Original studyClinical 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
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.
References (31)
- et al.
Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed
J Thorac Oncol
(2011) - et al.
Anaplastic lymphoma kinase translocation: a predictive biomarker of pemetrexed in patients with non-small cell lung cancer
J Thorac Oncol
(2011) - et al.
The enzymatic activity of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase is enhanced by NPM-ALK: new insights in ALK-mediated pathogenesis and the treatment of ALCL
Blood
(2009) - et al.
Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study
Lancet Oncol
(2012) - et al.
Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer
J Thorac Oncol
(2012) - et al.
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)
Eur J Cancer
(2009) - et al.
Pemetrexed-based chemotherapy in patients with advanced, ALK-positive non-small cell lung cancer
Ann Oncol
(2013) - et al.
Activity of pemetrexed on brain metastases from Non-small cell lung cancer
Lung Cancer
(2010) - et al.
Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer
Nature
(2007) - et al.
Results of a global phase II study with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC)
ASCO Meeting Abstracts
(2012)
Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer
N Engl J Med
Crizotinib versus chemotherapy in advanced ALK-positive lung cancer
N Engl J Med
LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes
Cancer Res
Enzyme inhibition, polyglutamation, and the effect of LY231514 (MTA) on purine biosynthesis
Semin Oncol
Treating ALK-positive lung cancer–early successes and future challenges
Nat Rev Clin Oncol
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2017, CellCitation Excerpt :For example, in the case of non-small cell lung cancers having ALK rearrangement (Shaw et al., 2013), independent action predicts that a combination of crizotinib plus pemetrexed should confer benefit in excess of monotherapy but that this should not be true of crizotinib plus docetaxel (Figure 5D). The combination of crizotinib plus pemetrexed is reportedly tolerable at full doses (Gandhi et al., 2013) and exhibits no cross-resistance (Berge et al., 2013); these are the traits desirable in combinations of drugs that act independently. To thoroughly explore variables impacting the efficacy of independent drug action, we adapted a classic model of tumor kinetics, developed by Steel (1967), in which tumor growth depends on the balance between cell growth (g) and cell loss (ϕ) (Figure 6A and STAR Methods).
Diagnosis and Treatment of Anaplastic Lymphoma Kinase–Positive Non–Small Cell Lung Cancer
2017, Hematology/Oncology Clinics of North AmericaCitation Excerpt :In the pivotal phase II study comparing crizotinib to single-agent chemotherapy, pemetrexed monotherapy demonstrated a 29% overall response rate (ORR) compared with 7% with docetaxel monotherapy.19 The place of pemetrexed in the sequence of ALK-positive treatment still needs to be further elucidated, because small retrospective studies comparing the outcomes of patients who received pemetrexed before or after crizotinib have suggested it may be less effective following crizotinib.47 Although immune checkpoint blockade has been a major advance in the treatment of NCSLC, its role for patients with ALK-positive tumors is less clear.
Relationship of Driver Oncogenes to Long-Term Pemetrexed Response in Non-Small-Cell Lung Cancer
2015, Clinical Lung CancerCitation Excerpt :Rationalizing that progression in the central nervous system (CNS) alone may reflect the failure of CNS penetration due to the blood–brain barrier and that systemic disease may maintain sensitivity, we observed that a group of patients who developed brain metastases had radiosurgical brain treatment, then resumed pemetrexed for an additional median of 4.0 months of PFS. This strategy has been previously described in other studies of pemetrexed in ALK-positive patients,8,18 and it is also a recommended practice guidelines option for patients with EGFR- or lung cancer receiving treatment with tyrosine kinase inhibitors. The prospective ASPIRATION trial19 also showed that continuing erlotinib beyond Response Evaluation Criteria in Solid Tumors (RECIST) PD is feasible, with additional median PFS of 3.1 months in post-PD erlotinib patients.
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