Lorlatinib in Combination With Chemotherapy in Participants With Metastatic Anaplastic Lymphoma Kinase Positive (ALK+) Non-small Cell Lung Cancer (NSCLC) Who Progressed on Single-agent Lorlatinib

Inclusion Criteria:

1. Written informed consent, according to local guidelines, signed and dated by theparticipant or by a legal guardian prior to the performance of any study-specificprocedures, sampling, or analyses
2. At least 18 years-of-age at the time of signature of the informed consent form (ICF)
3. Metastatic ALK+ NSCLC
4. Clinical and/or radiological progressive disease while receiving lorlatinibmonotherapy or within 3 weeks of stopping lorlatinib monotherapy due to clinicaland/or radiological progressive disease
5. Adequate hematologic function defined as:

• Absolute neutrophil count (ANC) ≥1500/μL
• Hemoglobin (Hb) ≥9 g/dL
• Platelets ≥100,000/μL

6. Adequate liver function defined as:

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × theupper limit of normal (ULN)
• Total bilirubin ≤1.5 × ULN (Participants with known Gilbert disease: serumbilirubin level ≤ 3 × ULN)

7. Adequate renal function defined as calculated creatinine clearance ≥45 mL/min ascalculated by Cockcroft and Gault Formula
8. Male or female participants. Male participants with female partners of childbearingpotential and female participants of childbearing potential are required to use twoforms of acceptable contraception, including one barrier method, during theirparticipation in the study and for 90 days following last dose. Male participants mustalso refrain from donating sperm during their participation in the study.

Exclusion Criteria:

1. Prior treatment with platinum-based standard of care doublet chemotherapy withpemetrexed
2. ECOG Performance Status score ≥3
3. Current treatment with any of the following:

• Known strong CYP3A inhibitors (e.g., atazanavir, boceprevir, clarithromycin,conivaptan, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil,nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir,telithromycin, troleandomycin, voriconazole, grapefruit juice orgrapefruit/grapefruit-related citrus fruits [e.g., Seville oranges, pomelos]).The topical use of these medications (if applicable), such as 2% ketoconazolecream, is allowed.
• Known strong CYP3A inducers (e.g., avasimibe, carbamazepine, phenobarbital,phenytoin, rifatutin, rifampin, St. John's Wort)
• CYP3A substrates with a narrow therapeutic index (e.g., alfentanil, cyclosporine,dihydroergotamine, ergotamine, fentanyl including transdermal patch, pimozide,quinidine, sirolimus, tacrolimus) within 12 days prior to the first dose oflorlatinib
• Known P-gp substrates with a narrow therapeutic index (e.g., digoxin)
• Currently receiving treatment with therapeutic doses of warfarin sodium. Low-molecular-weight heparin is allowed.
• Major surgery (excluding placement of vascular access) within 4 weeks of firstdose of study drug(s).

4. Has any history of ILD (including pulmonary fibrosis or radiation pneumonitis), hasclinically significant ILD, or is suspected to have such disease by imaging duringscreening. If imaging findings are unlikely to indicate a history of pneumonitis, thenthe Investigator should discuss the considerations with the Study Chair aboutpotential enrollment and record the reasoning in the source documentation.
5. Clinically severe pulmonary compromise (based on Investigator's assessment) resultingfrom intercurrent pulmonary illnesses including, but not limited to:

• any underlying pulmonary disorder (e.g., severe asthma, severe chronicobstructive pulmonary disease, restrictive lung disease)
• any autoimmune, connective tissue or inflammatory disorder with pulmonaryinvolvement (e.g., rheumatoid arthritis, Sjögren's syndrome, sarcoidosis) ORprior pneumonectomy

6. Women who are pregnant, nursing, or plan to become pregnant while in the study and forat least 6 months after the last administration of study treatment
7. Men who plan to father a child while in the study and for at least 3 months after thelast administration of study treatment
8. Presence of active gastrointestinal disease or other condition that will interferesignificantly with the absorption, distribution, metabolism, or excretion oflorlatinib (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea Grade ≥2, malabsorption syndrome)
9. Any of the following cardiac criteria:

• Any clinically important abnormalities (as assessed by the Investigator) inrhythm, conduction, or morphology of resting electrocardiograms (ECGs), e.g.,complete left bundle branch block, third-degree heart block
• Congestive heart failure (New York Heart Association ≥ Grade 2)
• Any factors that increase the risk of QTc prolongation or risk of arrhythmicevents such as heart failure, hypokalemia, congenital long QT syndrome, familyhistory of long QT syndrome or unexplained sudden death under 40 years-of-age, orany concomitant medication known to prolong the QT interval
• Second degree or third-degree AV block (unless paced) or any AV block with PR >220 msec

10. As judged by the Investigator, any evidence of severe or uncontrolled systemicdiseases, including uncontrolled hypertension, uncontrolled diabetes mellitus, activebleeding diatheses, or active infection, including hepatitis B, hepatitis C, and humanimmunodeficiency virus. Screening for chronic conditions is not required.
11. Presence of other active invasive cancers other than the one treated in this studywithin 5 years prior to screening, except appropriately treated basal cell carcinomaof the skin, in situ carcinoma of uterine cervix, or other local tumors consideredcured by local treatment