Clinical InsAIghts Report: The INSPIRE Trial

Study Overview

  • Study Acronym: INSPIRE

  • Study Design: Randomized, open-label, multicenter, phase III study

  • Study Phase: III

  • Population under Investigation: Patients with ALK TKI-naïve locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC)

  • Intervention under Investigation: Iruplinalkib (WX-0593)

  • Control Group: Crizotinib

  • Number of Patients: 292 patients (143 with iruplinalkib and 149 with crizotinib)

  • Duration of Follow-up: Median follow-up time was 26.7 months for the iruplinalkib group and 25.9 months for the crizotinib group

  • Main Efficacy Outcomes:

    • Progression-free survival (PFS) was significantly longer in the iruplinalkib group (median PFS 27.7 months) compared to the crizotinib group (median PFS 14.6 months; HR 0.34, p<0.0001).

    • Objective response rate (ORR) was 93.0% in the iruplinalkib group versus 89.3% in the crizotinib group.

    • Intracranial ORR for patients with measurable baseline CNS metastases was 90.9% in the iruplinalkib group compared to 60.0% in the crizotinib group.

  • Main Safety Outcomes:

    • Incidence of grade 3 or 4 treatment-related adverse events was 51.7% in the iruplinalkib group and 49.7% in the crizotinib group.

 

Clinical InsAIghts Report

The INSPIRE trial (1) represents a significant milestone in the treatment of ALK-positive non-small cell lung cancer (NSCLC), a condition characterized by the aberrant activity of the anaplastic lymphoma kinase (ALK) gene leading to tumor growth and proliferation (2). The pathophysiology of ALK-positive NSCLC involves genetic alterations that result in the activation of the ALK tyrosine kinase, which promotes oncogenesis (3). Epidemiologically, ALK rearrangements are present in a smaller subset of NSCLC, affecting approximately 3-7% of patients, often younger and non-smokers (4).

The intervention under investigation, iruplinalkib (WX-0593), is a novel ALK tyrosine kinase inhibitor (TKI) designed to target and inhibit the activity of the ALK protein, thereby halting the growth and spread of cancer cells. This mechanism of action is similar to that of crizotinib, the current standard treatment for ALK-positive NSCLC, but with potentially enhanced efficacy and penetration into the central nervous system (CNS), as suggested by the intracranial objective response rates observed in the trial.

As per the latest clinical guidelines up to my last training update, crizotinib has been the standard first-line treatment for ALK-positive NSCLC, based on its ability to improve progression-free survival (PFS) compared to chemotherapy (5). However, resistance to crizotinib and central nervous system (CNS) metastases remain significant challenges (6).

The findings from the INSPIRE trial indicate that iruplinalkib significantly outperforms crizotinib in terms of PFS, with a median PFS of 27.7 months compared to 14.6 months for crizotinib, and an objective response rate (ORR) of 93.0% versus 89.3% for crizotinib. Notably, the intracranial ORR for iruplinalkib was 90.9%, significantly higher than the 60.0% observed with crizotinib, indicating superior efficacy in patients with CNS metastases—a critical consideration given the propensity of ALK-positive NSCLC to metastasize to the brain.

Comparing these findings with seminal studies in the treatment of ALK-positive NSCLC, we observe a marked advancement. For example, the pivotal PROFILE 1014 trial (7), which established crizotinib as a first-line treatment, showed a median PFS of approximately 10.9 months for crizotinib over chemotherapy. Subsequent trials exploring second-generation ALK inhibitors, such as ceritinib in the ASCEND-4 trial (8), alectinib in the ALEX trial (9), and brigatinib in the ALTA-1L trial (10), have demonstrated improved outcomes over crizotinib, particularly in CNS penetration and resistance management. However, the INSPIRE trial's results suggest that iruplinalkib may offer further benefits in terms of PFS and intracranial control, with a safety profile comparable to that of crizotinib.

The clinical implications of the INSPIRE trial are profound. It suggests that iruplinalkib could redefine the standard of care for ALK-positive NSCLC, particularly for patients with CNS involvement. Its superior efficacy in controlling disease progression and managing CNS metastases, coupled with a manageable safety profile, positions iruplinalkib as a potentially preferred first-line option, pending further comparative studies and long-term outcomes.

In conclusion, the INSPIRE trial's findings signify a potential shift in the treatment paradigm for ALK-positive NSCLC, emphasizing the need for ongoing innovation and the development of therapies with enhanced CNS activity and resistance profiles. This study underscores the importance of molecularly targeted therapies in improving outcomes for patients with specific oncogenic drivers.

References

  1. Shi Y, Chen J, Yang R, Wu H, Wang Z, Yang W, et al. Iruplinalkib (WX-0593) versus crizotinib in ALK TKI-naïve locally advanced or metastatic ALK-positive non-small cell lung cancer: interim analysis of a randomized, open-label, phase III study (INSPIRE). J Thorac Oncol. 2024.

  2. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448(7153):561-6.

  3. Koivunen JP, Mermel C, Zejnullahu K, Murphy C, Lifshits E, Holmes AJ, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res. 2008;14(13):4275-83.

  4. Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363(18):1693-703.

  5. Planchard D, Popat S, Kerr K, Novello S, Smit EF, Faivre-Finn C, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl 4):iv192-iv237.

  6. Gainor JF, Dardaei L, Yoda S, Friboulet L, Leshchiner I, Katayama R, et al. Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer. Cancer Discov. 2016;6(10):1118-33.

  7. Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368(25):2385-94.

  8. Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014;370(13):1189-97.

  9. Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2017;377(9):829-38.

  10. Camidge DR, Kim HR, Ahn MJ, Yang JC, Han JY, Lee JS, et al. Brigatinib versus Crizotinib in ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2018;379(21):2027-39.