Jmdb trial pemetrexed

However, the efficacy in the first-line setting was unclear. Camidge et al. Regarding adverse events, a linkage was made between ALK inhibitors, such as Alectinib, Ceritinib, Crizotinib, and Brigatinib to pneumonitis. The overall incidence of ALK inhibitor-related pneumonitis was 2. ALK inhibitors have also been associated with liver toxicities, raising the levels of alanine transaminase ALT and aspartate aminotransferase AST in The c-MET mesenchymal epithelial transition protein is another key factor in the progression of NSCLC, making this a promising target for new cancer therapies.

HGF causes the dimerization of two adjacent c-MET receptors, which alters the tridimensional structure of the protein in a manner that allows the auto-phosphorylation and subsequent activation of the tyrosine-kinase domains in the extracellular part of c-MET. As mentioned before, these are pathways related to cell proliferation, invasion, and undifferentiation, and therefore contribute to oncogenesis [ 65 , 66 ].

These mutations cause lower rates of c-MET ubiquitination and degradation, therefore leading to amplified proliferation pathways and more aggressive tumor characteristics [ 66 , 67 ]. Capmatinib showed more promising results.

Capmatinib mainly targets amplified and exon 14 mutated MET. The study also found that the PFS was higher by almost 4 months in previously untreated patients when compared to previously treated patients [ 73 ].

Another study combined Onartuzumab with Bevacizumab and Pemetrexed-based chemotherapy and found that Onartuzumab did not provide benefits when added to these therapies, and only increased the rates of adverse effects such as peripheral edema and thromboembolism [ 76 ]. As such, PD-1 along with its ligand PD-L1 plays an important role in tumor immune escape, inducing T-cell apoptosis, or exhaustion.

PD-1 and PD-L1 are immunotherapy targets. Some examples of immunotherapy agents are Pembrolizumab, Nivolumab, and Atezolizumab approved as second-line therapies or in combination with chemotherapy in the first-line [ 78 ]. Pembrolizumab significantly improved the OS in combination with chemotherapy at 12 months Median progression-free survival was Adverse events were lower in the pembrolizumab group [ 80 ].

Nivolumab was assessed at the second line by the CheckMate and CheckMate trials. Checkmate evaluated patients with non-squamous NSCLC after progression during or after platinum chemotherapy. After This efficacy was independent of PD-L1 levels. No new safety concerns were identified [ 81 ]. Hellmann et al. Ipilimumab is a fully human anti-cytotoxic T-lymphocyte antigen 4 CTLA-4 antibody that has already been associated with Nivolumab to treat patients with melanoma or renal-cell carcinoma.

Median DOR also showed benefit in the combined arm Considering the entire study population, the incidence of grade 3 or 4 treatment-related adverse events was higher with chemotherapy Atezolizumab was evaluated in an open-label, phase 3 trial by Socinski et al. The most common grade 3 or 4 treatment-related adverse effects were neutropenia, decreased neutrophil count, febrile neutropenia, and hypertension [ 83 ].

OS was improved similarly in patients with squamous or non-squamous histology. Systemic therapy consists of chemotherapy, targeted therapy, or immunotherapy, each one with its own indications. Crizotinib can be used to treat patients with advanced NSCLC who have ALK gene rearrangements or ROS1 rearrangements; however, should be discontinued if the patient presents life-threatening pneumonitis.

It is also recommended as subsequent therapy in those patients with ALK-positive disease. Alectinib was shown to be active in patients with ALK rearrangements who had progressed on Crizotinib.

Other meaningful chemotherapy agents are Vinorelbine, Ifosfamide, and Pemetrexed. The last one is sometimes associated with Cisplatin or Carboplatin [ 85 ]. Furthermore, while resistance via TM mutation can be overcome with the use of third-generation TKIs i. This scenario raised the concern of which is the best choice when resistance to a third-generation TKI is acquired. CS-generated resistance possibly will be overcome by a fourth-generation inhibitor, EAI This drug achieved great tumor regression when administered with cetuximab in mouse models carrying LR, TM, and CS mutations.

