Table 3.

Safety Outcomes on ALK Plus MET-Directed Therapy

Patient	Prior ALK TKIs	ALK/MET Therapy	Duration of Treatment	Dose Hold	Dose Reductiona	Treatment-Related Adverse Eventsb
1	Ceritinib	Crizotinib 250 mg BID	<1 mo	No	No	None reported
2	Alectinib	Crizotinib 250 mg BID	3.5 mo	No	No	Peripheral edema (grade 1)
3	Ceritinib, alectinib, lorlatinib	Lorlatinib 75 mg QDc + crizotinib 250 mg BID	3 mo	No	No	Nausea (grade 1), lightheadedness (grade 1)
4	Alectinib, lorlatinib	Lorlatinib 50 mg QD + crizotinib 250 mg BID	<1 mo	No	No	None reported
5	Alectinib	Lorlatinib 50 mg QDa + crizotinib 250 mg BID	11 mo	Yes	Yes	Irritability (grade 2), anxiety (grade 2), confusion (grade 2), peripheral edema (grade 1), weight gain (grade 1)
6	Alectinib, brigatinib, lorlatinib	Lorlatinib 50 mg QD + crizotinib 250 mg BID	<1 mo	No	No	None reported
7	Alectinib, lorlatinib	Lorlatinib 50 mg QD + crizotinib 250 mg BID	6 mo	No	No	Peripheral edema (grade 1), weight gain (grade 1), CPK elevation (grade 1), diarrhea (grade 1)
8	Alectinib	Lorlatinib 50 mg QD + crizotinib 250 mg BID	<1 mo	No	No	Weight gain (grade 2), peripheral edema (grade 2), speech change (grade 1)
9	Alectinib	Alectinib 600 mg BIDa + capmatinib 400 mg BID	9 mo	No	Yes	Peripheral edema (grade 2), transaminase elevation (grade 1), constipation (grade 1), dry mouth (grade 1), thrombocytopenia (grade 1), nausea (grade 1), muscle soreness (grade 1)
10	Alectinib	Alectinib 600 mg BID + capmatinib 400 mg BIDa	10 mo	Yes	Yes	Headache (grade 1), bilirubin increase (grade 1), fatigue (grade 1), pyrexia (grade 1), rash (grade 1), transaminase elevation (grade 1), peripheral edema (grade 2), joint stiffness (grade 1)
11	Alectinib, lorlatinib	Alectinib 600 mg BID + capmatinib 300 mg BID	7 mo	Yes	No	Weight gain (grade 1), fatigue (grade 1), nausea (grade 1), peripheral edema (grade 2)
12	Alectinib	Alectinib 600 mg BID + crizotinib 200 mg BID	6 mo	No	No	Bradycardia (grade 1), creatinine elevation (grade 1)

QD, daily; BID, twice daily; CPK, creatine phosphokinase; RECIST, Response Evaluation Criteria in Solid Tumors; TKI, tyrosine kinase inhibitor.

^aLorlatinib reduced to 25 mg for neurocognitive toxicity for patient 5. Alectinib escalated to 900 mg BID for patient 9 for brain progression, at which time capmatinib reduced to 300 mg BID, capmatinib reduced to 200 and 300 mg BID from 400 mg BID for patient 10 for pyrexia.

^bExcluding asymptomatic lipid elevation.

^cLorlatinib initially given at 50 mg and then escalated to 75 mg after 2 weeks for patient 3.