Predictive factors for a long-term response duration in non-squamous cell lung cancer patients treated with pemetrexed

Park, Sojung; Kim, Hyun Jung; Choi, Chang‐Min; Lee, Dong Hoon; Lee, Jung–Shin; Kim, Woo Sung; Choi, Se Hoon; Rho, Jin Kyung; Lee, Jae Cheol

doi:10.1186/s12885-016-2457-0

Cited by 16 publications

(20 citation statements)

References 31 publications

(31 reference statements)

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“…High tumor burden and brain metastasis are considered typical predictors of poor treatment outcome in lung cancer. In a Korean study, two or more metastatic sites and intra‐abdominal metastasis were poor prognostic factors for pemetrexed treatment . However, this study enrolled a majority of patients previously treated with other chemotherapeutic agents ( n = 270, 86.0%).…”

Section: Discussionmentioning

confidence: 99%

Predictive factors for long‐term responders of pemetrexed maintenance treatment in non‐small cell lung cancer

et al. 2019

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Background We determined the clinical characteristics and predictive factors of long‐term response to pemetrexed maintenance therapy as first‐line treatment for non‐small cell lung cancer (NSCLC). Methods A total of 950 advanced NSCLC patients received pemetrexed (500 mg/m 2 ) plus cisplatin (60 mg/m 2 ) (Pem‐Cis) induction chemotherapy every three weeks as first‐line treatment between January 2010 and August 2018. Patients who did not show progression after four cycles of Pem‐Cis and received at least one cycle of pemetrexed maintenance were recruited ( n = 199). Results Patients were divided into subgroups according to total cycles of pemetrexed: ≤ 10 (F10, n = 134) and > 10 (M10, n = 65). The M10 group had a higher proportion of patients with stage M1a (intrathoracic metastasis alone) and exhibited lower levels of thymidylate synthase (TS) than the F10 group (median H‐score 10.0% vs. 60.0%; P = 0.031). Further subgrouping identified extreme responders: ≤ 7 (F7, n = 101) and ≥ 20 (M20, n = 26) cycles. The M20 group showed lower mean serum CEA levels before (17.5 vs. 147.0; P = 0.099) and after (6.9 vs. 53.2; P = 0.001) Pem‐Cis treatment, and a higher incidence of normalization after Pem‐Cis (abnormal 41.7% vs. 68.5%; P = 0.015). M1a stage, normalization of CEA levels after Pem‐Cis, and lower TS H‐score were predictors of progression‐free survival in patients administered pemetrexed maintenance. Conclusion M1a stage and lower TS expression were predictors of long‐term response to pemetrexed maintenance. CEA normalization after Pem‐Cis could be an additional surrogate marker of positive response to long‐term treatment.

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Section: Discussionmentioning

confidence: 99%

Predictive factors for long‐term responders of pemetrexed maintenance treatment in non‐small cell lung cancer

et al. 2019

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“…According to Lee et al, NSCLC patients with an EML4-ALK rearrangement showed significantly higher response rates to PEM and improved progression-free survival than control patients [9]. Several studies have also shown that PEM treatment in NSCLC with an EML4-ALK rearrangement is superior in response rate and survival than without this rearrangement [10][11][12][13]. These results suggest that an alteration in the intracellular signaling pathway involved in EML4-ALK has a synergistic effect on the cytotoxic effect of PEM; however, the detailed mechanism has yet to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Afatinib Overcomes Pemetrexed-Acquired Resistance in Non-Small Cell Lung Cancer Cells Harboring an EML4-ALK Rearrangement

Kwon

Kim

Sung

et al. 2019

Cells

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Background: The aim of this study is to elucidate the mechanisms of acquired resistance to pemetrexed in echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer. Methods: We analyzed the sensitivity to pemetrexed and the expression patterns of various proteins after pemetrexed treatment in the cell lines, A549, NCI-H460, NCI-H2228 harboring EML4-ALK variant 3, and NCI-H3122 harboring EML4-ALK variant 1. Pemetrexed-resistant cell lines were also generated through long-term exposure to pemetrexed. Results: The EML4-ALK variant 1 rearranged NCI-H3122 was found to be more sensitive than the other cell lines. Cell cycle analysis after pemetrexed treatment showed that the fraction of cells in the S phase increased in A549, NCI-H460, and NCI-H2228, whereas the fraction in the apoptotic sub-G1 phase increased in NCI-H3122. The pemetrexed-resistant NCI-H3122 cell line showed increased expression of EGFR and HER2 compared to the parent cell line, whereas A549 and NCI-H460 did not show this change. The pan-HER inhibitor afatinib inhibited this alternative signaling pathway, resulting in a superior cytotoxic effect in pemetrexed-resistant NCI-H3122 cell lines compared to that in the parental cells line. Conclusion: The activation of EGFR-HER2 contributes to the acquisition of resistance to pemetrexed in EML4-ALK rearranged non-small cell lung cancer. However, the inhibition of this alternative survival signaling pathway with RNAi against EGFR-HER2 and with afatinib overcomes this resistance.