Further studies are necessary to determine its role in EGFR inhibition and possible effects in humans [ 87 ]. Besides, resistance to all types of TKIs can be acquired by activation of alternative pathways in the proliferation of cancer cells, which can be achieved with BRAF murine sarcoma viral oncogene homolog B1 mutation and MET hepatocyte growth factor receptor or HER2 human epidermal growth factor receptor 2 amplification [ 49 ].

Anti-ALK therapy is one of the backbones in the fight against NSCLC; Crizotinib led to important progress in this scenario and is considered more efficient and less toxic than standard chemotherapy regimens. Alectinib demonstrated impressive results in the ALEX trial published in , is considered the standard of care, offered in the frontline setting to patients harboring ALK gene fusion [ 56 ]. Ceritinib has also significantly improved endpoints when compared to chemotherapy with pemetrexed, despite a lower response rate in CNS when cross-trial compared to Alectinib and Brigatinib [ 58 ].

Nevertheless, when thinking from the health system perspective, more evidence from the pharmacoeconomic field is lacking, considering the high cost and the need for smart and concise decisions, especially when we think of limited resources to be shared with several diseases and conditions. Pembrolizumab was the backbone of immunotherapy in lung cancer.

The addition of pembrolizumab also improved outcomes in squamous cell cancers, without adding substantial toxicity.

Nivolumab significantly improved OS in the second line against docetaxel, setting back again chemo agents. The combination of Nivolumab and Ipilimumab has demonstrated a superior OS compared with chemotherapy in the Checkmate trial. In a median follow-up of 17 months, those assigned to atezolizumab and chemotherapy experienced an improved PFS 6.

Palliative care should be considered according to each case [ 85 ]. Other drugs are still being tested in major clinical trials, improving scientific knowledge, and opening new possibilities for treating NSCLC. One example is the Checkmate 9LA trial, comparing the combination of Nivolumab and Ipilimumab with chemotherapy or chemotherapy alone, which will soon be published. Rossi [ 92 ]. Wang et al. A phase 1 study by Creelan et al. Enrollment is presented as an estimated number of participants.

Start and end dates account for the estimated study start or conclusion date respectively. The other authors have no potential conflict of interest in this manuscript. The other author have no conflict of interst. National Center for Biotechnology Information , U. Journal List J Clin Med v. J Clin Med. Published online Nov 3.

Find articles by Hakaru Tadokoro. Find articles by Pedro Castelo-Branco. Author information Article notes Copyright and License information Disclaimer. Received Sep 22; Accepted Oct This article has been cited by other articles in PMC. Keywords: non-small-cell lung cancer, target therapy, tyrosine kinase inhibitors, ALK inhibitors, immunotherapy.

Introduction 1. Epidemiology Lung cancer LC is the most common neoplasm worldwide [ 1 ]. Mortality LC is the main cause of death worldwide and accounts for approximately 1. Evolution in Treatment Considerable advances have been made regarding LC treatment, which was initially restricted to cytotoxic chemotherapy [ 12 ]. Cytotoxic Therapy Chemotherapy was the backbone of lung cancer treatment for several years.

Open in a separate window. Figure 1. Target Agents 2. Figure 2. TM Targeting Despite the great clinical benefits of first and second-generation TKIs, almost all patients who undergo TKI treatment will develop resistance in a median of 9 to 13 months of treatment [ 47 ].

Systemic Therapy Systemic therapy consists of chemotherapy, targeted therapy, or immunotherapy, each one with its own indications. Table 1 Abbreviations used throughout this review. Funding There was no funding to the preparation of this manuscript. References 1. Visconti R. Siegel R. Cancer statistics, CA Cancer J. Osmani L. Current WHO guidelines and the critical role of immunohistochemical markers in the subclassification of non-small cell lung carcinoma NSCLC : Moving from targeted therapy to immunotherapy.

