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Molecular Drivers in Lung Adenocarcinoma: Therapeutic Implications
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Imayavaramban Lakshmanan, Apar Kishor Ganti
Similar to the experience with EGFR TKIs, most patients develop resistance to ALK TKIs, especially crizotinib, after a while. This phenomenon appears due to an acquired secondary mutation within the ALK tyrosine kinase domain [37]. The most common mutation seen after crizotinib is the L1196M mutation, while other common mutations include G1269A, C1156Y and I1171T/N/S. Ceritinib use is associated with the development of G1202R, F1174C/L and V1180L mutations and deletion of G1202, while S1206Y, and E1210K are commonly seen after alectinib use. Lorlatinib, an ALK inhibitor currently under investigation, appears to have activity against many of these mutations, including the G1202R, which confers resistance to ceritinib, alectinib and brigatinib [38]. Hence, it is important to re-biopsy at disease progression and check for mutation status, in order to choose the most sensitive treatment option. There has been a single report of a patient who progressed on sequential crizotinib and lorlatinib, but a biopsy following lorlatinib showed that the tumor now had a mutation that paradoxically increased the sensitivity to crizotinib. The patient derived clinical benefit with a rechallenge of crizotinib [39].
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Lorlatinib (LorviquaTM), marketed under the brand name LorbrenaTM in the US, Canada, and Japan, was developed by Pfizer as an orally administered inhibitor of ALK and ROS1, two enzymes that play a key role in the development of cancer. It differs from other agents of this class in having a highly unusual 12-memberd central macrocyclic ring.
EML4-ALK Fusion Gene and Therapy with ALK-Targeted Agents in Non-Small Cell Lung Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Francisco E. Vera-Badillo, Janet E. Dancey
The frequency of intracranial disease progression seems to be similar with crizotinib and chemotherapy [25]. However, in the alectinib studies, there was a significant improvement seen in PFS for patients with brain metastases compared to crizotinib for an impressive HR of 0.08 in the Japanese study and 0.40 in the international study (95% CI 0.01–0.61 and 0.25–0.64; respectively); the duration of response was also much better for patients receiving alectinib (17.3 vs. 5.5 months) [61, 62]. Brigatinib also demonstrated superior efficacy versus crizotinib, demonstrating a lower intracranial disease progression of 9% versus 19% [56]. Cetirinib was also superior to chemotherapy with an intracranial response of 73% versus 27%. Lorlatinib, as previously discussed, was developed to overcome ALK-resistance and improved CNS penetration resulting in it being efficacious for patients with progressive disease and CNS metastases. Finally, in the phase 2 trial, alectinib demonstrated an intracranial response rate of 63% and a median duration of intracranial response of 14.5 months [64]. For patients progressing to alectinib in the CNS, a case report suggested that an increase in the dose to 900 mg twice daily can be an effective therapeutic approach [52].
Pharmacological and clinical properties of lorlatinib in the treatment of ALK-rearranged advanced non-small cell lung cancer
Published in Expert Opinion on Pharmacotherapy, 2020
Haidar El Darsa, Omar Abdel-Rahman, Randeep Sangha
The mean ratio of CSF to plasma concentration was 0.75 which corresponds to 75% of unbound plasma concentration. Moreover, 48% and 41% of radiolabeled lorlatinib were detected in the urine and feces, respectively, following a single 100 mg oral intake. Loraltinib pharmacokinetics are not affected by proton pump inhibitors, food intake nor clinical characteristics such as age, gender, race, or weight [18,37]. In addition, the pharmacokinetics of lorlatinib are not affected by mild to moderate renal impairment or mild hepatic impairment. However, the effect of severe renal impairment or moderate to severe hepatic impairment is still unknown and being investigated [18].
Lorlatinib for the treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer
Published in Expert Review of Clinical Pharmacology, 2019
Lorlatinib was developed by Pfizer Inc and was approved by US FDA for the treatment of patients with ALK-positive metastatic NSCLC whose disease has progressed on first generation or second generation ALKi. This indication was approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. The recommended dosage of lorlatinib is 100 mg orally once daily, with or without food, until disease progression or unacceptable toxicity [12].
Lorlatinib for the treatment of ALK-positive metastatic non-small cell lung cancer
Published in Expert Review of Anticancer Therapy, 2020
Lorlatinib is indicated for the treatment of patients with ALK-positive NSCLC that has progressed on prior crizotinib and at least one other ALK inhibitor for metastatic disease; or after progression on alectinib or ceritinib as the first ALK inhibitor therapy for metastatic disease. The United States Food and Drug Administration (US FDA) has granted accelerated approval based on tumor response rate and duration of response observed in phase II trials, and continued approval is contingent upon verification of benefit in confirmatory trials.