Hello, my name is John Murphy and I'm a fourth year medical student at Albany Medical College. Today I'll be discussing the impact of brain metastasis status on adverse events requiring dose reduction among patients receiving lorlatinib. I do not have any financial relationships to disclose today. I'd like to start with a little bit of background. ALK positive and ROS1 positive non-small cell lung cancers are associated with a propensity towards CNS dissemination. Lorlatinib is a third generation ALK and ROS1 TKI that penetrates the CNS and has robust intracranial and extracranial activity in patients previously treated with first and second generation TKIs. Lorlatinib has a unique side effect profile which includes neurocognitive adverse events. The impact of pretreatment brain metastasis on the risk of developing CNS toxicity from lorlatinib has not been fully explored. To explore the relationship between pretreatment brain metastasis and development of adverse events, we conducted a retrospective review of 130 patients who received lorlatinib at Massachusetts General Hospital through phase one and two clinical trials, including compassionate use and expanded access protocols between 2014 and 2019. Adverse events were captured prospectively by the treating investigators and graded according to CTCA version 4.03. All categories of adverse events that prompted dose reduction were captured in a retrospective fashion. Adverse events were categorized as either CNS or non-CNS. The frequency of CNS and non-CNS adverse events in patients with pretreatment brain metastasis was compared to their counterparts without pretreatment brain metastasis. Our study population included 130 patients. 33 patients had ROS1-positive non-small cell lung cancer and 97 patients had ALK-positive non-small cell lung cancer. In total, 106 patients had pretreatment brain metastasis, comprising 82% of the study population. This table summarizes the baseline characteristics of our total study population as well as the subset of patients with and without brain metastasis. The demographic characteristics of the overall population are consistent with our current understanding of ALK-positive and ROS1-positive non-small cell lung cancer. Specifically, the majority of patients were never smokers with adenocarcinoma and two-thirds of patients had received multiple TKIs prior to commencing treatment with lorlatinib. Importantly, there were no relevant statistically significant differences in the subgroup of 106 patients with brain metastasis compared to the 24 patients who did not have CNS involvement. This table summarizes the CNS adverse events requiring dose reduction that were experienced by patients in the study. In total, 50 of 106 patients with baseline brain metastasis experienced a CNS adverse event that prompted dose reduction. The most common CNS adverse events meeting these criteria included cognitive effects, which were reported in 26% of patients, mood effects, which were reported in 19% of patients, and speech effects, which were reported in 9% of patients. The majority of CNS adverse events requiring dose reduction were grade 1 and 2 in intensity. However, of note, there were two cases of grade 3 cognitive disturbances requiring dose reduction. In comparison, 13 of 24 patients with baseline brain metastasis experienced a CNS adverse event that required dose reduction. Similar to patients with brain metastasis, the most common of such toxicity were cognitive effects, which were observed in 21% of patients, mood effects, which were reported in 17% of patients, and speech effects, which were reported in 13% of cases. All of the CNS adverse events that necessitated dose reduction were grade 1 and 2 in intensity. We then compared the frequency of treatment-related adverse events requiring dose reduction between the two groups. In total, 47% of patients with baseline brain metastasis developed an adverse event that necessitated dose reduction compared to 54% of patients without brain metastasis. This difference did not reach statistical significance. Furthermore, there was also no statistically significant difference in the frequency of CNS-specific, non-CNS, and combined CNS and non-CNS adverse events when both groups were compared. Of note, at least 25% of patients in each group experienced a CNS-related adverse event that prompted dose reduction. Finally, we assessed the timing of dose reductions for both groups. The blue bars represent patients with brain metastasis, while the red bars represent patients without brain metastasis. CNS-specific dose reductions are indicated with a yellow triangle, whereas a blue triangle denotes a dose reduction that was prompted by a non-CNS adverse event. Dose reductions triggered by a combination of CNS and non-CNS adverse events are captured with an orange triangle. Our data demonstrated that dose reductions occurred early for patients with and without brain metastasis, as you can see on the figure on the left and the table on the right. In conclusion, irrespective of brain metastasis status, patients treated with lorlatinib often require dose reductions. In at least 25% of patients treated with lorlatinib in our study, CNS toxicity has contributed to the decision to decrease the lorlatinib dose. As such, localization of metastasis to the CNS does not appear to enrich for the neurocognitive adverse events that distinguish lorlatinib from other LTKIs. Further research is indicated to identify mechanisms underlying CNS adverse events in patients being treated with lorlatinib. Our study also had many limitations that can be viewed on the slide. That concludes my presentation, and I would like to thank you all for taking the time to listen. I'd also like to thank our patients who participated in these clinical trials.

retrospective review

lorlatinib

ALK-positive

ROS1-positive

non-small cell lung cancers