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 ( IC ) activity after failure of 2nd-gen TKIs.
As treatment discontinuation for extracranial (EC) 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 DOR 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 induces 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. ( Xagena_2020 )

Source: American Society of Clinical Oncology ( ASCO ) Virtual Meeting, 2020

Xagena_Medicine_2020