With the FDA’s recent OK for Takeda’s Alunbrig bringing the number of approved ALK inhibitors to four, this small segment of the non-small cell lung cancer market might seem to be getting rather competitive. But the little-known US biotech Xcovery has not been put off.
The group released impressive phase I/II data on its candidate ensartinib at the European Lung Cancer Conference this weekend – just as well, since Xcovery began a phase III study, Exalt3, with ensartinib last year. Xcovery is now in a race with four Goliaths of the industry, and its asset will have to live up to its early-stage promise.
The phase I/II data do show remarkable intracranial responses in patients with ALK-positive NSCLC and central nervous system metastases. Activity against CNS metastases looks set to become a key battleground for the second-generation ALK inhibitors.
Xcovery’s phase I/II study enrolled 26 ALK TKI-naive and Xalkori and/or a second-generation ALK TKI-experienced patients. CNS responses were observed in all three types.
At baseline, 13 patients (50%) had CNS target lesions with or without non-target lesions, and the other 50% had only CNS non-target lesions. The cohort with baseline CNS target lesions demonstrated an intracranial response rate, assessed by the investigator, of 69%, including one complete response. Stable disease was observed in the remaining 31%, giving a 100% disease control rate.
Source: Dr Karen Reckamp of City of Hope
Dr Sanjay Popat from the UK’s Royal Marsden Hospital, who discussed the results, said that ensartinib showed impressive initial intracranial activity. However, he said the unanswered questions for ALK-positive advanced NSCLC is whether there are any meaningful intracranial efficacy differences between the second-generation ALK TKIs.
In this space Xcovery is squaring off against four giants: Novartis, whose Zykadia is under review, and Roche, whose Alex study of Alecensa has just read out positively, as well as Takeda and Pfizer, which have longer-term plays with Alunbrig and lorlatinib.
Zykadia, which is already available for second-line use, looks set to be the first to challenge Xalkori’s first-line position. The FDA accepted Zykadia’s filing in February and granted priority review, so this drug could be approved by mid-year. Novartis’s Ascend-4 study in first-line disease, which reported in December, showed a median PFS of 16.6 months, versus 8.1 months for the control arm of platinum-pemetrexed chemotherapy, equivalent to a 45% reduction in the risk of disease progression.
The study design closely matched the registration trial of Xalkori, which showed a median PFS of 10.9 months versus 7.0 months for chemo, representing a 55% reduction in the risk of progression. In a prespecified analysis of patients with brain metastases at baseline the median PFS for Zykadia was 10.7 months versus 6.7 months for chemo.
Although Zykadia appears to have outperformed Xalkori, any change that arises in the treatment sequence could be short-lived. Last month, Roche said Alecensa had shown a statistically significant increase in PFS relative to Xalkori; it will present details from the phase III Alex trial as a late-breaker at Asco (abstract LBA9008).
The consensus among analysts is that Alecensa has beaten Zykadia, though the different control arms in the Ascend-4 and Alex studies will complicate the across-trial comparison.
The use of Xalkori as the control in the three remaining ongoing phase III trials will make across-trial comparisons cleaner, but could make enrolment more difficult if the Pfizer drug has ceased to be standard of care. That problem might have to be addressed later.
|Phase III studies under way in first line ALK-positive NSCLC|
|Roche||Alecensa||Alex||303||Positive, no details yet||NCT02075840|
|All four studies have PFS as the primary endpoint and use Xalkori as the control arm.|