New treatment options for crizotinib-resistant ALK-positive non-small cell lung cancer patients

The fusion of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small cell lung cancer (NSCLC) was first reported by Soda et al. in 2007 (1). ALK rearrangements, known as a typical example with the EML4-ALK fusion gene, have been identified in approximately 5% of NSCLCs and are now widely recognized as targets for molecular targeting drugs for NSCLCs (2). Crizotinib was developed as a tyrosine kinase inhibitor (TKI) against the ALK, MET, and ROS1 receptors, and clinical trials of crizotinib for ALK-positive NSCLC patients were initiated immediately after the EML4-ALK gene fusion in NSCLC was identified. Crizotinib was shown in the PROFILE 1007 trial to significantly prolong PFS in second-line treatment of ALK-positive NSCLC patients compared with existing standard chemotherapy with docetaxel or pemetrexed (3). In addition, crizotinib was shown in the PROFILE 1014 trial to significantly prolong progression-free survival (PFS) in the first-line treatment of ALK-positive nonsquamous NSCLC patients compared with the existing standard chemotherapy combination of pemetrexed plus cisplatin or carboplatin (4). Next, alectinib was developed as a second-generation ALK TKI. Three randomized controlled trials reported that alectinib significantly prolonged PFS compared to crizotinib in first-line treatment of ALK-positive NSCLC (5-7). Subsequently, a series of second-generation ALK-TKIs were developed, with brigatinib and lorlatinib proving superiority over crizotinib in clinical trials (8,9). As with all molecular-targeted drugs, resistance to ALK-TKIs has been reported (10), and treatment strategies must consider the choice of drug when resistance develops (11).

Shi et al. conducted a single-arm phase II trial of iruplinalkib, a new second-generation ALK- and ROS1-TKI, for crizotinib-resistant ALK-positive NSCLC (12). Iruplinalkib is an ALK/ROS1-TKI developed in China, and this phase 2 study is being conducted after a phase 1 study completed also in China (13). This was a collaborative phase 2 single-arm study conducted at 41 centers in China. The primary inclusion criteria for this trial were patients with ALK-positive NSCLC who were resistant to prior therapy with crizotinib and had at least one measurable extracranial lesion. The main exclusion criteria for this trial were prior treatment with an ALK-TKI other than crizotinib or continuous steroid treatment for more than 30 days. Patients received iruplinalkib 180 mg orally once daily for a 21-day cycle with a 7-day lead-in phase at 60 mg once daily, as recommended in the previously cited phase 1 study (13). The primary endpoint in this study was the independent review committee (IRC)-assessed objective response rate (ORR).

From August 7, 2019, to October 30, 2020, 146 ALK-positive crizotinib-resistant advanced NSCLC patients were enrolled in this study. The response rate for iruplinalkib in all 146 patients was 102 (69.9%) for partial response (PR), 9 (6.2%) for non-complete response (CR)/non-progressive disease (PD), 30 (20.5%) for stable disease (SD), and 1 (0.7%) for PD. IRC-assessed ORR was 69.9% [95% confidence interval (CI): 61.7–77.2%]. In this study, the primary endpoint was met because the lower limit of the 95% CI was above the pre-defined threshold of 40%. A phase 2 study of alectinib in crizotinib-resistant ALK-positive NCSLC patients reported an ORR of 48% (95% CI: 36–60%) (14). A phase 2 study of brigatinib in crizotinib-resistant ALK-positive NCSLC patients reported an ORR of 54% (97.5% CI: 43–65%) (15,16). In the previous crizotinib with or without chemotherapy arm of the phase 2 study of lorlatinib in ALK-positive NCSLC patients, the ORR was reported to be 69.5% (95% CI: 56.1–80.8%) (17). A phase 2 study of ceritinib in ALK-positive NCSLC patients who progressed after crizotinib and platinum combination therapy reported an ORR of 38.6 (95% CI: 30.5–47.2%) (18). The results of this study were comparable to the results of treatment with second-generation and later ALK-TKIs that have already been reported.

In this study, treatment-related adverse events (TRAEs) of iruplinalkib were observed in 93.2% of patients, but grade 3–4 TRAEs were observed in 30.8% of patients (12). Alectinib caused grade 3–5 adverse events (AEs) in 41% of patients in the ALEX trial (6). Brigatinib caused grade 3 or higher AEs in 61% of patients in the ALTA-1L trial (15). Lorlatinib caused grade 3–4 AEs in 72% of patients in the CROWN trial (9). Ceritinib caused grade 3–4 AEs in 78% of patients in the ASCEND-4 trial (19). Based on these results, the AEs with iruplinalkib were not worse than with other ALK-TKIs and were within acceptable limits. The most common TRAEs of iruplinalkib in this study were aspartate transaminase (AST) increased (43.2%), alanine transaminase (ALT) increased (37.0%), blood creatine phosphokinase increased (34.9%), and no AEs characteristic of this treatment were observed (12). Discontinuations of iruplinalkib due to TRAEs were reported in four patients (2.7%), each due to increased blood creatinine, interstitial lung disease, rash, and intracranial hemorrhage; three patients recovered from their respective TRAEs after discontinuation of iruplinalkib, but one patient with intracranial hemorrhage had a TRAE and died from a TRAE. In addition, two patients (1.4%) had grade 2 pneumonia, leading to discontinuation in one patient and dose reduction in one patient, respectively. Pneumonia did not recur after iruplinalkib treatment was continued (12).

The results of this study suggest that iruplinalkib is a potential treatment option for crizotinib-resistant ALK-positive NSCLC patients. However, the National Comprehensive Cancer Network (NCCN) guidelines indicate that crizotinib is no longer superior in the current primary treatment of ALK-positive NSCLC patients, and in fact, second-generation and later ALK-TKIs are recommended for first-line treatment (20). Therefore, this study, which focused on crizotinib-resistant cases, does not have a significant impact on current clinical decision-making on treatment strategy for ALK-positive NSCLC patients. However, given the high ORR in post crizotinib setting, it may be a reasonable option in the sites of the world where crizotinib is still used as first line.

An important limitation in interpreting this study is that the study was conducted in only one race (Chinese). It is unclear whether the results can be expected to be similar for all races, so a multiracial comparative study should be conducted.

Many ALK-TKIs have been developed, and therapeutic development of what order to use these drugs in terms of drug resistance is awaited. In fact, since iruplinalkib has shown promise for crizotinib-resistant ALK-positive NSCLC patients in this trial, we are very interested to see how this iruplinalkib will treat other second-generation ALK-TKI-resistant patients. We are also interested in the therapeutic potential of iruplinalkib against other second-generation ALK-TKI resistance. Similarly, future studies are awaited to determine which patients will benefit more from iruplinalkib. In addition, a phase 3 trial (INSPIRE study: NCT04632758) comparing iruplinalkib with crizotinib in the first-line treatment of ALK-positive NSCLC patients is also ongoing, and the results of this trial will also be of interest.

Acknowledgments

Funding: None.

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