While there is consensus that lorlatinib, a third generation ALK inhibitor, has enhanced potency, central nervous system (CNS) disease penetration, and coverage of ALK resistance mutations compared to second generation ALK inhibitors, questions remain about whether the TKI is the optimal first-line treatment for all ALK-positive cancer patients.
Lyudmila Bazhenova, MD, and Justin Gainor, MD, debated the efficacy of employing lorlatinib as the standard of care for first-line treatment of all NSCLC patients at the 2023 Targeted Therapies of Lung Cancer Meeting. Registered TTLC 23 attendees can view the session on-demand.
Because of its superior systemic efficacy, Dr. Bazhenova, who is clinical professor of medicine at the University of California, San Diego, asserted that lorlatinib should be used in the first line for all ALK-positive patients. She presented data that compared next-generation TKIs to previous generations and concluded that lorlatinib had superior progression-free survival (PFS).1 She said the research also showed that lorlatinib was the most effective treatment for CNS disease.
Dr. Bazhenova also argued that the relatively low rates of CNS toxicities made the TKI an appealing treatment option. She conceded that while some patients unfortunately deal with toxicities due to lorlatinib, these symptoms only affect about 25% of patients. Additionally, research shows that these side effects decrease with time. For patients who struggle with this treatment’s toxicity profile, Dr. Bazhenova said dose reduction may effectively curtail these negative symptoms.
“It’s very important to state that lorlatinib dose reduction did not significantly impact CNS efficacy,” she said.
However, Dr. Gainor, who is director of the Center for Thoracic Cancers at Massachusetts General Hospital, Boston, contended that patients who dealt with the toxic effects of lorlatinib experienced a negative shift in their overall quality of life.
According to the data from his presentation, 44% of patients treated with the TKI experienced weight gain, with 20% of patients showing grade-three weight increases (20% or more above baseline). Patients also have experienced cognitive, mood, speech, and psychotic effects after receiving lorlatinib.
“There are some risk factors for these neurocognitive effects as well, including a history of brain metastases, prior brain radiation, psychiatric illness, and use of neurotropic medications,” Dr. Gainor said. “So, it may be that lorlatinib isn’t the right drug for some of these patients.”
While some providers might be hesitant to use lorlatinib as a first-line treatment due to anticipated future genomic mutations, Dr. Bazhenova explained that no compound mutations were detected yet with lorlatinib.
“We have to use the best drug first because if we leave it for last, it might no longer be the best,” Dr. Bazhenova concluded.
Dr. Gainor countered that while the historical approach had been to use the most active agent first, that principle might not be applicable in cases with median survivals of 7 years where patients are experiencing toxicities for 4 or 5 years. He argued that since most patients are able to receive a second-line agent without positive disease, providers still have effective secondary options for patients treated with second-generation inhibitors first. He also cautioned that the absence of on-target compound mutations could suggest a potential for off-target resistance mutations that would be harder to treat.
“Ultimately, the essence of precision medicine is that we shouldn’t take a ‘one size fits all’ approach where every single patient gets the exact same thing,” Dr. Gainor concluded.
References
- 1.. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib Versus Crizotinib in Advanced ALK Inhibitor-Naive ALK-Positive Non-Small Cell Lung Cancer: Second Interim Analysis of the Phase III ALTA-1L Trial. J Clin Oncol. 2020;38(31):3592-3603. doi:10.1200/JCO.20.00505
