Elsevier

Clinical Lung Cancer

Volume 14, Issue 6, November 2013, Pages 636-643
Clinical Lung Cancer

Original study
Clinical Benefit From Pemetrexed Before and After Crizotinib Exposure and From Crizotinib Before and After Pemetrexed Exposure in Patients With Anaplastic Lymphoma Kinase-Positive Non–Small-Cell Lung Cancer

https://doi.org/10.1016/j.cllc.2013.06.005Get rights and content

Abstract

Background

Crizotinib produces high response rates and prolonged PFS in ALK+ NSCLC. Retrospective analyses suggest enhanced sensitivity to pemetrexed in crizotinib naive ALK+ NSCLC. Cross-resistance between crizotinib and pemetrexed has not been previously investigated.

Patients and Methods

Patients with stage IV ALK+ NSCLC treated with PEM-CRIZ, or CRIZ-PEM were identified. Overall PFS and PFS excluding central nervous system events (eCNS) were compared.

Results

Objective response rates in evaluable patients were 66% (PEM-CRIZ) and 75% (CRIZ-PEM) for pemetrexed and 84% (CRIZ-PEM) and 66% (PEM-CRIZ) for crizotinib. For PEM-CRIZ (n = 29), median PFS and eCNS PFS were both 6 months with pemetrexed, and 10 and 14.5 months, respectively, with crizotinib. For CRIZ-PEM (n = 9), median PFS and eCNS PFS were 4.5 and 3 months, respectively, with pemetrexed, and 8.5 and 7.5 months, respectively, with crizotinib. There was a statistically significant increase in the risk of an overall PFS event with pemetrexed when administered after crizotinib (P = .0277; hazard ratio [HR], 2.5898; 95% confidence interval [CI], 1.1100-6.0424), but differences in the risk of an eCNS PFS event were not significant (P = 0.4913; HR, 1.3521; 95% CI, 0.5727-3.1920). Neither overall nor eCNS PFS for patients while taking crizotinib was associated with a sequence effect relative to pemetrexed.

Conclusion

Crizotinib and pemetrexed are active drugs in ALK+ NSCLC. PFS benefit appeared higher with crizotinib than with pemetrexed. PFS benefit from pemetrexed was less after crizotinib compared with before crizotinib, however, this difference was only statistically significant for overall and not eCNS PFS. Pemetrexed exposure did not seem to affect crizotinib outcomes.

Introduction

The discovery of anaplastic lymphoma kinase (ALK) gene fusions as oncogenic drivers in non–small-cell lung cancer (NSCLC)1 and the early promise of crizotinib in this population led to the accelerated FDA approval of this agent in ALK-positive (ALK+) NSCLC.2, 3 The PROFILE 1007 randomized phase III study demonstrated that progression-free survival (PFS) with crizotinib is superior to a composite control arm of 2 standard second-line chemotherapies (docetaxel or pemetrexed) in ALK+ NSCLC.4 Yet many questions remain regarding the natural history of ALK+ NSCLC beyond its sensitivity to crizotinib, in particular with regard to its sensitivity to different standard cytotoxic chemotherapies.

Pemetrexed is a multitarget antifolate with activity against several key enzymes involved in nucleotide synthesis including thymidylate synthase (TS), dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC).5, 6 ALK rearrangements have largely been reported among lung cancers with adenocarcinoma histology and, when only considering lung adenocarcinomas, pemetrexed monotherapy has been associated with a median PFS of 3.5 months and an objective response rate (ORR) of 12.5%.7, 8, 9 However, in a small retrospective series we previously demonstrated significantly longer PFS values from pemetrexed-based treatment regimens (monotherapy or combination therapy) in ALK+ crizotinib-naive tumors compared with an ALK-negative, epidermal growth factor receptor (EGFR) Kirsten rat sarcoma viral oncogene homolog (KRAS) wild type group.10 These observations were later replicated by others, who also showed a significant increase in the ORR to pemetrexed in ALK+ NSCLC compared with EGFR mutant and ALK-negative/EGFR wild type control groups.11

