ORR (84% vs 65%) and significantly longer PFS (24.8 months vs 11.2 months, p < 0.001; hazard ratio for disease progression or death = 0.48) with first-line selpercatinib compared with chemotherapy with or without pembrolizumab in the overall intention-to-treat population [26]. However, the 3-year OS rate was comparable at best between the selpercatinib group and the pembrolizumab plus chemotherapy group. In the LIBRETTO-001 trial, patients who received sequential therapy of ICI followed by selpercatinib had a significantly higher incidence of treatment-related hypersensitivity reactions (17/22, 77%) than patients who received selpercatinib alone (5/22, 23%) [35]. However, AEs were generally manageable among these patients, with 19 patients whose treatment-related hypersensitivity reactions were managed by dose adjustments and/or temporary treatment discontinuation, wherein supportive care was administered before the resumption of selpercatinib treatment. As of the study follow-up time, 14 patients previously treated with ICIs had sustained clinical benefit with twice-daily doses of selpercatinib [26]. We speculate that the patients who developed treatment-related hypersensitivity reactions with selpercatinib had tumor microenvironments that were immune active, particularly those who were previously exposed to ICIs. In addition, the occurrence of hypersensitivity reactions manageable by clinical interventions may potentially serve as a protective factor that represents selpercatinib’s efficacy. However, this requires a larger sample population to explore. Moreover, the safety profiles were manageable in the LIBRETTO-001 and LIBRETTO-431 studies [26, 35]. Currently, a few targeted drugs that specifically target RET rearrangements are available on the market, but they are cost-prohibitive for many families. Therefore, first-line ICI plus chemotherapy may serve as an alternative treatment option. RET-TKIs may be considered in patients who have experienced disease progression in a later-line setting.

Our study also highlighted the manageable safety profile of ICI-based combination strategies in previously treated patients with uncommon driver alterations in genes such as ERBB2, BRAF, RET, and MET, where standard targeted therapies are limited. Our study underscores the relative safety of ICI-based combination therapies in patients harboring uncommon driver gene alterations in ERBB2, BRAF, RET, and MET. We found that TRAEs were more frequent in the group who received ICI plus chemotherapy as first-line treatment (61.1%) compared to those who received ICI-based combination regimen as second-/third-line treatment (46.0%), with severe TRAEs (grade 3/4) also being more common at first-line (15.3% vs. 8.0%). Despite this, the treatment discontinuation rate due to TRAEs was relatively low (5.3% in first-line, 6.0% in second-/third-line), and no fatalities were attributed to TRAEs. Both groups experienced common TRAEs like leukopenia, neutropenia, anemia, and thyroid issues, with over 30% of patients in each group encountering irAEs. In light of the findings from our study and corroborating evidence from existing literature, the safety profile of ICI-based combination regimens remains manageable despite the combination of multiple therapeutic modalities [36]. As highlighted in various studies, while the incidence of irAEs tends to be higher in ICI combination therapies compared to monotherapy, these adverse events are generally manageable with timely and appropriate interventions [36,37,38]. This aligns with our study’s observations, where a notable percentage of patients experienced TRAEs, yet no fatalities were attributed to these events, and the majority were manageable. This finding suggests that even with the complexity and intensity of combined therapies, the overall safety and tolerability of the treatment regimen can be maintained, provided there is careful monitoring and management of adverse events. This reinforces the potential of combination immunotherapy as a viable treatment option, balancing efficacy with an acceptable safety profile. Shroff et al. discussed the shift in advanced NSCLC treatment from empirical chemotherapy to a personalized approach. This approach includes targeted therapies directed at oncogenic driver alterations and immunotherapy aimed at stimulating the immune system. This personalized approach is not only more effective but also tends to have a more manageable safety profile compared to traditional chemotherapy methods. The emphasis on molecular markers and the immune system’s role in recognizing and responding to cancer has been pivotal in improving safety outcomes for patient [39]. Moya-Horno et al. detailed the significant improvements in the treatment of advanced NSCLC through targeted inhibition of angiogenesis and genomic alterations, such as EGFR mutations and ALK rearrangements. The integration of ICIs has redefined the management of NSCLC, achieving substantial and durable responses with a manageable safety profile. This indicates that while these combination therapies are effective, they also maintain a safety level acceptable for clinical use [40].

Nevertheless, it is important to acknowledge certain limitations inherent in our study. Firstly, its retrospective design may influence the robustness of the findings. Additionally, the relatively small sample size for specific molecular subgroups could limit the generalizability of our results. The follow-up period was also constrained, which restricts our ability to comprehensively analyze long-term outcomes. Furthermore, the variability in the ICI-based combination strategies employed in second- and third-line treatments contributes to the complexity of this analysis. Despite these challenges, our research has demonstrated favorable clinical outcomes with ICI-based combination strategies across these distinct molecular subsets of NSCLC, providing valuable insights that contribute to the evolving landscape of NSCLC treatment.

In conclusion, this study demonstrates the encouraging clinical benefits of ICI plus chemotherapy as first-line or subsequent-line treatment of patients with NSCLCs that harbor genetic alterations in ERBB2, RET, and MET with whom standard targeted inhibitors are currently limited. These findings suggest the potential of ICI-based strategies as alternative treatment options for this molecular subset of NSCLC.

