Lorlatinib in patients with ALK-positive lung cancer with brain-only progression
Lorlatinib ( Lorviqua ) is a 3rd-generation ALK tyrosine kinase inhibitor ( TKI ) developed to penetrate the central nervous system ( CNS ) and overcome resistance to 2nd-generation ( 2nd-gen ) ALK TKIs.
In a phase II study, Lorlatinib has demonstrated significant intracranial activity after failure of 2nd-gen TKIs.
As treatment discontinuation for extracranial progression can confound assessment of durability of intracranial response, researchers have performed a phase II study to selectively evaluate Lorlatinib activity in ALK+ patients with CNS-only disease.
Between 11/2016 and 1/2019, 22 patients with intracranial progression on an ALK TKI with no other sites of measurable disease were enrolled at 2 institutions.
Patients received Lorlatinib at a starting dose of 100 mg QD.
The primary endpoint was the intracranial disease control rate ( DCR ) at 12 weeks per modified RECIST v1.1.
Secondary endpoints were intracranial objective response rate ( ORR ), duration of response ( DOR ), and progression-free survival ( PFS ).
Of the 22 patients enrolled, 21 ( 95% ) had progressed on a 2nd-gen ALK TKI and 14 ( 64% ) had previously received CNS radiation ( median 21.1 months between radiation and Lorlatinib ).
Median number of prior ALK TKIs was 2 ( range 1-4 ).
As of the data cutoff of 12/15/19, median follow-up was 14 months.
At 12 weeks, the intracranial-DCR was 95%, including 8 patients with stable disease.
Best intracranial ORR was 59% with 6 complete and 7 partial responses.
Nine ( 41% ) patients relapsed on study, including 3 intracranial-only, 5 extracranial-only, and 1 combined relapse.
Four patients continued treatment beyond extracranial-only progression.
Although median intracranial duration of response and progression-free survival were not estimable due to few progression events, the intracranial progression-free rate at 12 months was 81% ( 95% CI: 53-94% ).
Twelve patients have discontinued study treatment due to progression ( n = 6 ), edema ( n = 1 ), pulmonary hypertension ( n = 1 ), or transition to commercial Lorlatinib ( n = 4 ).
In conclusion, Lorlatinib has induced durable intracranial responses in patients with CNS-only progression on 2nd-gen ALK TKIs, suggesting that CNS-specific relapses are primarily driven by ALK-dependent mechanisms.
Further studies are needed to characterize the molecular basis of sensitivity to Lorlatinib in this unique subgroup of patients with ALK+ lung cancer. ( Xagena )
Source: American Society of Clinical Oncology ( ASCO ) Virtual Meeting, 2020
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