In contrast, ALK+ patients appear to show no such differential sensitivity to platinum-based regimens that do not contain pemetrexed.12 Consistent with what might be a specific pemetrexed effect with regard to cytotoxic sensitivity, in PROFILE 1007 the response rate to pemetrexed was 29% compared with 7% with docetaxel, and the PFS with pemetrexed was 4.2 months compared with 2.6 months with docetaxel.4 Although the underlying biology behind the differential response to pemetrexed in ALK+ NSCLC remains under investigation, evidence from other ALK+ diseases suggests that aspects of ALK biology and pemetrexed's mechanism of action might converge at key points in nucleotide biosynthesis.13, 14, 15, 16

What is currently not clear is whether these data offer any insights into optimal treatment paradigms for ALK+ NSCLC when pemetrexed and crizotinib are used sequentially as different lines of therapy. Because ALK inhibition and antifolate agents might affect a common intracellular pathway, a potential concern arises—that clinical resistance to pemetrexed therapy might confer resistance to crizotinib and vice versa.14, 16 Within PROFILE 1007, and all of the published retrospective studies, all of the ALK+ pemetrexed-treated patients were crizotinib-naive and their outcomes from subsequent crizotinib use were not reported.4, 10, 11 Similarly, considering that acquired resistance to crizotinib has been noted to develop after 7 to 10 months of therapy, and multiple different mechanisms of acquired resistance have now been described, it is unknown whether pemetrexed-based regimens will show equally high activity in ALK+ NSCLC when treatment with crizotinib fails.3, 4, 7, 17 Here we explore the potential for cross-resistance between these 2 drugs by investigating correlations between the clinical benefit (PFS and ORR) of sequential pemetrexed and crizotinib using 2 separate patient cohorts: a stage IV ALK+ NSCLC cohort given crizotinib after progression while taking pemetrexed (PEM-CRIZ), and another stage IV ALK+ NSCLC cohort given pemetrexed after progression while taking crizotinib (CRIZ-PEM).

Section snippets

Patients

Patient data were obtained from our updated Colorado Molecular Correlates (CMOCO) database, from the Karmanos Cancer Institute (Detroit, MI), and the Peter MacCallum Cancer Center (Melbourne, Australia). Tumor biopsies from NSCLC patients were tested for ALK gene rearrangements using fluorescence in situ hybridization (FISH) using the Vysis ALK break-apart probe set (Abbott Laboratories, Abbott Park, IL) as described previously.18, 19 Briefly, a tumor sample was considered ALK+ if more than 15%

Anaplastic Lymphoma Kinase-Positive Patients Sequentially Treated With Pemetrexed and Crizotinib

From October 2008 until June 2012, we identified 19 patients at the University of Colorado Cancer Center and 10 patients at Karmonos Cancer Center with ALK+ stage IV NSCLC that had undergone treatment with pemetrexed for their metastatic disease and then subsequent treatment with crizotinib after progression (PEM-CRIZ cohort). We also identified 5 patients at the University of Colorado Cancer Center and 4 patients at Peter MacCallum Cancer Center that had undergone treatment with crizotinib and

Discussion

Our retrospective study, including data from 3 separate sites and on patients treated with pemetrexed monotherapy and combination therapy, continues to reinforce previous findings that stage IV ALK+ NSCLC demonstrates enhanced sensitivity to pemetrexed, with a longer overall PFS and a higher response rate (6 months and 60%, respectively, in the pre-crizotinib cohort) compared with either unselected NSCLC or adenocarcinoma patients treated within the original pemetrexed monotherapy and platinum

Conclusion

PFS benefit from pemetrexed was less after crizotinib compared with before crizotinib, however, this difference was only statistically significant for overall and not eCNS PFS. A larger prospective series is required, adjusting for relevant confounding effects, ideally with some rebiopsy-based information on the specific mechanisms of resistance expressed by the patient's tumor.

Disclosure

D.R.C.: Consultation roles and honoraria from Pfizer and Eli Lilly. R.C.D.: Consultation roles and honoraria from Pfizer and research grants from Eli Lilly and Pfizer. All other authors have no conflicts of interest.

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