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

1. Prior treatment with platinum-based standard of care doublet chemotherapy with pemetrexed

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 or grapefruit/grapefruit-related citrus fruits \[e.g., Seville oranges, pomelos\]). The topical use of these medications (if applicable), such as 2% ketoconazole cream, 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 of lorlatinib

* 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 first dose of study drug(s).

4. Has any history of ILD (including pulmonary fibrosis or radiation pneumonitis), has clinically significant ILD, or is suspected to have such disease by imaging during screening. If imaging findings are unlikely to indicate a history of pneumonitis, then the Investigator should discuss the considerations with the Study Chair about potential enrollment and record the reasoning in the source documentation.

5. Clinically severe pulmonary compromise (based on Investigator's assessment) resulting from intercurrent pulmonary illnesses including, but not limited to:

* any underlying pulmonary disorder (e.g., severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease)

* any autoimmune, connective tissue or inflammatory disorder with pulmonary involvement (e.g., rheumatoid arthritis, Sjögren's syndrome, sarcoidosis) OR prior pneumonectomy

6. Women who are pregnant, nursing, or plan to become pregnant while in the study and for at 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 the last administration of study treatment

8. Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of lorlatinib (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) in rhythm, 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 arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age, or any 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 systemic diseases, including uncontrolled hypertension, uncontrolled diabetes mellitus, active bleeding diatheses, or active infection, including hepatitis B, hepatitis C, and human immunodeficiency virus. Screening for chronic conditions is not required.

11. Presence of other active invasive cancers other than the one treated in this study within 5 years prior to screening, except appropriately treated basal cell carcinoma of the skin, in situ carcinoma of uterine cervix, or other local tumors considered cured by local treatment

What this study is about