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  • Adjuvant chemotherapy has proved to be of

    2019-08-26

    Adjuvant chemotherapy has proved to be of benefit in patients with stage IIA-IIIB NSCLC [25], and though its use in stage IB patients remains controversial, many centers offer adjuvant chemotherapy to patients with tumors ≥4 cm [26]. In our cohort, 20.4% with stage IA disease surprisingly received adjuvant chemotherapy while the majority of patients with stage IB disease did not receive any adjuvant therapy. A subgroup analysis in stage IIA-IIIB patients with adenocarcinoma or squamous cell carcinoma was undertaken and since the majority of NSCLC patients in our cohort had stage I disease, this decision resulted in less statistical power (n = 202). Nevertheless, univariate and multivariate Cox regression analysis showed a statistically significant positive impact on OS for c-MET H score ≥20. The PFS benefit was more profound in the multivariate analyses in this subgroup of patients. c-MET has been implicated in resistance to chemotherapy, including platinum [27], which would be in PSB 1115 to our finding that a higher c-MET score is beneficial in patients treated with adjuvant platinum-based chemotherapy. On the other hand, c-MET has been implicated in the process of metastasis and our results may be explained by the fact that patients with a higher c-MET expression derive a greater benefit from adjuvant chemotherapy than those with a lower expression. The major limitation of our study is its retrospective nature making it prone to selection bias. There is also a risk of information bias regarding missing data mostly on patients receiving adjuvant therapy. Information bias regarding c-MET H-scoring is limited due to the methodology used (see methods), but can not be avoided Tumour fixation is important for the reliability of IHC staining, because overfixation or underfixation can cause false positive or false negative results, respectively.Interobserver variability, a major problem in interpreting IHC results, has been reduced in our study by considering the H-score as a continuous variable. Another consideration is that TMAs may not be representative of the entire tumour, because of intratumoral heterogeneity, this being a limitation in all published trials with IHC or H-scoring. Missing data regarding EGFR-mutation is not a major limitation since there is no evidence suggesting that it could be a confounder in this context [28]. However, there was a large number of patients included in our trial and we had available data regarding the use of adjuvant therapy for 444 patients. The real-life character of this cohort trial adds strength to the external validity of our results. Future trials should probably not be based on IHC alone. However, the use of MET kinase inhibitors for IHC positive or MET amplified tumors has not been fruitful. The exception might be patients with MET exon 14 skipping mutation positive tumors, where new treatments are currently under development [29]. The importance of MET amplification or MET exon 14 skipping mutation as oncogenic drivers is still unclear. The development of conjugate drugs (c-MET antibodies with cytotoxic drug combinations) might be the solution for the successful treatment of c-MET positive patients, and in such a case, the IHC expression of c-MET is the most relevant biomarker which should be tested.
    Conclusion
    Conflict of interest
    Funding Stockholm Cancer Society, Stockholm County Council.
    Introduction Use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has proven effective therapy for advanced lung adenocarcinoma with mutant EGFR [[1], [2], [3], [4]]. The exon 21 p.L858R mutation and exon 19 deletions (19DEL) are the most common mutations and are sensitive to EGFR TKIs [[5], [6], [7]]. However, uncommon EGFR mutations have shown various responses to different EGFR TKIs [[8], [9], [10]]. An irreversible ErbB family blocker, afatinib, was found to be more effective against uncommon EGFR mutations than the first-generation TKIs gefitinib and erlotinib [[8], [9], [10]]. In addition, our previous real-world study of afatinib showed nearly equal objective response rates (ORRs) and progression-free survival (PFS) in patients with subgroups of common and uncommon mutations, excluding the primary resistant exon 20 insertion [11].