Emerging EGFR-Mutated Subclones in a Patient With Metastatic ALK-Rearranged Lung Adenocarcinoma Treated With ALK-Targeted Therapy: A Case Report

We report a case of pathologically confirmed ALK-rearranged metastatic lung adenocarcinoma with emergence of EGFR L858R mutation on disease progression after two lines of treatment with ALK inhibitors. At initial diagnosis, tumoral ALK expression was detected without EGFR mutation by standard allele-specific polymerase chain reaction. There was sustained partial response to both first-line crizotinib and subsequent brigatinib. On disease progression to brigatinib, result of a liquid biopsy with circulating tumor DNA revealed only EGFR L858R, which was confirmed by tumor rebiopsy on the supraclavicular lymph node. The patient was then treated initially with pemetrexed and carboplatin, and erlotinib was subsequently added after two cycles of chemotherapy. The combination treatment has resulted in very good partial response and mild adverse effects. The overall clinical course would suggest the initial presence of two separate tumor clones, with ALK dominance at diagnosis. The subsequent breakthrough disease progression after initial response to brigatinib was related to uncontrolled growth of the EGFR-mutated tumor subpopulation. The implication on defining molecular mechanism of acquired resistance and treatment strategy would be discussed

Asian Subgroup Analysis of the Randomized Phase 3 CROWN Study of First-Line Lorlatinib Versus Crizotinib in Advanced ALK-Positive NSCLC

Introduction: Lorlatinib is a potent, third-generation inhibitor of ALK. In the planned interim analysis of the ongoing, phase 3, randomized, global CROWN trial (NCT03052608), lorlatinib resulted in significantly longer progression-free survival than crizotinib in patients with previously untreated, advanced, ALK-positive NSCLC. Here, we present a subgroup analysis of Asian patients in the CROWN study. Methods: Patients received lorlatinib 100 mg once daily or crizotinib 250 mg twice daily. The primary end point was progression-free survival assessed by blinded independent central review. Objective response rate (ORR), intracranial ORR, safety, and select biomarkers were secondary end points. Results: At data cutoff (September 20, 2021), 120 patients were included in the Asian intention-to-treat subgroup (lorlatinib n = 59; crizotinib n = 61). At 36 months, 61% (95% confidence interval [CI]: 47–72) and 25% (95% CI: 12–41) of patients in the lorlatinib and crizotinib groups, respectively, were alive without disease progression (hazard ratio for disease progression by blinded independent central review or death: 0.40; 95% CI: 0.23–0.71). ORR was 78% (95% CI: 65–88) versus 57% (95% CI: 44–70) for patients treated with lorlatinib and crizotinib, respectively. In patients with measurable, nonmeasurable, or both measurable and nonmeasurable brain metastases at baseline, intracranial ORR was 73% (95% CI: 39–94) versus 20% (95% CI: 4–48) for patients treated with lorlatinib and crizotinib, respectively. The definition of nonmeasurable brain metastases is: a brain lesion less than 10 mm in MRI scan is defined as nonmeasurable brain metastasi based on RECIST criteria (Clinical trial evaluation criteria). Hypercholesterolemia, hypertriglyceridemia, and edema were the most frequently reported adverse events with lorlatinib. Conclusions: Lorlatinib efficacy and safety in the Asian subgroup of CROWN were consistent with those in the overall population