Efficacy analysis of ALK inhibitors for treating lung squamous carcinoma patients harboring ALK rearrangement

Introduction

At present, targeted therapy has emerged as a prominent treatment option for lung cancer, with specific genetic alterations being targeted by corresponding drugs. Echinoderm microtubule-associated protein-like 4 (EML4) anaplastic lymphoma kinase (ALK) rearrangement has been detected in around 3–7% of non-small cell lung cancer (NSCLC) patients, mostly those with adenocarcinoma (1,2). ALK rearrangement has been reported to account for only 0–2.5% of lung squamous cell carcinoma (SCC) patients (3).

For NSCLC patients with ALK rearrangement, previous studies have shown that ALK inhibitor-targeted therapy has better efficacy than conventional chemotherapy (4,5). With the emergence of second-generation ALK tyrosine kinase inhibitors (TKIs), many studies have shown that its comprehensive efficacy is better than the first-generation ALK TKIs. The ALEX study showed that patients with ALK rearrangement receiving crizotinib and alectinib had progression-free survival (PFS) of 10.4 and 25.7 months (6). The ALTA-1L study data showed that the median PFS of the brigatinib group and crizotinib group were 24.0 and 11.0 months, and the objective response rate (ORR) was 74% and 62%, respectively (7). However, since ALK rearrangements are a rare subtype of SCC, data on the efficacy of ALK TKIs in patients with ALK-rearranged SCC have been reported in only a few case reports. Furthermore, there is a lack of previous studies comparing the efficacy of first-generation and second-generation ALK TKIs in ALK rearrangement patients with lung SCC.

We reviewed 11 patients with ALK-rearranged pulmonary SCC to systematically answer these questions. To investigate ALK-mutated lung SCC, we conducted a literature search and performed a collaborative analysis on 34 patients. Our aim was to assess the effectiveness of ALK TKIs and compare the first- and second-generation ALK TKIs in treating patients with ALK-rearranged lung SCC. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-7/rc).

Methods

Study design

We conducted a retrospective study at Zhejiang Cancer Hospital in Hangzhou, China, from March 2015 to October 2022, involving 11 patients with advanced lung SCC who received ALK TKIs. The follow-up rate for all patients included was 100%. The median follow-up period was 42.33 months. The study included patients who met specific criteria, such as an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0–2, confirmation of stage IIIB–IV lung SCC by cytology or histology, at least one measurable lesion, presence of ALK rearrangements, treatment with ALK TKIs, and provision of complete survival data. Patients were excluded if they had non-SCC based on pathological examination, if their treatment regimens included ALK TKIs combined with chemotherapy or antiangiogenic agents, or if follow-up data was incomplete. NSCLC histology was classified using the World Health Organization’s 2021 criteria (8). ALK rearrangement was analyzed by ALK immunohistochemistry (IHC), reverse transcriptase polymerase chain reaction (PCR), or next-generation sequencing (NGS). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Institutional Ethics Committee at Zhejiang Cancer Hospital (IRB- 2023-151). Informed consent for this retrospective analysis was waived.

Treatment and response evaluation criteria

During therapy with crizotinib and alectinib, we collected data on patients diagnosed with ALK rearrangement SCC. Tumor response was evaluated by two oncologists following the Response Evaluation Criteria in Solid Tumors guidelines (version 1.1), using chest computed tomography and brain magnetic resonance imaging. Evaluations were performed after the first cycle (every 28-day cycle) of treatment, and subsequently every two cycles.

Treatment response was classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). ORR (CR + PR) and disease control rate (DCR) (CR + PR + SD) were calculated. PFS referred to the duration from first use of ALK inhibitor until disease progression or death from any cause, while overall survival (OS) was the duration between confirmed diagnosis of advanced lung cancer and either death from any cause or the latest follow-up date.