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“…Jiang et al 26 reported significant better overall response rate and median PFS in the EGFR -mutated lung adenocarcinoma patients receiving first-line pemetrexed/platinum combinations compared to those without EGFR mutation. In contrast, Park et al 17 recently demonstrated the significant association of the EGFR mutation with poor PFS in nonsquamous NSCLC patients treated with first-line pemetrexed-containing chemotherapy. In our study, the median OS for pemetrexed maintenance was 22.3 months which is much longer than those of previous trials.…”

Section: Discussionmentioning

confidence: 89%

“…Third, the ALK translocation test was performed only in a portion of the population, thus the possible influence of this driving rearrangement on the clinical outcome could not be excluded. Although conflicting data exist, several studies have suggested that ALK rearrangement may be associated with better clinical outcome for those treated with pemetrexed-based chemotherapy than wild-type for ALK 17 30 . Fourth, treatment-related quality of life and side effects according to different treatment strategy were not investigated.…”

Section: Discussionmentioning

confidence: 99%

“…It is important to prove the effiefficacy of pemetrexed continuation maintenance chemotherapy for patients without driving mutations, as this maintenance strategy is currently utilized only in those patients in real-world practice. Moreover, the efficacy of pemetrexed-containing chemotherapy according to EGFR mutational status is still controversial 17 18 .…”

Section: Introductionmentioning

confidence: 99%

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Pemetrexed Continuation Maintenance versus Conventional Platinum-Based Doublet Chemotherapy in EGFR-Negative Lung Adenocarcinoma: Retrospective Analysis

et al. 2018

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BackgroundAlthough targeted therapy and immuno-oncology have shifted the treatment paradigm for lung cancer, platinum-based combination is still the standard of care for advanced non-small cell lung cancer (NSCLC). Pemetrexed continuation maintenance therapy has been approved and increasingly used for patients with nonsquamous NSCLC. However, the efficacy of this strategy has not been proven in patients without driving mutations. The objective of this study was to compare the clinical benefit of pemetrexed continuation maintenance to conventional platinum-based doublet in epidermal growth factor receptor (EGFR)-negative lung adenocarcinoma.MethodsA total of 114 patients with EGFR-negative lung adenocarcinoma who were treated with platinum doublet were retrospectively enrolled. We compared the survival rates between patients received pemetrexed maintenance after four-cycled pemetrexed/cisplatin and those received at least four-cycled platinum doublet without maintenance chemotherapy as a first-line treatment.ResultsForty-one patients received pemetrexed maintenance and 73 received conventional platinum doublet. Median progression-free survival (PFS), which was defined as the time from the day of response evaluation after four cycles of chemotherapy to disease progression or death, was significantly higher in the pemetrexed maintenance group compared to conventional group (5.8 months vs. 2.2 months, p<0.001). Median overall survival showed an increasing trend in the pemetrexed maintenance group (22.3 months vs. 16.1 months, p=0.098). Multivariate analyses showed that pemetrexed maintenance chemotherapy was associated with better PFS (hazard ratio, 0.73; 95% confidence interval, 0.15–0.87).ConclusionCompared to conventional platinum-based chemotherapy, premetrexed continuation maintenance treatment is associated with better clinical outcome for the patients with EGFR wild-type lung adenocarcinoma.

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Predictive factors for a long-term response duration in non-squamous cell lung cancer patients treated with pemetrexed

Cited by 16 publications

References 31 publications

Predictive factors for long‐term responders of pemetrexed maintenance treatment in non‐small cell lung cancer

Predictive factors for long‐term responders of pemetrexed maintenance treatment in non‐small cell lung cancer

Afatinib Overcomes Pemetrexed-Acquired Resistance in Non-Small Cell Lung Cancer Cells Harboring an EML4-ALK Rearrangement

Pemetrexed Continuation Maintenance versus Conventional Platinum-Based Doublet Chemotherapy in EGFR-Negative Lung Adenocarcinoma: Retrospective Analysis

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