Ensartinib as Treatment for ALK-Rearranged NSCLC

Abstract

lung cancer, lungs, NSCLC: lung cancer, lungs, NSCLCThe results of phase III eXalt3 trial were recently presented at the IASLC World Conference on Lung Cancer Presidential Symposium, revealing improved outcomes with first-line ensartinib over crizotinib in patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). Ensartinib, a potent next-generation ALK tyrosine kinase inhibitor (TKI), is a new addition to the treatment armamentarium in this subtype of NSCLC. The Evolution of ALK TKIs ALK rearrangements, most commonly fusions between ALK and echinoderm microtubule-associated protein-like 4 (EML4), are oncogenic driver mutations that occur in 3-5 percent of NSCLC (Clin Cancer Res 2013;19(15):4273-81; Clin Cancer Res 2008;14(13):4275-83; Cancer 2009;115(8):1723-33). Although patients with ALK-rearranged NSCLC generally share clinical characteristics such as younger age and light or never smoking histories, definitive laboratory identification of ALK mutations is necessary for optimal selection and sequencing of treatments. The presence of ALK rearrangement predicts response to treatment with ALK TKIs, the cornerstone of treatment for this patient population after having demonstrated improved outcomes compared to traditional cytotoxic chemotherapy or immunotherapy. Crizotinib was the first ALK TKI that demonstrated superiority over chemotherapy, initially in the recurrent setting after progression on platinum-based chemotherapy (N Engl J Med 2013;368(25):2385-94), and eventually also in the first-line setting (J Clin Oncol 2018; 36(22):2251-2258; N Engl J Med 2014;371(23):2167-77). Despite initial efficacy, the inevitability of acquired resistance and eventual disease progression led to the development of newer-generation ALK TKIs. Important shortcomings of crizotinib that are overcome by newer TKIs are improved central nervous system (CNS) penetration and breadth of activity against ALK resistance mutations. Ceritinib was the first second-generation ALK TKI to gain FDA approval after it demonstrated efficacy following progression on crizotinib (Lancet Oncol 2017;18(7):874-886), and then superiority in the first-line setting compared to chemotherapy (Lancet 2017;389(10072): p. 917-929). Multiple second-generation TKIs have since been developed: alectinib versus crizotinib among treatment-naïve patients in the ALEX trial and brigatinib versus crizotinib in ALK TKI-naïve patients in the ALTA-1L trial. Improvement in progression-free survival (PFS) was seen for both alectinib (34.8 vs. 10.9 months, HR 0.43) and brigatinib (29.4 vs. 9.2 months, HR 0.43) compared to crizotinib. Given the high incidence of brain metastases in ALK-positive cancers (Lung Cancer 2015;88(1):108-11), improved CNS penetration as evidenced by intracranial disease response was also superior with both agents: intracranial response was 78 percent versus 29 percent for brigatinib and 81 percent versus 50 percent for alectinib (N Engl J Med 2018;379(21):2027-2039; J Clin Oncol 2020: p. Jco2000505; Ann Oncol 2018;29(11):2214-2222; Ann Oncol 2020;31(8):1056-1064; N Engl J Med 2017;377(9):829-838). Lorlatinib, a third-generation ALK TKI, is currently FDA-approved for second- or third-line treatment of ALK-positive advanced NSCLC. In a phase II trial by Solomon et al, objective response rate (ORR) of 90 percent was reported in treatment-naïve patients and 47 percent in patients with at least one previous ALK TKI (Lancet Oncol 2018;19(12):1654-1667). A recent press release announced the phase III CROWN trial of first-line lorlatinib versus crizotinib in previously untreated ALK-positive NSCLC patients met its primary endpoint of PFS with results anticipated shortly (NCT03052608). eXalt3 Trial Results The eXalt3 trial included 290 ALK-positive, TKI-naïve patients with stage IIIB/IV NSCLC treated with up to one line of prior chemotherapy. Ensartinib demonstrated a significantly improved blinded independent review committee-assessed PFS of 25.8 months compared to crizotinib of 12.7 months, HR 0.51 (95% CI 0.35-0.72, p=0.0001). In the 247 patients with tumors that were ALK-positive via central confirmation (modified intention to treat, mITT), the median PFS was not reached for ensartinib compared to 12.7 months for crizotinib, HR 0.45 (95% CI 0.30-0.66, p<0.0001). ORR and duration of response were both superior in the ensartinib cohort: 75 percent versus 67 percent (14% vs. 6% complete response) and unreached versus 27.3 months, respectively. Ensartinib also showed superior efficacy in terms of CNS penetration over crizotinib. Among 30 patients with measurable brain metastases, ensartinib achieved an intracranial ORR of 64 percent compared to 21 percent with crizotinib, while in patients without brain metastases, the time to treatment failure at 12 months was 4.2 percent for ensartinib compared to 23.9 percent for crizotinib, HR 0.32 (95% CI 0.15-0.64, p=0.0011). Importantly, ensartinib demonstrated a favorable safety profile. A common treatment-related adverse event (TRAE) that has not been traditionally seen with other ALK TKIs was grade 1/2 sunburn-like rash. TRAE events were 8 percent with ensartinib compared to 6 percent with crizotinib. Dose reduction (24% vs. 20%) or treatment discontinuation (9% vs. 7%) were similar between treatment arms. Future Direction Multiple ALK TKIs are now approved in the first-line setting for patients with advanced ALK-positive NSCLC. This poses the question of what the optimal approach is when choosing a first-line ALK inhibitor for a patient. Consideration should be given to systemic and CNS activity, side effect profile, as well as patient specific comorbidities. Among patients with ALK-positive NSCLC, crizotinib and ceritinib have shown improvement in PFS compared to chemotherapy, with alectinib, brigatinib, and ensartinib having shown improvement in PFS compared to crizotinib along with favorable safety profiles. Optimal sequencing of ALK TKIs has yet to be determined. Lorlatinib is a third-generation ALK TKI with a unique structure that maintains activity against ALK kinase mutations, including the most common resistance mechanism ALK G1202R (Lancet Oncol 2017;18(12):1590-1599). Although treatment with second-generation ALK TKIs is the preferred first-line treatment of ALK-positive NSCLC, testing for resistance mechanisms at the time of progression is becoming increasingly important to guide subsequent treatment decisions. The ongoing phase II NCI-NRG ALK Protocol (NCT03737994) aims to answer some of these questions by looking at how different combinations of biomarkers and ALK inhibitors work in patients with stage IV ALK-positive NSCLC who progress on frontline ALK TKI therapy. There has been significant progress in the therapeutic approach to patients with NSCLC, with ensartinib adding to the treatment armamentarium for patients with advanced ALK-positive disease. Despite initial response, resistance to current therapies invariably develops and continued research is needed to potentially predict or prevent acquired resistance, as well as determine the optimal next-line therapy. An understanding of the underlying biology of NSCLC in addition to rationally designed clinical trials are essential to identifying patients who may benefit from specific ALK inhibitors and how to best sequence these. SELINA K. WONG, MD, FRCPC, is completing a subspecialty fellowship in Thoracic Oncology; AMANDA S. CASS, PHARMD, BCPS, is Clinical Pharmacy Specialist in Thoracic Oncology; and LEORA HORN, MD, MSC, is Clinical Director of the Thoracic Oncology Program, all at Vanderbilt University Medical Center.Selina K. Wong, MD, FRCPC: Selina K. Wong, MD, FRCPCAmanda S. Cass, PharmD, BCPS: Amanda S. Cass, PharmD, BCPSLeora Horn, MD, MSc: Leora Horn, MD, MSc