Statistical analyses

Statistical analysis of the differences between variables was conducted using Fisher’s exact tests. PFS and OS curves were generated using the Kaplan-Meier method, and a log-rank test was utilized to compare the curves of different subgroups. Two-tailed P values of less than 0.05 were considered indicative of statistical significance. All statistical analyses were performed using SPSS (version 25.0; SPSS Inc., Chicago, IL, USA) and GraphPad Prism (version 9.2.0; GraphPad, San Diego, CA, USA).

Results

Patient characteristics

From March 2015 to October 2022, 11 lung SCC patients with ALK rearrangements were enrolled from Zhejiang Cancer Hospital. The details are shown in Table 1. The median age was 58 years (range, 43–74 years). Females (n=4) accounted for 36.4%. Two (18.2%) patients were stage IIIB and nine (81.8%) patients were stage IV. Eight patients (72.7%) had never smoked. Two patients (18.2%) (2/11) had an ECOG PS of 2. ALK rearrangement was detected in one patient (9.1%) by PCR, in six patients (54.5%) by Ventana IHC, and in four (36.4%) patients by NGS. Six patients, accounting for 54.5%, received crizotinib, and five (45.5%) received alectinib as the initial ALK TKIs. For all patients, seven (63.6%) patients received initial ALK TKIs as the first-line therapy and four (36.4%) patients as the second- or further-line therapy.

Efficacy of the 11 cases

The ORR of the 11 lung SCC patients with ALK rearrangements was 45.4% (5/11), and the DCR was 72.7% (8/11). The median PFS for these patients with ALK rearrangements was 2.80 months [95% confidence interval (CI): 0.00–5.82], and the median OS was 16.00 months (95% CI: 7.12–24.88).

The ORR and DCR for the ALK rearrangement patients (n=6) receiving crizotinib as the initial ALK TKI were 33.3% (2/6) and 66.7% (4/6), respectively. The ORR and DCR for ALK rearrangement patients (n=5) who received alectinib as the initial ALK TKI were 60.0% (3/5) and 80.0% (4/5), respectively. The ORR (P=0.57) and DCR (P>0.99) did not manifest a statistical difference. The median PFS of the patients treated with crizotinib and alectinib was 1.20 months (95% CI: 0.00–2.40) and 4.00 months (95% CI: 1.42–6.58, P=0.71), respectively (Figure 1A). A trend suggested that therapy with alectinib for ALK-rearrangement SCC patients might prolong the survival more than therapy with crizotinib [OS: 26.53 months (95% CI: 7.64–45.42) vs. 9.13 months (95% CI: 1.09–17.17), P=0.08] (Figure 1B).

Figure 1 The Kaplan-Meier estimates of PFS and OS. The Kaplan-Meier estimates of (A) PFS and (B) OS according to the treatment regimens (crizotinib vs. alectinib) in 11 lung SCC patients with ALK rearrangement. Kaplan-Meier estimates of (C) PFS and (D) OS according to therapy line of initial ALK TKIs (first-line vs. further-line) in 11 lung SCC patients with ALK rearrangement. mPFS, median progression-free survival; mOS, median overall survival; SCC, squamous cell carcinoma; ALK, anaplastic lymphoma kinase; TKI, tyrosine kinase inhibitor.

The ORR and DCR for the patients (n=7) receiving initial ALK TKIs as the first-line therapy (n=7) were 57.1% (4/7) and 71.4% (5/7), respectively. The ORR and DCR for patients (n=4) who received it as second- or further-line therapy were 25.0% (1/4) and 75.0% (3/4), respectively. The ORR (P=0.55) and DCR (P>0.99) did not manifest a statistical difference. The median PFS for first-line therapy was longer than second- or further-line therapy [7.20 months (95% CI: 0.00–18.49) vs. 1.20 months (95% CI: 0.22–2.18), P=0.10] (Figure 1C), and therapy with ALK TKIs as the first line prolonged the OS compared to second- or further-line therapy [OS: 26.53 months (95% CI: 0.00–53.55) vs. 9.13 months (95% CI: 1.22–17.04), P=0.047] (Figure 1D).