Cancer Biol. Inamura K. Duma N. Mayo Clin. Herbst R. The biology and management of non-small cell lung cancer. Tamura T. Specific organ metastases and survival in metastatic non-small-cell lung cancer. Malhotra J.

Risk factors for lung cancer worldwide. Raaschou-Nielsen O. Kanwal M. Familial risk for lung cancer. Naylor E. Targeted Therapy and Immunotherapy for Lung Cancer. Baudino T. Gridelli C. Non-small-cell lung cancer. Trends in the incidence, treatment, and survival of patients with lung cancer in the last four decades. Cancer Manag. Dietrich M. Cancer Treat. Lee S. Baxevanos P. Novel chemotherapy regimens for advanced lung cancer: Have we reached a plateau?

Pemetrexed therapy in elderly patients with good performance status: analysis of two phase III trials of patients with nonsquamous non-small-cell lung cancer.

Clin Lung Cancer. Epub Jan National Library of Medicine U. National Institutes of Health U. Department of Health and Human Services. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators.

Non Small Cell Lung Carcinoma. Drug: pemetrexed Drug: gemcitabine Drug: cisplatin. Phase 3. Study Type :. Interventional Clinical Trial. Actual Enrollment :. Study Start Date :. Actual Primary Completion Date :. Actual Study Completion Date :. July 16, Key Record Dates. Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.

Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting. The submission nominated gemcitabine in combination with cisplatin as the comparator. The PBAC agreed that this was the appropriate comparator.

The basis of the submission was a pre-specified sub-group analysis from this non-inferiority trial. The study published at the time of the submission is as follows:. The overall survival results for all randomised patients of the key trial are summarised in the table below.

Summary of overall survival months — all randomised patients. The non-inferiority margin was accepted by the PBAC. The overall survival results for all randomised patients by histological subgroups are summarised in the table below: Overall survival in histological subgroups — all randomised patients.

In contrast, the analysis for patients with squamous cell carcinoma suggests worse overall survival 1. The results for progression -free survival PFS by histologic group, a secondary efficacy outcome, are shown in the table below:.

Source: Table B. The wider confidence intervals may reflect the smaller sample sizes in these specific subgroups. The proportion of patients with adenocarcinoma and large cell carcinoma experiencing any possibly study-drug related treatment emergent adverse events TEAEs was similar between treatment arms.

For both treatment arms, the most commonly reported possibly study-drug related TEAEs were anaemia, neutropenia, nausea, vomiting, anorexia, and fatigue. In patients with adenocarcinoma and large cell carcinoma histology there were statistically significantly fewer transfusions i. In patients with adenocarcinoma and large cell carcinoma histology there were statistically significantly fewer anti-anaemia medications i.

The PBAC considered pemetrexed combined with cisplatin was non-inferior to gemcitabine combined with cisplatin in the treatment of locally advanced or metastatic NSCLC.

A modelled economic evaluation was presented. Survival, or life years gained was the primary health outcome, however, utilities were applied to the life years gained in sensitivity analyses. Costs were calculated independently of health outcomes, based on resource use during the 30 month trial period, which are assumed to occur within the first year. The costs included are those associated with the primary chemotherapy agents, premedication, post-discontinuation chemotherapy treatments, transfusion-related costs and resource use associated with serious adverse events and major toxicities.

Similar results were obtained for the trial-based and calibration model, both based on the month duration of the trial. Extrapolating two years beyond the trial period resulted in a more favourable incremental cost per life year. The results of the sensitivity analyses indicated that the model is most sensitive to the price of pemetrexed by changing the price directly, or by changing the assumed body surface area of the cohort and the incremental survival between treatment arms.

These figures were considered to be understimates given that market share for pemetrexed as first-line chemotherapy is likely to exceed that predicted in the submission.