Author: By Lynda Williams, Senior medwireNews Reporter
medwireNews: Positive findings from the eXalt3 trial of ensartinib in patients with advanced ALK-rearranged non-small-cell lung cancer (NSCLC) have been reported at the 2020 Virtual Presidential Symposium of the World Congress on Lung Cancer.
Presenting author Leora Horn, from Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, USA, explained that ensartinib is a “next-generation, once-daily oral ALK inhibitor, with potency 10 times greater than crizotinib in enzymatic assays and broad preclinical activity in ALK resistance mutations.”
The phase III trial comparing ensartinib 225 mg/day with crizotinib 250 mg twice daily recruited patients with stage IIIB–IV NSCLC who had received up to one chemotherapy regimen but no prior ALK inhibitor despite a local US FDA-approved assay for ALK alterations.
The primary endpoint of independent review committee-assessed median progression free survival (PFS) in the intention-to-treat (ITT) population was 25.8 months for the 143 patients randomly assigned to receive ensartinib and followed up for a median 23.8 months versus 12.7 months for the 147 patients who received crizotinib and were followed up for a median 20.2 months.
The hazard ratio (HR) for progression or death was therefore a significant 0.51 in favour of ensartinib, the investigator said.
PFS was also determined for a modified (m)ITT group of 247 patients whose ALK status was subsequently confirmed by a central Abbott FISH test, with the median duration unreached for the 121 ensartinib-treated patients versus 12.7 months for the 126 patients given crizotinib, giving a significant HR of 0.45.
In this mITT population, the objective response rate was 75% with ensartinib and 67% for crizotinib, with complete responses reported for 14% and 6%, respectively.
The corresponding durations of response in these groups were unreached and 27.3 months; a similar proportion of patients in the ensartinib and crizotinib groups continued to have response at 2 years (58.7 vs 50.0%), but by 3 years, the rates were 58.7% versus 26.7%.
In addition, 64% of the 11 patients given ensartinib who had measurable brain metastases at baseline experienced an intracranial objective response, including three complete responses. This compared with just 21% of 19 patients given crizotinib, two of whom achieved a complete response.
And among the mITT population without brain metastases, the median PFS was significantly longer with ensartinib than crizotinib, at not reached versus 16.6 months and a significant HR of 0.40. In all, 61% of ensartinib-treated patients achieved 3-year PFS compared with 25% of those given crizotinib.
Overall survival data are yet to mature with a median duration unreached in both groups. At 24 months, 78% of both treatment arms were alive, the investigator said.
“Ensartinib showed a favourable safety profile”, commented Leora Horn. Serious treatment-related adverse events (TRAEs) occurred in 8% of the ensartinib-treated patients and 6% of those given crizotinib.
Although some TRAEs in both trial arms led to dose reductions (24 vs 20%) or discontinuation (9 vs 7%), the most frequent side effects associated with ensartinib were “low-grade rash and transaminitis”, the presenter noted, whereas crizotinib was most commonly associated with elevations in liver enzymes, gastrointestinal side effects and oedema.
Leora Horn concluded: “Ensartinib represents a new first-line treatment option for patients with ALK-positive NSCLC.”
In the discussant session, Christine Lovly, also from Vanderbilt-Ingram Cancer Center, highlighted ongoing questions on the optimal use of ALK inhibitors, such as selection of agents, resistance, and the sequencing and combination of ALK inhibitors in the clinic, including “dynamic monitoring” and “consideration of co-mutations (such as TPF3).”
While acknowledging that “ensartinib showed promising efficacy” as a first-line therapy in ALK-rearranged NSCLC, the presenter concluded that alternative methods of targeting ALK may be required, such as use of allosteric inhibitors, small molecule proteolysis-targeting chimeras or vaccines.
Reference
Selvaggi G, Wakelee HA, Mok T, et al. Phase III randomized study of ensartinib vs crizotinib in anaplastic lymphoma kinase (ALK)-positive NSCLC patients: eXalt3. WCLC Virtual Presidential Symposium 2020.
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