Pooled analysis

Through a review of the literature, we discovered 25 instances of patients with ALK-rearranged lung SCC who were administered either crizotinib or alectinib as treatment. Patients and treatment characteristics are shown in Table 2. This pooled analysis encompassed a total of 36 cases, which included the 11 previously unreported patients at our center. Of the 36 SCC patients with ALK rearrangement, the majority of patients were female (18/36, 50.0%) and had never smoked (24/36, 66.7%). The median age was 53.50 years (32–78 years). Crizotinib was given to 25 (69.4%) patients and alectinib was given to 11 (30.6%) patients. Among these, 20 (55.6%) patients received initial ALK TKIs as the first-line therapy and 16 (44.4%) as the second or further-line therapy.

Tumor response was reported as follows: 19 patients (52.8%) achieved PR, 9 patients (25.0%) had SD, and 8 patients (22.2%) developed PD as their best response. The ORR and DCR were 52.8% (19/36) and 77.8% (28/36), respectively. Of these patients who received crizotinib or alectinib, 27 (75.0%) patients developed progression or had died at the time of reporting and the median PFS was 7.10 months (95% CI: 2.81–11.39).

The ORR and DCR for patients (n=25) who received crizotinib were 48.0% (12/25) and 72.0% (18/25), respectively. The ORR and DCR for patients (n=11) who received alectinib were 63.6% (7/11) and 90.9% (10/11), respectively. The ORR (P=0.39) and DCR (P=0.41) did not manifest a statistical difference. Patients treated with crizotinib had a median PFS of 6.00 months (95% CI: 0.42–11.58), while those treated with alectinib had a median PFS of 9.00 months (95% CI: 1.46–16.54, P=0.60) (Figure 2A).

Figure 2 Kaplan-Meier estimates of PFS in 36 lung SCC patients based on different treatment regimens and therapy lines of initial ALK TKIs. (A) PFS Kaplan-Meier estimates in 36 lung SCC patients comparing treatment regimens (crizotinib vs. alectinib). (B) PFS Kaplan-Meier estimates in 36 lung SCC patients based on the therapy line of initial ALK TKIs (first-line vs. further-line). mPFS, median progression-free survival; SCC, squamous cell carcinoma; ALK, anaplastic lymphoma kinase; TKI, tyrosine kinase inhibitor.

The ORR of patients who received initial ALK TKIs as the first-line therapy and second- or further-line therapy was 55.0% (11/20) and 50.0% (8/16, P=0.77), respectively. The DCR for first-line therapy and the second- or further-line therapy were 75.0% (15/20) and 81.3% (13/16, P=0.96), respectively. The median PFS was 9.00 months (95% CI: 6.24–11.76) for first-line therapy and 6.00 months (95% CI: 2.77–9.23, P=0.26) for second- or further-line therapy (Figure 2B).

Discussion

This pooled analysis demonstrated that patients with ALK-rearranged SCC obtained moderate clinical benefit from ALK-inhibitor therapy. However, the study found no significant difference in efficacy between alectinib and crizotinib in treating ALK-positive lung SCC. This is the largest study to date evaluating ALK TKIs in ALK-rearranged lung SCC patients and the first to compare crizotinib and alectinib. In addition, we further identified potential beneficial therapy lines of ALK TKIs in lung SCC.

