Lorlatinib/lorlatinib in the treatment of ROS1-rearranged non-small cell lung cancer

For patients with non-small cell lung cancer carryingROS1 rearrangements, currently available targeted therapy options are limited. Compounds used in the first line are crizotinib and entrectinib, which are better than crizotinib in patients with brain metastases, and repotrectinib, neither of which has been approved by the EMA or FDA. Following positive results from the PROFILE 1001 clinical trial, crizotinib is the first TKI approved for ROS1+ non-small cell lung cancer. The study involved 50 patients with ROS 1 – NSCLC, the majority (86%) of whom had received at least one standard treatment for advanced NSCLC and showed high efficacy, with an ORR of 72%.

Inthe 2019 study update, survival data were mature, with a median OS of 51.4 months and a 12-month survival probability of 79%. Responses were durable, with a median duration of response (DoR) of 24.7 months and a median PFS of 19.3 months. Unfortunately, virtually all ROS1-positive patients treated with crizotinib will experience disease progression due to on-target mutations (most commonly Gly2032Arg, which sterically blocks compound binding), off-target mutations, and CNS progression.

According to ESMO and NCCN guidelines, lorlatinib may be considered a treatment option for patients with metastatic ROS1 non-small cell lung cancer who have previously received crizotinib, certinib or entrectinib. However, neither the FDA nor the EMA has approved lorlatinib for this use.

In the multicenterNCT01970865 study, the clinical efficacy of lorlatinib in ROS1-non-small cell lung cancer was studied. The study included 69 patients with ROS 1-positive advanced non-small cell lung cancer without limitations in terms of central nervous system metastasis. A total of 40 patients had previously received crizotinib treatment, 8 patients had previously received one or more non-crizotinib TKIs, and 21 patients were TKI-naïve. Lorlatinib produced rapid and durable responses in both pre-crizotinib exposure and crizotinib-naïve patients. The median DoR was 25.3 months in the TKI-naïve group and 13.8 months in the crizotinib pretreatment group, with ORRs of 61.5% and 26.5% respectively. Among 25 patients with brain metastases, the ORR was 52.6% in crizotinib-pretreated patients and 66.7% in crizotinib-naïve patients. Of note, lorlatinib appears to be more effective in first-time TKI patients. Further analysis showed that lorlatinib was not effective in patients with the G2032R mutation, which could support this difference.

G2032R is one of the most common ROS1-targeted mutations after crizotinib treatment. Although in vitro studies reported promising results on lorlatinib's ability to overcome this resistance mutation, preclinical activity did not translate into clinical efficacy. The Italian PRFOST study and NCT01970865 study showed that lorlatinib had poor disease control ability and no disease response in ROS1 G2032 mutated non-small cell lung cancer. On the other hand, acquisition of the ROS1 G2032R mutation has also been documented during lorlatinib treatment.

The GLASS study, a retrospective trial involving 123 patients (including 17 patients with ROS1 NSCLC and 106 patients with ALK-rearranged NSCLC), demonstrated the effectiveness of lorlatinib in controlling extracranial and extracranial disease, with an ORR of 67% in patients receiving second-line lorlatinib (pretreated with other TKIs or chemotherapy) and 100% in patients receiving third-line treatment.

The LORLATU study is the largest study evaluating ROS 1-non-small cell lung cancer treatment sequencing after failure of at least one ROS 1 TKI. The safety and efficacy of lorlatinib were specifically studied as secondary objectives. The trial enrolled 80 patients, 51 of whom developed intracranial metastases while receiving lorlatinib. Of note, the median PFS was 7.1 months, the intracranial response was 72%, and the ORR was 45%. Noteworthy responses were documented in patients pretreated with at least one ROS1-TKI. In particular, the study showed that patients before crizotinib exposure had a median PFS of 8.5 months, an ORR of 35%, and an intracranial response of 50%. This evidence allows the authors to suggest that lorlatinib may be a valuable treatment for patients who are resistant to at least one ROS1-TKI.

APhase 2 study evaluated intracranial response in patients with brain-only progression to crizotinib (brain parenchyma and leptomeninges and prior radiation therapy). The study showed that lorlatinib has significant efficacy in controlling brain diseases, with an intracranial ORR of 87% and 60% of patients with complete intracranial response. The median intracranial tumor-free survival time was 38.8 months, and the extracranial tumor-free survival time was 41.1 months.

Although data related to ROS1-driven NSCLC and lorlatinib are limited, resistance to lorlatinib has been established since early stage trials. The mechanisms of resistance to lorlatinib are not fully understood. Targeted mutations have been shown to be responsible for drug resistance. ROS1 G2032R and ROS1 L2086F mutations confer resistance to lorlatinib and are therefore unsuitable for lorlatinib use. In patients with the G2032R mutation who progress to first-line therapy, clinicians should evaluate new promising agents such as repotrectinib and taletrectinib, while the L2086F mutation predicts response to cabozantinib.

In conclusion, taking into account the literature to date, the efficacy of lorlatinib in the treatment of patients affected byROS1 non-small cell lung cancer is certain. However, in the absence of comparative studies, it is insufficient to determine the therapeutic context of this drug.