This trial is testing two novel combinations (temozolomide plus osimertinib OR temozolomide plus lorlatinib) which have not been evaluated in clinical trials. Thus, the exact benefits of these novel combinations are unclear. However, based on the mechanism of action of temozolomide and CNS(Central Nervous System) penetration/activity in other tumor types, it is hypothesized that adding temozolomide to osimertinib or temozolomide to lorlatinib may provide improvement in CNS disease control in patients with CNS progression on either of these latter two TKIs (Tyrosine kinase inhibitors).
Name: Temozolomide plus Osimertinib
Name: Temozolomide plus Lorlatinib
Description: Adverse events will be determined by the common terminology criteria for adverse events version 5.0
Measure: Adverse events Time: Up to 3.5 yearsDescription: Central Nervous System response rate according to the Response assessment in neuro-oncology (RANO) criteria per investigator assessment. Evaluable CNS lesions may not have been previously irradiated unless they are definitively progressing following radiation and prior to enrollment on the study.
Measure: CNS response rate Time: Up to 3.5 yearsDescription: Extra-CNS response rate according to response evaluation criteria in solid tumors (RECIST) v1.1 per investigator assessment.
Measure: Extra-CNS response rate Time: Up to 3.5 yearsDescription: Overall response rate including both RANO criteria for CNS response rate and RECIST v1.1 for extra-CNS response rate per investigator assessment.
Measure: Overall response rate Time: Up to 3.5 yearsDescription: Incidence of improvement in neurological function on two successive exams when compared to baseline as determined by one of two study neuro-oncologists
Measure: Incidence of improvement in neurological function Time: Up to 3.5 yearsDescription: PFS will be defined as time from enrollment until development of CNS progressive disease according to the RANO criteria, development of extra-CNS disease progression according to RECIST v1.1 or death.
Measure: Progression free survival (PFS) Time: Up to 3.5 yearsDescription: CNS PFS will be defined as time from enrollment until development of CNS progressive disease per investigator assessment according to the RANO criteria or death.
Measure: CNS PFS Time: Up to 3.5 yearsDescription: Extra-CNS PFS will be defined as time from enrollment until development of progressive disease outside the CNS per investigator assessment according RECIST v1.1 or death.
Measure: Extra-CNS PFS Time: Up to 3.5 yearsDescription: OS will be defined as time from enrollment until death.Patients alive at date of end of study visit will be censored for survival.
Measure: Overall Survival Time: Up to 3.5 yearsAllocation: Non-Randomized
Parallel Assignment
There are 3 SNPs
Compound mutations are defined as 2 or more mutations in the EGFR tyrosine kinase domain with the following exceptions: 1. C797S and EGFR exon 19 deletion or EGFR exon 21 point mutation and 2. T790M mutation and EGFR exon 19 deletion or EGFR exon 21 point mutation. --- C797S ---
3. Male or female subject ≥ 18 years old 4. ECOG performance status 0-2 5. Stage IV NSCLC with progression of disease in the CNS on osimertinib 80 mg daily for patients with EGFR activating mutations (EGFR exon 19 deletions or EGFR L858R exon 21 point mutations) -OR- Stage IV NSCLC with progression of disease in the CNS on lorlatinib 100 mg daily for patients with ALK fusions 6. Evaluable CNS disease is required, measurable CNS disease is not required 7. Patients who are on corticosteroids must be on stable or decreasing doses of corticosteroids for at least 14 days. --- L858R ---
Compound mutations are defined as 2 or more mutations in the EGFR tyrosine kinase domain with the following exceptions: 1. C797S and EGFR exon 19 deletion or EGFR exon 21 point mutation and 2. T790M mutation and EGFR exon 19 deletion or EGFR exon 21 point mutation. --- C797S --- --- T790M ---