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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
Common side effects of crizotinib include GI (e.g., nausea, vomiting, constipation, diarrhea, decreased appetite, dyspepsia, disturbed taste) and cardiac (e.g., syncope, QT-interval prolongation, bradycardia, cardiac failure) disturbances, bone marrow suppression, dizziness, fatigue, hypophosphatemia, interstitial lung disease, neuropathy, edema, pneumonitis, renal cyst, and vision disorders.
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
Evidence suggests that ROS1 is another therapeutic target of the ALK inhibitor crizotinib. First, the kinase domains of ALK and ROS1 share 77% amino acid homology within the ATP-binding sites. Consistent with this homology, crizotinib binds with high affinity to both ALK and ROS1 [101]. Second, the studies of the inhibition of kinase autophosphorylation in cell-based assays have found that ALK and ROS1 are sensitive to crizotinib with a half-maximal inhibitory concentration of 40 to 60 nM. Third, in cell lines expressing ROS1 fusions, crizotinib potently inhibits ROS1 signaling and cell viability [85, 102, 103]. Finally, case reports have described marked responses to crizotinib in patients with ROS-1 rearranged NSCLC [104].
Late-onset Ocular Toxicity Presenting as Uveitis Caused by Crizotinib
Published in Neuro-Ophthalmology, 2022
Megumi Iseki, Toshikatsu Kaburaki, Makoto Aihara, Hiromasa Sawamura
Crizotinib, a tyrosine kinase inhibitor that targets anaplastic lymphoma kinase (ALK), is a standard treatment for ALK-positive non-small-cell lung cancer (NSCLC).1 In clinical trials of crizotinib, the most frequent adverse events have been visual disturbances including photopsia, blurred vision, and vitreous floaters, which have been observed in about 40–60% of patients, mostly within the first week of starting crizotinib treatment.1–4 Because the visual disturbances associated with crizotinib are mostly transient and/or have little impact on daily activities, discontinuing or reducing the crizotinib dosage has been deemed unnecessary.2,3 A recent study demonstrated that crizotinib modifies the responses to light stimuli by ganglion cells, implying that abnormal signal processing in these cells may be the cause of the visual disturbances.5 Abnormal signal-processing function has been suggested; however, detailed ophthalmological evaluations for abnormalities in the retina or optic disc in patients with visual disturbances due to ocular toxicity from crizotinib have not been reported.4 One report describes a case of bilateral optic neuropathy due to crizotinib; however, it was lacking a description of the associated ocular findings.6 Herein, we present a case study in which the patient presented with and uveitis and unilateral whitish, massive optic disc oedema associated with crizotinib administration.
Ocular Complications of Checkpoint Inhibitors and Immunotherapeutic Agents: A Case Series
Published in Ocular Immunology and Inflammation, 2021
Ruby A. Parikh, Benjamin C. Chaon, Meghan K. Berkenstock
The final novel finding in this series was the observation of retinal hemorrhages in patient 6, who was treated with crizotinib. The mechanism of action of crizotinib is an inhibitor of multiple protein kinases, anaplastic lymphoma kinase (ALK), c-Met, and ROS-1, which activate multiple downstream mediators including the MEK/BRAF pathways.71–73 Inhibition of phosphorylation of these protein kinases results in a downstream decrease in cell turnover and metastasis.71 The most common side effect associated with crizotinib in Phase I and II clinical trials was visual disturbances, which occurred in 62% of participants.70 These changes in vision were defined as, “visual impairment, photopsia, blurred vision, vitreous floaters, photophobia and diplopia,” which commonly manifested within the first 14 days of treatment.71 Further analysis in the Phase II trial included the addition of a Visual Symptom Assessment Questionnaire (VSAQ) to assess the impact on activities of daily living at the start of each treatment cycle.73,74 Similar to our patient, study participants transient flashing lights, floaters, or shadows stable over all cycles of crizotinib therapy.74 Only 27% of patients had dilated fundus exams during the trial, and all were reported as unremarkable.74
Targeting MET Amplification with Crizotinib in a Case of Sinonasal Undifferentiated Carcinoma
Published in Cancer Investigation, 2021
Hannah Robinson, Michelle Green, Gauri Radkar, Neal Ready, John Strickler
Prior to receiving crizotinib, our patient experienced disease progression on two lines of multi-modality treatment with chemotherapy, radiation, and surgery. Comprehensive molecular profiling identified an IDH2 R172x mutation, previously characterized in SNUC as above (10,11). Interestingly, it also identified a high-level MET amplification with 164-fold increase in copy number. In comparison, prior studies of MET amplification in the setting of non-small cell lung cancer (NSCLC) have classified high-level MET amplification at ≥5 gene copies per cell by fluorescence in situ hybridization (FISH) or ≥3 gene copy number by RT-PCR (13). Based on these findings, our patient was treated with crizotinib, a TKI known to inhibit c-MET. The patient demonstrated a complete response to treatment. Interestingly, she experienced tumor growth after dose-reduction of crizotinib, with subsequent response following resumption of full dose therapy. The duration of response to crizotinib was four months from the time of treatment initiation.