Earlier studies have indicated that ALK TKIs, which are specifically designed to inhibit ALK rearrangement, are effective for treating ALK-positive NSCLC patients. Furthermore, second-generation ALK inhibitors have been shown to be more effective than the first-generation inhibitors (28). In NSCLC, crizotinib produced a median PFS of 7.7–10.9 months (4-6). Compared with crizotinib, alectinib with a median PFS of 25.7 months showed superior efficacy in the primary treatment of ALK-positive NSCLC (6). Due to the low incidence of ALK fusion in lung SCC, there is limited information available on the effectiveness of targeted therapy, with only a few case reports available. Table 2 indicates that there are only a few reported cases of ALK-rearranged lung SCC patients who have responded to treatment with either crizotinib or alectinib. From past case reports, it was found that there is still controversy about whether ALK TKIs have good efficacy in ALK-rearranged lung SCC. In a retrospective study conducted by Meng et al. (22) in which the clinical characteristics of 31 patients with ALK-rearranged SCC were analyzed, with 20 of these cases having received ALK TKIs as either first- or second-line treatment. In these patients, the median duration time of therapy was 6.4±4.4 months, much longer than in patients with chemotherapy (22). Our study involved 11 patients with ALK-rearranged lung SCC who were treated with either crizotinib or alectinib. For the 11 patients, ALK TKIs did not show the desired efficacy, and the median PFS and median OS were 2.80 and 16.00 months, respectively. Further analysis of the 11 patients showed no significant difference in the efficacy between crizotinib and alectinib. At the same time, we reviewed previous studies, summarized previous case reports, and pooled 36 patients for analysis. We found that the PFS with ALK TKIs in the treatment of ALK-rearranged SCC reached 7.10 months, which is better than the data with previous chemotherapy for lung SCC (29). The efficacy of alectinib did not show a statistically significant advantage over crizotinib. Although prior studies have suggested that alectinib exhibits superior efficacy over crizotinib in ALK-positive adenocarcinoma, our study is hampered by limitations including a small cohort size, treatment line heterogeneity, and a retrospective design. Consequently, definitive conclusions regarding the optimal TKI for ALK-positive SCC cannot be drawn. Future large-scale prospective investigations are warranted to elucidate discrepancies in efficacy and safety profiles among different generations of ALK TKIs.

Additionally, we assessed the impact of the treatment line with ALK TKIs on treatment outcomes and patient survival. Analyzing data from 11 patients at our institution, we found that patients receiving ALK TKIs as first-line therapy exhibited significantly better PFS and OS compared to those receiving ALK TKIs as second- or later-line therapy. These findings underscore the importance of prioritizing ALK TKIs as first-line therapy in treatment strategies, potentially offering patients prolonged survival and reduced risk of disease progression. However, this conclusion warrants validation in a broader patient population and consideration of other factors that may influence treatment outcomes. Interestingly, the identification of ALK fusions even within the subset of smokers in our study underscores the imperative of conducting comprehensive genomic profiling in all cases of SCC. Such an approach not only facilitates the detection of genetic aberrations, including ALK fusions, but also furnishes pivotal insights into the potential efficacy of TKI within this patient cohort. Consequently, integrating NGS or PCR-based genetic testing into the routine diagnostic regimen for SCC patients may hold promise in identifying viable candidates for targeted therapies, thereby augmenting treatment stratification and ultimately enhancing patient outcomes.

Our research had some limitations. Our study was a retrospective study, and the sample size was small. For this reason, there might be information bias. We did not analyze or exclude the effect of biomarkers, such as TP53 and EML4-ALK variants, on the efficacy of targeted drugs. Further studies of the efficacy of ALK TKIs in ALK-mutant lung SCC require a larger sample size. Finally, because of the inconsistent ALK testing methods used in the enrolled patients, there may be false positives or false negatives, which may affect the results.

Conclusions

Patients with ALK-rearranged lung SCC obtained moderate benefit from ALK-inhibitor therapy. As compared with crizotinib, alectinib did not show superior efficacy in the treatment of ALK-positive lung SCC. Further high-quality trials are warranted.

Acknowledgments

Funding: The study was supported by the Medical Scientific Research Foundation of Zhejiang Province (No. 2022KY653).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-7/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-7/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-7/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-7/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Institutional Ethics Committee at Zhejiang Cancer Hospital (IRB- 2023-151). The need for informed consent was waived by the Institutional Review Board of the Zhejiang Cancer Hospital, because of the retrospective nature of the study.

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

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