Anaplastic Lymphoma Kinase Gene Rearrangements in Non-small Cell Lung Cancer are Associated with Prolonged Progression-Free Survival on Pemetrexed

Abstract

Hypothesis To explore whether the progression-free survival (PFS) with pemetrexed differs between anaplastic lymphoma kinase (ALK)-positive and other major molecular subtypes of non-small cell lung cancer. Methods In an ALK-enriched population, patients with metastatic non-small cell lung cancer were screened by ALK fluorescence in situ hybridization and for epidermal growth factor receptor (EGFR) and KRAS mutations. Triple-tested, pemetrexed-treated patients (monotherapy or combination therapy) were identified and PFS with pemetrexed captured retrospectively. Results Eighty-nine eligible cases were identified (19 ALK fluorescence in situ hybridization positive, 12 EGFR mutant, 21 KRAS mutant, and 37 triple negatives). Eighty-three cases (93%) were adenocarcinomas, two were adenosquamous, one squamous, and three had large cell histology. None of the ALK-positive patients had received crizotinib before pemetrexed. Pemetrexed was first-line therapy in 48% (72% as platinum-based combinations). Median PFS (95% confidence interval) data were EGFR mutant (5.5 months; 1–9), KRAS mutant (7 months; 1.5–10), ALK positive (9 months; 3–12), and triple negative (4 months; 3–5). In a multivariate analysis adjusting for line of therapy, mono- versus platinum and nonplatinum combination therapy, age, sex, histology, and smoking status, the only variable associated with prolonged PFS on pemetrexed was ALK+ (hazard ratio = 0.36 [95% confidence interval: 0.17– 0.73], p = 0.0051). Conclusions In this exploratory analysis, ALK-positive patients have a significantly longer PFS on pemetrexed compared with triple-negative patients, whereas EGFR or KRAS mutant patients do not. This information should be considered when sizing randomized studies in ALK-positive patients that involve pemetrexed. Pemetrexed should also be prioritized as a cytotoxic to explore further in patients with known ALK-positive disease.

First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer

“…The efficacy of pemetrexed-based first-line chemotherapy has since been documented in ALK-positive NSCLC, 29,30 a finding that supports this selection. A potential limitation of our study was that pemetrexed was not continued beyond the planned six cycles of pemetrexed-plus-platinum chemotherapy, since this was not considered to be a standard approach when the study was initiated.…”

Distinct clinical features and outcomes in never‐smokers with nonsmall cell lung cancer who harbor EGFR or KRAS mutations or ALK rearrangement

“…It has been reported recently that ALK-positive patients may have prolonged responses to pemetrexed-based chemotherapy. 46 Therefore, it is important to know whether each genotype was well balanced in terms of the aforementioned confounding factors. In our study, each genotype was well balanced in terms of the line of therapy and the number of therapies.…”

Esophagitis resulting from treatment with crizotinib for anaplastic lymphoma kinase rearrangement-positive lung adenocarcinoma: A case report

“…Firstly, ALK positivity is associated with lower levels of thymidylate synthase, one of the targets of pemetrexed (15). Secondly, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase, a catalytic enzyme, may be a substrate for ALK-mediated phosphorylation and a direct target for pemetrexed (13). It is possible that the efficacy of pemetrexed in the present case was associated with ALK positivity.…”

“…Pemetrexed is a promising treatment for NSCLC with non-squamous cell histology, although this drug was recently reported to have a prominent activity in ALK-positive NSCLC. Among NSCLC patients treated with pemetrexed, the median PFS in ALK-positive patients was nine months, compared with four months in an EGFR, ALK and KRAS wild-type control group (13). Two initial hypotheses were considered to explain the 'super-sensitivity' of ALK-positive NSCLC to pemetrexed (14).…”