Availability of data and materials

The data sets used and analyzed for the current study are included as Supplementary Table S1, Table S2. Other relevant data are available from the corresponding author on request.

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Acknowledgements

The authors would like to thank Dr. Analyn Lizaso for their editing support.

Funding

This work received financial support from the Natural Science Foundation of Hunan Province (grant numbers: 2021RC3118, 2021SK51105, 2023JJ30368, and 2020NSFC-A002), and Guangdong Association of Clinical Trials (GACT)/Chinese Thoracic Oncology Group (CTONG) and Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (grant number: CTONG-YC20200203). The funding agencies had no role in the study design, data collection, analysis, interpretation, manuscript writing, and the decision to submit the article for publication.

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Author notes

  1. Haoyue Qin and Huan Yan contributed equally to this work and should be regarded as co-first authors.

Authors and Affiliations

  1. Hengyang Medical School, Graduate Collaborative Training Base of Hunan Cancer Hospital, University of South China, Hengyang, 421001, Hunan, China

    Haoyue Qin, Huan Yan, Yangqian Chen, Xing Zhang, Nong Yang & Yongchang Zhang

  2. Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, The Affiliated Cancer Hospital of Xiangya School of Medicine, Hunan Cancer Hospital, Central South University, Changsha, 410013, China

    Haoyue Qin, Huan Yan, Yangqian Chen, Zhe Huang, Wenjuan Jiang, Zhan Wang, Li Deng, Xing Zhang, Nong Yang, Liang Zeng & Yongchang Zhang

  3. Department of Medical Oncology, Qinghai Provincial People’s Hospital, Xining, 810000, China

    Qinqin Xu

  4. Department of Radiotherapy, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, 410008, Hunan, China

    Lin Zhang

  5. Early Clinical Trial Center, The Affiliated Cancer Hospital of Xiangya School of Medicine, Hunan Cancer Hospital, Central South University, Changsha, 410013, Hunan, China

    Yongchang Zhang

  6. Furong Laboratory, Changsha, 410013, Hunan, China

    Yongchang Zhang

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Contributions

Liang Zeng and Yongchang Zhang: Responsible for conceptualization, organization, data collection, auditing, supervision, project management, funding acquisition, writing review, and editing. Haoyue Qin, Zhe Huang, and Huan Yan: Responsible for data curation, methodology, formal analysis, original draft preparation, writing review and editing. Yangqian Chen, Qinqin Xu, Wenjuan Jiang, and Liang Zeng: Responsible for software operation, data validation, writing review and editing. Zhan Wang, Haoyue Qin, Huan Yan, Xing Zhang, Li Deng, and Lin Zhang: Responsible for formal analysis and visualization, writing review and editing. Nong Yang and Liang Zeng: Responsible for critical comments and suggestions, writing review and editing. All authors approved the final version of the manuscript.

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Correspondence to Liang Zeng or Yongchang Zhang.

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Ethics approval was provided by the institutional review board of the Hunan Cancer Hospital, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, with the requirement for informed consent waived given the retrospective nature of the study (approval number 2020-YYB-SSQ-012).

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Supplementary Information

12885_2024_12748_MOESM1_ESM.pdf

Supplementary Material 1. Figure S1. The three-dimensional pie chart shows the overall percentage of ERBB2, BRAF, RET and MET. The table shows the distribution of molecular subtypes for each gene and their incidence. Figure S2. Kaplan Meier curve comparing the overall survival of patients with RET-altered NSCLC who received first-line immune checkpoint inhibitor plus chemotherapy and after disease progression received either RET tyrosine kinase inhibitor (TKI) (n=12) or non-RET-TKI regimens (n=11). Figure S3. Kaplan Meier curve comparing the progression-free survival (PFS) and overall survival (OS) of patients who were smokers (n=69) and non-smokers (n=62) and received treatment with first-line immune checkpoint inhibitor plus chemotherapy. Figure S4. Kaplan Meier curve comparing the progression-free survival (PFS) and overall survival (OS) of patients with PD-L1 tumor proportion score (TPS) of ≥90% (n=16) or <90% (n=88) and received treatment with first-line immune checkpoint inhibitor plus chemotherapy. The component bar chart illustrates the objective response for each subgroup. Figure S5. Kaplan Meier curve comparing the progression-free survival (PFS) and overall survival (OS) of patients who received pemetrexed-based ICI (n=109) or paclitaxel-based ICI (n=22) as first-line treatment. Table S1. Evaluation of treatment outcomes for ICI-based combination strategy. Table S2. Median progression-free survival (PFS) with first-line immune checkpoint inhibitor combined with chemotherapy across molecular subgroups based on baseline characteristics. Table S3. Treatment regimens patients received prior to receiving the ICI-based combination therapy in the second-/third-line.

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Qin, H., Yan, H., Chen, Y. et al. Clinical outcomes for immune checkpoint inhibitors plus chemotherapy in non-small-cell lung cancer patients with uncommon driver gene alterations. BMC Cancer 24, 952 (2024). https://doi.org/10.1186/s12885-024-12748-y

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BMC Cancer

ISSN: 1471-2407

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